Patricia J. Sulak, MD

DR SULAK: The estrogen and progestin doses in oral contraceptives (OCs) have steadily decreased since the 1960s; however, until recently, we’ve kept the same 21/7-day regimen. Due to the high doses in the first-generation OCs, the hormones lingered into the week off. With the low-dose pills and a 7-day hormone-free interval (HFI), we have seen problems such as ovulation, estrogen withdrawal symptoms, and unscheduled bleeding (ie, breakthrough bleeding or spotting).

DR LIU: The physiology of ovarian follicle development explains why many of these problems occur. In the normal menstrual cycle, follicle-stimulating hormone (FSH) levels increase dramatically during the first 2 days of menses, driving the development of as many as 10 early (primordial) follicles. As estrogen and inhibin B levels increase and suppress FSH, only the follicle with the greatest ability to generate FSH receptors within itself survives this low-FSH environment to become the “egg of the month.”

During the HFI of an OC regimen, FSH begins to rebound just as it does in a normal menstrual cycle. With very-low-dose estrogen/progestin OCs, this rebound occurs rapidly and follicles begin to develop. If the follicle develops to a critical stage—which might be as small as 14 mm—escape ovulation may occur, despite the resumption of active OC pills and dampening of FSH.¹ In fact, up to 30% of women may ovulate on OCs when the HFI is increased.¹

DR SULAK: It is amazing how rapidly the pituitary wakes up and starts producing FSH—and how responsive the ovary is! Studies have shown that the dramatic rise in FSH occurs around the fourth day of a 7-day HFI, followed rapidly by the rise in 17-beta estradiol from the ovarian follicles.^2,3 We reported a 500% increase in estradiol, from 10 pg to almost 60 pg—and that was using a 30 mcg pill.²

I am amazed that more people taking OCs do not conceive. The reason failure rates are not higher is due in large part to the “backup mechanisms” of the pill, such as cervical mucous thickening and thinning of the endometrial lining.

Development of extended-regimen OCs

DR LIU: Starting in 1998 with the approval of Mircette, we’ve begun to see a number of modifications to the 21/7 regimen.

DR SULAK: Mircette is a regimen of 21 days of 20 mcg ethinyl estradiol (EE) and 0.15 mg desogestrel, 2 placebo days, and 5 days of 10 mcg EE pills. Comparing Mircette with a 21/7 regimen of the same hormones, researchers found that women experienced greater ovarian suppression and less follicular development when a 10 mcg EE pill replaced the last 5 placebo pills.⁴

Interestingly, even though Mircette is a 20 mcg EE pill, its bleeding profile is comparable to many OCs with 30 mcg EE.^5,6 Adding that low dose of estrogen suppresses the ovary and prevents “rebound” FSH and estrogen production; it is the production of endogenous estrogen that interferes with the next cycle and causes breakthrough bleeding.^6,7

All of the OCs that have been approved since 2003 feature modifications of the 21/7 regimen. Seasonale extended the OC regimen to 84 days of active pills followed by 7 days off. Loestrin 24 and Yaz shortened the HFI of a 28-day regimen and demonstrated that 20 mcg EE pills can have a good bleeding profile if the HFI is decreased.

Seasonique (84 days of levonorgestrel, 0.15 mg, and EE, 30 mcg; followed by 7 days of EE, 10 mcg) was developed when it became apparent that after prolonged suppression, FSH rises very quickly and the ovary is even more responsive; a 7-day HFI could lead to escape ovulation and other problems.^2,3,8 The most recently approved OC regimen is Lybrel, a continuous ultra-low-dose regimen of EE and levonorgestrel.

DR LIU: So the modifications to the HFI have been made based on our understanding of how follicular development can be suppressed and why escape ovulation occurs. Altering the HFI can address some of these problems. The use of a very-low-dose estrogen in place of the placebo suppresses the pituitary and attenuates the rise of FSH and inhibin B, so that a new crop of follicles does not begin to develop.⁹

Importance of correct, consistent use

DR LIU: For patients using an OC with an HFI, during which days of the regimen is missing a pill most likely to cause contraceptive failure?

DR SULAK: The first pill is the most important one in the pack! Particularly with low-dose OCs, it’s especially a problem if a patient misses a pill during the first week after a 7-day HFI.

DR LIU: I tell patients that it takes several tablets to suppress FSH; no single tablet will maintain a persistent effect. Missing a pill during the first 5 days is probably more risky than missing 1 or more in the second or third week.

DR SULAK: The rise in FSH and 17-beta estradiol during the 7-day HFI continues into the first week of active pills and takes 5 to 7 days to decrease significantly.²

Reducing hormone withdrawal symptoms

DR LIU: Clinicians started extending OC regimens for patients with endometriosis or suspected endometriosis, whose pelvic pain flared up with the onset of bleeding.

DR SULAK: Then we realized that the benefits of extended regimens went beyond endometriosis and could help patients with menstrual migraine headaches or severe premenstrual syndrome. With extended regimens, we have shown reductions in mood swings, pain, headaches, bloating, and swelling.^6,10-12

With a low-dose regimen and a 7-day HFI, we were actually creating estrogen-withdrawal headaches, cramps, bloating, and other symptoms.¹³ In our prospective randomized trial of Seasonale vs Seasonique, we observed a tendency toward fewer headaches during the estrogen-supplemented week.⁷ And we weren’t even looking at headaches in that study! Adding estrogen during that typical week off may have the potential to decrease some of these withdrawal symptoms, but this needs further study.

Bleeding and spotting: Managing expectations

DR LIU: When a patient begins an extended-regimen OC, how do you manage her expectations about spotting and bleeding?

DR SULAK: Any patient on an extended-regimen OC has to be a great pill-taker, so I suggest that she put her pills somewhere she’ll see them at about the same time everyday. I tell patients that particularly during that first cycle, there is a high incidence of unscheduled bleeding. When I prescribe an OC regimen that substitutes a low-dose estrogen pill for the traditional placebo week, I explain that the patient will have a progestin withdrawal bleed during the estrogen-only pills. I also mention that in subsequent packs, the unscheduled bleeding is greatly reduced.^14,15

Conclusions

DR LIU: The modifications to the HFI that we’ve seen in recently approved OCs represent an incremental advance in our understanding of the physiology of ovarian follicle development. Experience and studies have shown how altering the HFI can optimize patient outcomes.

DR SULAK: We do need to see the demise of the 7-day HFI. Practitioners should realize that these changes in OCs are not arbitrary. They are substantiated by real science and will mean a true improvement in the symptoms and quality of life our patients experience.

DR SULAK: The estrogen and progestin doses in oral contraceptives (OCs) have steadily decreased since the 1960s; however, until recently, we’ve kept the same 21/7-day regimen. Due to the high doses in the first-generation OCs, the hormones lingered into the week off. With the low-dose pills and a 7-day hormone-free interval (HFI), we have seen problems such as ovulation, estrogen withdrawal symptoms, and unscheduled bleeding (ie, breakthrough bleeding or spotting).

DR LIU: The physiology of ovarian follicle development explains why many of these problems occur. In the normal menstrual cycle, follicle-stimulating hormone (FSH) levels increase dramatically during the first 2 days of menses, driving the development of as many as 10 early (primordial) follicles. As estrogen and inhibin B levels increase and suppress FSH, only the follicle with the greatest ability to generate FSH receptors within itself survives this low-FSH environment to become the “egg of the month.”

During the HFI of an OC regimen, FSH begins to rebound just as it does in a normal menstrual cycle. With very-low-dose estrogen/progestin OCs, this rebound occurs rapidly and follicles begin to develop. If the follicle develops to a critical stage—which might be as small as 14 mm—escape ovulation may occur, despite the resumption of active OC pills and dampening of FSH.¹ In fact, up to 30% of women may ovulate on OCs when the HFI is increased.¹

DR SULAK: It is amazing how rapidly the pituitary wakes up and starts producing FSH—and how responsive the ovary is! Studies have shown that the dramatic rise in FSH occurs around the fourth day of a 7-day HFI, followed rapidly by the rise in 17-beta estradiol from the ovarian follicles.^2,3 We reported a 500% increase in estradiol, from 10 pg to almost 60 pg—and that was using a 30 mcg pill.²

I am amazed that more people taking OCs do not conceive. The reason failure rates are not higher is due in large part to the “backup mechanisms” of the pill, such as cervical mucous thickening and thinning of the endometrial lining.

Development of extended-regimen OCs

DR LIU: Starting in 1998 with the approval of Mircette, we’ve begun to see a number of modifications to the 21/7 regimen.

DR SULAK: Mircette is a regimen of 21 days of 20 mcg ethinyl estradiol (EE) and 0.15 mg desogestrel, 2 placebo days, and 5 days of 10 mcg EE pills. Comparing Mircette with a 21/7 regimen of the same hormones, researchers found that women experienced greater ovarian suppression and less follicular development when a 10 mcg EE pill replaced the last 5 placebo pills.⁴

Interestingly, even though Mircette is a 20 mcg EE pill, its bleeding profile is comparable to many OCs with 30 mcg EE.^5,6 Adding that low dose of estrogen suppresses the ovary and prevents “rebound” FSH and estrogen production; it is the production of endogenous estrogen that interferes with the next cycle and causes breakthrough bleeding.^6,7

All of the OCs that have been approved since 2003 feature modifications of the 21/7 regimen. Seasonale extended the OC regimen to 84 days of active pills followed by 7 days off. Loestrin 24 and Yaz shortened the HFI of a 28-day regimen and demonstrated that 20 mcg EE pills can have a good bleeding profile if the HFI is decreased.

Seasonique (84 days of levonorgestrel, 0.15 mg, and EE, 30 mcg; followed by 7 days of EE, 10 mcg) was developed when it became apparent that after prolonged suppression, FSH rises very quickly and the ovary is even more responsive; a 7-day HFI could lead to escape ovulation and other problems.^2,3,8 The most recently approved OC regimen is Lybrel, a continuous ultra-low-dose regimen of EE and levonorgestrel.

DR LIU: So the modifications to the HFI have been made based on our understanding of how follicular development can be suppressed and why escape ovulation occurs. Altering the HFI can address some of these problems. The use of a very-low-dose estrogen in place of the placebo suppresses the pituitary and attenuates the rise of FSH and inhibin B, so that a new crop of follicles does not begin to develop.⁹

Importance of correct, consistent use

DR LIU: For patients using an OC with an HFI, during which days of the regimen is missing a pill most likely to cause contraceptive failure?

DR SULAK: The first pill is the most important one in the pack! Particularly with low-dose OCs, it’s especially a problem if a patient misses a pill during the first week after a 7-day HFI.

DR LIU: I tell patients that it takes several tablets to suppress FSH; no single tablet will maintain a persistent effect. Missing a pill during the first 5 days is probably more risky than missing 1 or more in the second or third week.

DR SULAK: The rise in FSH and 17-beta estradiol during the 7-day HFI continues into the first week of active pills and takes 5 to 7 days to decrease significantly.²

Reducing hormone withdrawal symptoms

DR LIU: Clinicians started extending OC regimens for patients with endometriosis or suspected endometriosis, whose pelvic pain flared up with the onset of bleeding.

DR SULAK: Then we realized that the benefits of extended regimens went beyond endometriosis and could help patients with menstrual migraine headaches or severe premenstrual syndrome. With extended regimens, we have shown reductions in mood swings, pain, headaches, bloating, and swelling.^6,10-12

With a low-dose regimen and a 7-day HFI, we were actually creating estrogen-withdrawal headaches, cramps, bloating, and other symptoms.¹³ In our prospective randomized trial of Seasonale vs Seasonique, we observed a tendency toward fewer headaches during the estrogen-supplemented week.⁷ And we weren’t even looking at headaches in that study! Adding estrogen during that typical week off may have the potential to decrease some of these withdrawal symptoms, but this needs further study.

Bleeding and spotting: Managing expectations

DR LIU: When a patient begins an extended-regimen OC, how do you manage her expectations about spotting and bleeding?

DR SULAK: Any patient on an extended-regimen OC has to be a great pill-taker, so I suggest that she put her pills somewhere she’ll see them at about the same time everyday. I tell patients that particularly during that first cycle, there is a high incidence of unscheduled bleeding. When I prescribe an OC regimen that substitutes a low-dose estrogen pill for the traditional placebo week, I explain that the patient will have a progestin withdrawal bleed during the estrogen-only pills. I also mention that in subsequent packs, the unscheduled bleeding is greatly reduced.^14,15

Conclusions

DR LIU: The modifications to the HFI that we’ve seen in recently approved OCs represent an incremental advance in our understanding of the physiology of ovarian follicle development. Experience and studies have shown how altering the HFI can optimize patient outcomes.

DR SULAK: We do need to see the demise of the 7-day HFI. Practitioners should realize that these changes in OCs are not arbitrary. They are substantiated by real science and will mean a true improvement in the symptoms and quality of life our patients experience.

DR SULAK: The estrogen and progestin doses in oral contraceptives (OCs) have steadily decreased since the 1960s; however, until recently, we’ve kept the same 21/7-day regimen. Due to the high doses in the first-generation OCs, the hormones lingered into the week off. With the low-dose pills and a 7-day hormone-free interval (HFI), we have seen problems such as ovulation, estrogen withdrawal symptoms, and unscheduled bleeding (ie, breakthrough bleeding or spotting).

DR LIU: The physiology of ovarian follicle development explains why many of these problems occur. In the normal menstrual cycle, follicle-stimulating hormone (FSH) levels increase dramatically during the first 2 days of menses, driving the development of as many as 10 early (primordial) follicles. As estrogen and inhibin B levels increase and suppress FSH, only the follicle with the greatest ability to generate FSH receptors within itself survives this low-FSH environment to become the “egg of the month.”

During the HFI of an OC regimen, FSH begins to rebound just as it does in a normal menstrual cycle. With very-low-dose estrogen/progestin OCs, this rebound occurs rapidly and follicles begin to develop. If the follicle develops to a critical stage—which might be as small as 14 mm—escape ovulation may occur, despite the resumption of active OC pills and dampening of FSH.¹ In fact, up to 30% of women may ovulate on OCs when the HFI is increased.¹

DR SULAK: It is amazing how rapidly the pituitary wakes up and starts producing FSH—and how responsive the ovary is! Studies have shown that the dramatic rise in FSH occurs around the fourth day of a 7-day HFI, followed rapidly by the rise in 17-beta estradiol from the ovarian follicles.^2,3 We reported a 500% increase in estradiol, from 10 pg to almost 60 pg—and that was using a 30 mcg pill.²

I am amazed that more people taking OCs do not conceive. The reason failure rates are not higher is due in large part to the “backup mechanisms” of the pill, such as cervical mucous thickening and thinning of the endometrial lining.

Development of extended-regimen OCs

DR LIU: Starting in 1998 with the approval of Mircette, we’ve begun to see a number of modifications to the 21/7 regimen.

DR SULAK: Mircette is a regimen of 21 days of 20 mcg ethinyl estradiol (EE) and 0.15 mg desogestrel, 2 placebo days, and 5 days of 10 mcg EE pills. Comparing Mircette with a 21/7 regimen of the same hormones, researchers found that women experienced greater ovarian suppression and less follicular development when a 10 mcg EE pill replaced the last 5 placebo pills.⁴

Interestingly, even though Mircette is a 20 mcg EE pill, its bleeding profile is comparable to many OCs with 30 mcg EE.^5,6 Adding that low dose of estrogen suppresses the ovary and prevents “rebound” FSH and estrogen production; it is the production of endogenous estrogen that interferes with the next cycle and causes breakthrough bleeding.^6,7

All of the OCs that have been approved since 2003 feature modifications of the 21/7 regimen. Seasonale extended the OC regimen to 84 days of active pills followed by 7 days off. Loestrin 24 and Yaz shortened the HFI of a 28-day regimen and demonstrated that 20 mcg EE pills can have a good bleeding profile if the HFI is decreased.

Seasonique (84 days of levonorgestrel, 0.15 mg, and EE, 30 mcg; followed by 7 days of EE, 10 mcg) was developed when it became apparent that after prolonged suppression, FSH rises very quickly and the ovary is even more responsive; a 7-day HFI could lead to escape ovulation and other problems.^2,3,8 The most recently approved OC regimen is Lybrel, a continuous ultra-low-dose regimen of EE and levonorgestrel.

DR LIU: So the modifications to the HFI have been made based on our understanding of how follicular development can be suppressed and why escape ovulation occurs. Altering the HFI can address some of these problems. The use of a very-low-dose estrogen in place of the placebo suppresses the pituitary and attenuates the rise of FSH and inhibin B, so that a new crop of follicles does not begin to develop.⁹

Importance of correct, consistent use

DR LIU: For patients using an OC with an HFI, during which days of the regimen is missing a pill most likely to cause contraceptive failure?

DR SULAK: The first pill is the most important one in the pack! Particularly with low-dose OCs, it’s especially a problem if a patient misses a pill during the first week after a 7-day HFI.

DR LIU: I tell patients that it takes several tablets to suppress FSH; no single tablet will maintain a persistent effect. Missing a pill during the first 5 days is probably more risky than missing 1 or more in the second or third week.

DR SULAK: The rise in FSH and 17-beta estradiol during the 7-day HFI continues into the first week of active pills and takes 5 to 7 days to decrease significantly.²

Reducing hormone withdrawal symptoms

DR LIU: Clinicians started extending OC regimens for patients with endometriosis or suspected endometriosis, whose pelvic pain flared up with the onset of bleeding.

DR SULAK: Then we realized that the benefits of extended regimens went beyond endometriosis and could help patients with menstrual migraine headaches or severe premenstrual syndrome. With extended regimens, we have shown reductions in mood swings, pain, headaches, bloating, and swelling.^6,10-12

With a low-dose regimen and a 7-day HFI, we were actually creating estrogen-withdrawal headaches, cramps, bloating, and other symptoms.¹³ In our prospective randomized trial of Seasonale vs Seasonique, we observed a tendency toward fewer headaches during the estrogen-supplemented week.⁷ And we weren’t even looking at headaches in that study! Adding estrogen during that typical week off may have the potential to decrease some of these withdrawal symptoms, but this needs further study.

Bleeding and spotting: Managing expectations

DR LIU: When a patient begins an extended-regimen OC, how do you manage her expectations about spotting and bleeding?

DR SULAK: Any patient on an extended-regimen OC has to be a great pill-taker, so I suggest that she put her pills somewhere she’ll see them at about the same time everyday. I tell patients that particularly during that first cycle, there is a high incidence of unscheduled bleeding. When I prescribe an OC regimen that substitutes a low-dose estrogen pill for the traditional placebo week, I explain that the patient will have a progestin withdrawal bleed during the estrogen-only pills. I also mention that in subsequent packs, the unscheduled bleeding is greatly reduced.^14,15

Conclusions

DR LIU: The modifications to the HFI that we’ve seen in recently approved OCs represent an incremental advance in our understanding of the physiology of ovarian follicle development. Experience and studies have shown how altering the HFI can optimize patient outcomes.

DR SULAK: We do need to see the demise of the 7-day HFI. Practitioners should realize that these changes in OCs are not arbitrary. They are substantiated by real science and will mean a true improvement in the symptoms and quality of life our patients experience.

A roundtable discussion among key thought leaders in the area of hormonal contraception was held on October 20, 2006, in New Orleans, Louisiana. These experts addressed the critical questions regarding the practical management of extended regimen oral contraceptives based on information in the medical literature.

Oral contraceptives (OCs) have been available in the United States for nearly 50 years. It is easy to forget that the introduction of reliable oral contraception—a widely available method that allows women control of their fertility—was revolutionary at that time. The decision to use a 28-day pill regimen was not a response to a physiologic need for 13 cycles per year but was dictated by the social norms and pregnancy testing technology of the day. At a time when pregnancy testing was neither easy to perform nor highly sensitive, the 7-day hormone free interval (HFI) provided a monthly reassurance to the OC user that she was not pregnant. Over the ensuing years numerous improvements in oral contraception have taken place—lowering of estrogen content due to safety concerns, confirmation of the efficacy of low-dose pills, introduction of new progestins, and phasic regimens. These changes came about due to a large number of clinical trials and other scientific assessments of OC regimens. Now with research shifted toward reducing the HFI and maximizing ovarian follicular suppression, oral contraception is undergoing a second revolution. By altering or eliminating the HFI, the goal of reducing withdrawal bleeding and minimizing hormone withdrawal can be accomplished.

Both spontaneous menstrual bleeding associated with ovulatory cycles and iatrogenically induced scheduled bleeding associated with OCs are due to endogenous or exogenous hormone withdrawal. However, the similarity ends abruptly, as menstrual bleeding fulfills a physiologic need to slough the secretory endometrium after ovulation in preparation for a new cycle and possible pregnancy. In contrast, there is no health-related reason to bleed while taking OCs. Monthly menstruation in reproductive-age women is necessary unless the patient is pregnant, using hormonal contraception, breastfeeding, or has undergone hysterectomy. A lack of cyclical menstrual bleeding in women not taking hormonal contraception is indicative of a pathologic state, whether it is the hypoestrogenic state of premature ovarian failure or the unopposed estrogen anovulatory state characteristic of women with polycystic ovarian syndrome (TABLE 1). Conversely, the recurrent ovulation and menstruation that is common among today’s post-industrial women is associated with health risks (TABLE 2).

The focus on alteration of the HFI to further improve OC therapy began with the introduction of Mircette^® in 1998.¹ This was followed by the introduction of Seasonale^®, the first extended OC regimen² and subsequently 2 OC products, Yaz^® and Loestrin^® 24 Fe, that maintained the 28-day cycle with a shortened HFI.^3-5 A recently introduced OC product, Seasonique^®, uses an extended 91-day regimen with low-dose ethinyl estradiol (EE) during the HFI, thus eliminating the HFI completely (TABLE 3).⁶

TABLE 1

Conditions Associated With Oligomenorrhea/Amenorrhea

TABLE 2

Health Risks

TABLE 3

OC Products With Extended Regimens or Altered Hormone Free Interval

Are there specific clinical advantages to extended regimen OCs?

DR LONDON: The real advantage to the extended regimens is that they do not have the disadvantages known to exist with the 21/7 regimens.

DR KAUNITZ: There are 4 advantages to extended regimens:

• improvement in contraceptive success
• therapeutic use for hormone withdrawal symptoms
• treatment of gynecologic problems such as dysmenorrhea, endometriosis, and anemia
• accommodation of lifestyle preference

Once women understand that extending combined hormone contraceptives is safe, most will prefer fewer cycles.

DR SULAK: While we need to acknowledge that the decision to introduce the first OCs in a 21/7 regimen was a wise choice nearly 50 years ago, research has shown us that the low doses of EE and the 7-day HFI creates problems—incomplete pituitary-ovarian suppression, endogenous estradiol formation, follicular development, ovarian cyst formation, risk of escape ovulation, and hormone withdrawal symptoms. It doesn’t matter whether a pill, patch, or ring is used—a 7-day HFI is too long with today’s low-dose combined hormonal contraceptives.

Spona was the first to report greater suppression of ovarian activity with a shortened HFI.⁷ By increasing the number of active pills from 21 to 23 per cycle and decreasing the HFI from 7 to 5 days, there was lower residual ovarian activity and endogenous 17β-estradiol. The study also showed that 17β-estradiol levels began to rise during the HFI but the rise was earlier and greater in women assigned to the 21-day regimen.

DR KAUNITZ: Another fundamental issue focuses on the reason our patients use OCs—effective, convenient, and reversible contraception. Unfortunately, the current 21/7 paradigm may not be optimal. The “typical” failure rate with OCs—which is what applies to our patients—is 8%.⁸ I don’t think that is acceptable.

The HFI and the first few days of a new pill pack are the time at which women are at greatest risk for contraceptive failure and unintended pregnancy. By extending the overall duration of active pills and decreasing the duration of the HFI, we are setting our patients up for better contraceptive success.

DR SULAK: There is also the issue of symptoms during the HFI. We all recognize that menstrual symptoms—breast tenderness, headache, bloating, and cramping—increase during the HFI.⁹ Although our data reported significant hormone withdrawal symptoms in women taking OCs, women experience these symptoms with all forms of combined estrogen-progestin hormonal contraceptives regardless of route of administration.

Importantly, the study showed that the symptoms occurred consistently not only in the new start patients, but also in the established users—the women who had been on the pill for more than a year. There is a reason why so many women stop their OCs in less than a year—it’s not because they are feeling wonderful. They may stop because they feel terrible during the HFI.

DR NELSON: The symptoms are real and it is astonishing how many women experience them. Women have become so accustomed to feeling lousy once a month, whether it’s due to menstrual symptoms or hormone withdrawal, that they will not mention it.

Another advantage to extended use of combination estrogen-progestin contraception is the prolonged suppression of ovulation and menstruation, like that produced by the progestin-only regimens, without the negative effects on bone. Given the multitude of problems caused by recurrent ovulation and menstruation, it may be healthier for some women not to have periods every month.

DR KAUNITZ: There are also therapeutic uses for extended regimen OCs that we should not overlook. Decreased dysmenorrhea and menorrhagia are both included in the prescribing information for all OCs. Women suffering from these disorders will likely have additive benefit from extended regimens. In the same vein, the value of extended regimens in managing endometriosis has been known for years.¹⁰

DR SULAK: A very recent paper showed that extending the regimen can improve premenstrual symptoms.¹¹ When symptomatology was compared with that recorded during a 21/7 cycle, there was a significant improvement that was especially apparent in the women who had the greatest variability in their cycles.

Another important finding was that the greatest improvement was detected in the sixth month. That is a key counseling point—you need to stick with the regimen to see the benefits.

What practical advantages does an extended regimen offer to the patient?

DR LONDON: Convenience, convenience, convenience.

MS MOORE: The worst pill to miss in any cycle is the one that is still at the pharmacy. Once your patient has already had 7 hormone-free days, her risk of pregnancy increases with each day of delay in starting a new pack of pills.

DR LONDON: With an extended regimen, that risk occurs fewer times per year. Just as the change from 50-mcg pills to low-dose pills was an improvement, the extension of the regimen beyond 28 days is a real improvement in OC therapy.

DR NELSON: Access to pills is a real issue—it’s more than having to go to the pharmacy every few weeks. A recent paper from the California Family PACT (Planning, Access, Care and Treatment) Program showed that women who were dispensed a year’s supply of OCs at their first visit were more likely to continue therapy, were more likely to receive Papanicolaou tests and Chlamydia tests, and actually had a lower annual women’s health care–related costs than women who were dispensed 3 cycles.¹²

We recently presented data that support this conclusion—hormonal method continuation rates were higher among women who received 3 pill packs than in those who received only 1. Having the supply of pills available is one more way of promoting contraceptive success.

Are there side effects that are specific to the extended regimen OCs?

DR SULAK: We are in consensus that there are no side effects that are specific to the extended regimen OCs. The only side effect found to be increased with extended regimen is unscheduled bleeding, but some studies have shown less bleeding overall.¹³ Studies have shown a decrease in many typical side effects seen with 21/7 OCs such as premenstrual syndrome and headaches.¹⁴

DR KAUNITZ: I agree. We should, however, address unscheduled bleeding and spotting. It’s something that we see with every OC, but extending the regimen changes the pattern.

A number of years ago, a randomized trial showed that addition of low-dose estrogen to the HFI provided superior cycle control to that of a 20-mcg EE OC and similar to that reported with a 35-mcg pill.¹⁵ There are more recent data that suggest that once you have passed the first cycle, addition of low-dose estrogen to the HFI also improves unscheduled bleeding in 91-day regimens.⁶

MS MOORE: Patients must understand there will be some unscheduled bleeding/spotting as their endometrium transitions from a monthly cycle or withdrawal bleed to more complete ovarian suppression, but it is manageable.

DR LONDON: Some clinicians have concerns about estrogen exposure—specifically the risk of venous thromboembolism and breast cancer. When the published data regarding extended regimens are examined in total, the safety profile is virtually the same as for 21/7. The safety of 91-day regimens have been demonstrated in both 1-year trials as well as longer-term 2-year studies.^2,6,16

The Women’s CARE (Contraceptive and Reproductive Experiences) study really put concerns about the association of OC use and breast cancer to rest.¹⁷ There was no evidence of increased risk of breast cancer in either current or past users of OCs. Given that the study included women who had taken high-dose 50-mcg EE pills, it’s very reasonable to conclude that extended OC use poses no increased risk of breast cancer.

What can be done to ensure that an extended regimen is offered to all OC-appropriate patients regardless of age or pathology?

DR KAUNITZ: We still need to work on overcoming common misconceptions. Despite more than 45 years of use, a fundamental lack of understanding of how OCs work persists among patients and health care professionals outside the field of women’s health.

MS MOORE: Many of my students are incredulous when they realize that there is no physiologic reason for the 7-day HFI and cyclical bleeding for women taking OCs.

DR LONDON: We also need to dispel the myth that women taking OCs are having periods. Remember that no women taking an OC has a period. They have withdrawal bleeding.

DR SULAK: Extended regimens set my patients up for contraceptive success and should be considered for all women who are candidates for OCs. The advantages—avoidance of monthly withdrawal symptoms, less follicular development, and, overall, less bleeding—outweigh the issues of unscheduled bleeding and spotting.

DR NELSON: We should discuss bleeding with our patients and, perhaps, it is time to turn the tables and ask her why she feels the need to bleed every month. For women considering use of OCs, it opens up the conversation to use of regimens other than 21/7. For women who are established users of OCs, asking whether they are having symptoms every month will open up the same conversation.

DR KAUNITZ: We’re not here to suggest that women should no longer menstruate or that women should no longer experience monthly bleeding.

It’s all about choice. Using hormones not only to provide safe, effective contraception but also to allow women the option of choosing when to bleed is a second revolution in contraception.

With regard to symptoms, I ask about grouchiness. “Do you get headaches or feel grouchy or down during your HFI?” If the answer is yes, it moves the conversation in the direction of extended regimens.

MS MOORE: I agree. The extended regimen has become mainstream over the past couple of years—the only reason I can see for using 21/7 is if the patient demands it or if reimbursement drives the issue.

How important is breakthrough bleeding in OC product selection?

DR KAUNITZ: Breakthrough bleeding occurs with all OC products—it’s importance becomes a matter of how well you have prepared patients for it.

MS MOORE: I like to tell my patients that it is likely they will experience some breakthrough bleeding in the early cycles. Then they are prepared and those who do not have any are pleasantly surprised.

DR SULAK: It’s inevitable and it can be managed—to me, it’s more important to focus on eliminating hormone withdrawal symptoms.

Are all combined hormonal contraceptive products appropriate for use in extended regimens?

DR NELSON: At this time there are insufficient data regarding the safety and pharmacokinetics of extended regimen use of the transdermal patch. Until studies evaluating its use in multiple extended cycles become available, we cannot recommend its use in extended regimens.¹⁸

DR KAUNITZ: Traditional 21/7 pill packs can be used in extended regimens but I find this approach often poses challenges for the patient—from remembering not to take placebo pills to reimbursement to trips to the pharmacy every 3 weeks for a new pill pack.

DR LONDON: It seems intuitive that the multiphasic pills would not be optimal for use in extended regimens. Given the paucity of data supporting their use, I would not recommend initiating an extended regimen with a mutiphasic pill. I certainly would allow a patient who is using them successfully to continue.

What are practical options to manage breakthrough bleeding in patients taking extended regimen OCs?

DR SULAK: We find that patients usually don’t begin to have unscheduled bleeding until week 4 or later. In our prospective study, we found that women who had heavier daily flow ratings during the 21/7 lead-in cycle tended to have greater daily flow ratings and earlier occurrence of unscheduled bleeding when taking an extended regimen.¹³ We also showed that a 3-day pill holiday was helpful in managing breakthrough bleeding and/or spotting that had persisted for 7 consecutive days (TABLE 4).

MS MOORE: Essentially patients have 2 options: endure the bleeding or take a brief pill holiday. I let my patients decide—some are very bothered by even the slightest amount of breakthrough bleeding while others have no issue with it. The worse thing a patient can do is to stop taking pills without a back-up plan for contraception. It is critical that they take at least 3 weeks of active pills between drug holidays.

DR LONDON: It’s also important to remember that you cannot use a 3-day pill holiday to manage breakthrough bleeding/spotting with 21/7 regimens as the increased number of hormone-free days per cycle could lead to a greater chance of escape ovulation.

DR KAUNITZ: Let’s not forget the value of counseling. Just letting women know what to expect and what to do has certainly been proven to be valuable in improving continuation rates among women on other forms of long-term contraception^19,20 and would without doubt be beneficial for women receiving extended regimens (SIDEBAR).

DR SULAK: With the low-dose OCs, it is especially important to let the patient know at the time you write the prescription that she has to take her pills at about the same time each day. I have had patients tell me that they experience bleeding if they take their pills even a few hours late.

DR NELSON: There will be patients with breakthrough bleeding/spotting who need to be examined, such as a long-term pill user who reports it for the first time. If you can establish a history of good pill taking with no illnesses or medication interaction which might alter hormone absorption, this woman should be evaluated for infection and anatomic changes like cervical or endometrial polyps.

TABLE 4

Recommendations for Initiating Extended Regimens

Summary

DR SULAK: We are finally seeing the demise of 21/7 contraceptive regimens. Numerous studies of these regimens over the past decade have documented hormone withdrawal symptoms, inadequate pituitary-ovarian suppression, follicular development, and even ovulation. Regimens which shorten or eliminate the 7-day HFI by adding estrogen and providing greater duration of active pills will improve the side effect profile and efficacy.

Oral contraceptives first gave women control over their fertility; now, regimens that extend the cycle and eliminate the HFI give women the option of having fewer hormone withdrawal symptoms. In addition to the convenience of fewer cycles per year, women may experience further benefit from prolonged suppression of ovulation and menstruation.

While breakthrough bleeding and spotting occur with all OCs, the pattern seen with extended regimens differs. It can be managed with patient counseling and brief pill holidays. Additional strategies to manage breakthrough bleeding that should be evaluated in the future include additional estrogen only, nonsteroidal anti-inflammatory drugs, and changing the estrogen dose of the formulation (ie, increasing the dose from 20 mcg EE to 30-35 mcg EE).

Articles of interest

Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

Prospective trial of 1006 sexually active adult women of childbearing potential who received a 91-day extended regimen OC (30 mcg EE/150 mcg LNG) with continuous low-dose EE (10 mcg) during the hormone free interval. Cycle control and safety of the regimen were comparable to that reported for other OCs.

Anderson FD, Gibbons W, Portman D. Long-term safety of an extended-cycle oral contraceptive (Seasonale): a 2-year multicenter open-label extension trial. Am J Obstet Gynecol. 2006;195:92-96.

Long-term safety study of a 91-day extended cycle OC regimen. Overall rates of study discontinuation and incidence of adverse events were similar to those of an earlier Phase 3 clinical trial. The regimen was well tolerated and the numbers of reported bleeding and/or spotting days diminished during the study.

Foster DG, Parvataneni R, de Bocanegra HT, Lewis C, Bradsberry M, Darney P. Number of oral contraceptive pill packages dispensed, method continuation, and costs. Obstet Gynecol. 2006;108:1107-1114.

Evaluation of the effect of the number of cycles of OC pill packages dispensed on the method continuation, pill wastage, use of services, and health care costs among 82,319 women enrolled in the California Family PACT system. Dispensing a year’s supply of OCs during first visits was associated with a higher method continuation and lower health care costs than dispensing fewer cycles per visit.

Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.

A population-based, case-control study of 4575 women with breast cancer and 4682 controls to determine the risk of breast cancer among former and current users of OCs. The relative risk of breast cancer was 1.0 (95% CI, 0.8-1.3) for women who were currently using OCs and 0.9 (95% CI, 0.8-1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. Use of OCs by women with a family history of breast cancer was not associated with an increased risk of breast cancer nor was the initiation of OC use at a young age.

Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception. 1996;54:71-77.

Double-blind, randomized trial to determine the suppressive effect on ovarian activity of OCs administered for 21 or 23 days. Observed differences in 17β-estradiol levels and follicular development between a 21-day and 23-day preparation suggest that shortening the pill-free interval in combined OCs may increase the contraceptive safety margin in women on low-dose formulations.

Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:261-266.

Prospective evaluation to measure the timing, frequency, and severity of hormone-related symptoms in OC users. Pelvic pain, headaches, use of pain medication, bloating or swelling, and breast tenderness occurred significantly more frequently during the 7-day hormone free interval among both current users and new start users of OCs.

Sulak PJ, Kuehl TJ, Coffee A, Willis S. Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen. Am J Obstet Gynecol. 2006;195:935-941.

Single-center, prospective analysis of self-rated menstrual flow during a 21/7 regimen versus a 168-day extended OC regimen. Subjects with a heavier daily flow rating during the 21/7 day cycle tended to have greater daily flow ratings and earlier breakthrough bleeding during the 168-day extension cycle. The 168-day extended regimen had an acceptable bleeding profile with bleeding during the active pill interval effectively managed with institution of a 3-day hormone free interval.

Acknowledgment

The assistance of Kathryn Martin, PharmD, in providing background research and editorial support is acknowledged.

A roundtable discussion among key thought leaders in the area of hormonal contraception was held on October 20, 2006, in New Orleans, Louisiana. These experts addressed the critical questions regarding the practical management of extended regimen oral contraceptives based on information in the medical literature.

Oral contraceptives (OCs) have been available in the United States for nearly 50 years. It is easy to forget that the introduction of reliable oral contraception—a widely available method that allows women control of their fertility—was revolutionary at that time. The decision to use a 28-day pill regimen was not a response to a physiologic need for 13 cycles per year but was dictated by the social norms and pregnancy testing technology of the day. At a time when pregnancy testing was neither easy to perform nor highly sensitive, the 7-day hormone free interval (HFI) provided a monthly reassurance to the OC user that she was not pregnant. Over the ensuing years numerous improvements in oral contraception have taken place—lowering of estrogen content due to safety concerns, confirmation of the efficacy of low-dose pills, introduction of new progestins, and phasic regimens. These changes came about due to a large number of clinical trials and other scientific assessments of OC regimens. Now with research shifted toward reducing the HFI and maximizing ovarian follicular suppression, oral contraception is undergoing a second revolution. By altering or eliminating the HFI, the goal of reducing withdrawal bleeding and minimizing hormone withdrawal can be accomplished.

Both spontaneous menstrual bleeding associated with ovulatory cycles and iatrogenically induced scheduled bleeding associated with OCs are due to endogenous or exogenous hormone withdrawal. However, the similarity ends abruptly, as menstrual bleeding fulfills a physiologic need to slough the secretory endometrium after ovulation in preparation for a new cycle and possible pregnancy. In contrast, there is no health-related reason to bleed while taking OCs. Monthly menstruation in reproductive-age women is necessary unless the patient is pregnant, using hormonal contraception, breastfeeding, or has undergone hysterectomy. A lack of cyclical menstrual bleeding in women not taking hormonal contraception is indicative of a pathologic state, whether it is the hypoestrogenic state of premature ovarian failure or the unopposed estrogen anovulatory state characteristic of women with polycystic ovarian syndrome (TABLE 1). Conversely, the recurrent ovulation and menstruation that is common among today’s post-industrial women is associated with health risks (TABLE 2).

The focus on alteration of the HFI to further improve OC therapy began with the introduction of Mircette^® in 1998.¹ This was followed by the introduction of Seasonale^®, the first extended OC regimen² and subsequently 2 OC products, Yaz^® and Loestrin^® 24 Fe, that maintained the 28-day cycle with a shortened HFI.^3-5 A recently introduced OC product, Seasonique^®, uses an extended 91-day regimen with low-dose ethinyl estradiol (EE) during the HFI, thus eliminating the HFI completely (TABLE 3).⁶

TABLE 1

Conditions Associated With Oligomenorrhea/Amenorrhea

TABLE 2

Health Risks

TABLE 3

OC Products With Extended Regimens or Altered Hormone Free Interval

Are there specific clinical advantages to extended regimen OCs?

DR LONDON: The real advantage to the extended regimens is that they do not have the disadvantages known to exist with the 21/7 regimens.

DR KAUNITZ: There are 4 advantages to extended regimens:

• improvement in contraceptive success
• therapeutic use for hormone withdrawal symptoms
• treatment of gynecologic problems such as dysmenorrhea, endometriosis, and anemia
• accommodation of lifestyle preference

Once women understand that extending combined hormone contraceptives is safe, most will prefer fewer cycles.

DR SULAK: While we need to acknowledge that the decision to introduce the first OCs in a 21/7 regimen was a wise choice nearly 50 years ago, research has shown us that the low doses of EE and the 7-day HFI creates problems—incomplete pituitary-ovarian suppression, endogenous estradiol formation, follicular development, ovarian cyst formation, risk of escape ovulation, and hormone withdrawal symptoms. It doesn’t matter whether a pill, patch, or ring is used—a 7-day HFI is too long with today’s low-dose combined hormonal contraceptives.

Spona was the first to report greater suppression of ovarian activity with a shortened HFI.⁷ By increasing the number of active pills from 21 to 23 per cycle and decreasing the HFI from 7 to 5 days, there was lower residual ovarian activity and endogenous 17β-estradiol. The study also showed that 17β-estradiol levels began to rise during the HFI but the rise was earlier and greater in women assigned to the 21-day regimen.

DR KAUNITZ: Another fundamental issue focuses on the reason our patients use OCs—effective, convenient, and reversible contraception. Unfortunately, the current 21/7 paradigm may not be optimal. The “typical” failure rate with OCs—which is what applies to our patients—is 8%.⁸ I don’t think that is acceptable.

The HFI and the first few days of a new pill pack are the time at which women are at greatest risk for contraceptive failure and unintended pregnancy. By extending the overall duration of active pills and decreasing the duration of the HFI, we are setting our patients up for better contraceptive success.

DR SULAK: There is also the issue of symptoms during the HFI. We all recognize that menstrual symptoms—breast tenderness, headache, bloating, and cramping—increase during the HFI.⁹ Although our data reported significant hormone withdrawal symptoms in women taking OCs, women experience these symptoms with all forms of combined estrogen-progestin hormonal contraceptives regardless of route of administration.

Importantly, the study showed that the symptoms occurred consistently not only in the new start patients, but also in the established users—the women who had been on the pill for more than a year. There is a reason why so many women stop their OCs in less than a year—it’s not because they are feeling wonderful. They may stop because they feel terrible during the HFI.

DR NELSON: The symptoms are real and it is astonishing how many women experience them. Women have become so accustomed to feeling lousy once a month, whether it’s due to menstrual symptoms or hormone withdrawal, that they will not mention it.

Another advantage to extended use of combination estrogen-progestin contraception is the prolonged suppression of ovulation and menstruation, like that produced by the progestin-only regimens, without the negative effects on bone. Given the multitude of problems caused by recurrent ovulation and menstruation, it may be healthier for some women not to have periods every month.

DR KAUNITZ: There are also therapeutic uses for extended regimen OCs that we should not overlook. Decreased dysmenorrhea and menorrhagia are both included in the prescribing information for all OCs. Women suffering from these disorders will likely have additive benefit from extended regimens. In the same vein, the value of extended regimens in managing endometriosis has been known for years.¹⁰

DR SULAK: A very recent paper showed that extending the regimen can improve premenstrual symptoms.¹¹ When symptomatology was compared with that recorded during a 21/7 cycle, there was a significant improvement that was especially apparent in the women who had the greatest variability in their cycles.

Another important finding was that the greatest improvement was detected in the sixth month. That is a key counseling point—you need to stick with the regimen to see the benefits.

What practical advantages does an extended regimen offer to the patient?

DR LONDON: Convenience, convenience, convenience.

MS MOORE: The worst pill to miss in any cycle is the one that is still at the pharmacy. Once your patient has already had 7 hormone-free days, her risk of pregnancy increases with each day of delay in starting a new pack of pills.

DR LONDON: With an extended regimen, that risk occurs fewer times per year. Just as the change from 50-mcg pills to low-dose pills was an improvement, the extension of the regimen beyond 28 days is a real improvement in OC therapy.

DR NELSON: Access to pills is a real issue—it’s more than having to go to the pharmacy every few weeks. A recent paper from the California Family PACT (Planning, Access, Care and Treatment) Program showed that women who were dispensed a year’s supply of OCs at their first visit were more likely to continue therapy, were more likely to receive Papanicolaou tests and Chlamydia tests, and actually had a lower annual women’s health care–related costs than women who were dispensed 3 cycles.¹²

We recently presented data that support this conclusion—hormonal method continuation rates were higher among women who received 3 pill packs than in those who received only 1. Having the supply of pills available is one more way of promoting contraceptive success.

Are there side effects that are specific to the extended regimen OCs?

DR SULAK: We are in consensus that there are no side effects that are specific to the extended regimen OCs. The only side effect found to be increased with extended regimen is unscheduled bleeding, but some studies have shown less bleeding overall.¹³ Studies have shown a decrease in many typical side effects seen with 21/7 OCs such as premenstrual syndrome and headaches.¹⁴

DR KAUNITZ: I agree. We should, however, address unscheduled bleeding and spotting. It’s something that we see with every OC, but extending the regimen changes the pattern.

A number of years ago, a randomized trial showed that addition of low-dose estrogen to the HFI provided superior cycle control to that of a 20-mcg EE OC and similar to that reported with a 35-mcg pill.¹⁵ There are more recent data that suggest that once you have passed the first cycle, addition of low-dose estrogen to the HFI also improves unscheduled bleeding in 91-day regimens.⁶

MS MOORE: Patients must understand there will be some unscheduled bleeding/spotting as their endometrium transitions from a monthly cycle or withdrawal bleed to more complete ovarian suppression, but it is manageable.

DR LONDON: Some clinicians have concerns about estrogen exposure—specifically the risk of venous thromboembolism and breast cancer. When the published data regarding extended regimens are examined in total, the safety profile is virtually the same as for 21/7. The safety of 91-day regimens have been demonstrated in both 1-year trials as well as longer-term 2-year studies.^2,6,16

The Women’s CARE (Contraceptive and Reproductive Experiences) study really put concerns about the association of OC use and breast cancer to rest.¹⁷ There was no evidence of increased risk of breast cancer in either current or past users of OCs. Given that the study included women who had taken high-dose 50-mcg EE pills, it’s very reasonable to conclude that extended OC use poses no increased risk of breast cancer.

What can be done to ensure that an extended regimen is offered to all OC-appropriate patients regardless of age or pathology?

DR KAUNITZ: We still need to work on overcoming common misconceptions. Despite more than 45 years of use, a fundamental lack of understanding of how OCs work persists among patients and health care professionals outside the field of women’s health.

MS MOORE: Many of my students are incredulous when they realize that there is no physiologic reason for the 7-day HFI and cyclical bleeding for women taking OCs.

DR LONDON: We also need to dispel the myth that women taking OCs are having periods. Remember that no women taking an OC has a period. They have withdrawal bleeding.

DR SULAK: Extended regimens set my patients up for contraceptive success and should be considered for all women who are candidates for OCs. The advantages—avoidance of monthly withdrawal symptoms, less follicular development, and, overall, less bleeding—outweigh the issues of unscheduled bleeding and spotting.

DR NELSON: We should discuss bleeding with our patients and, perhaps, it is time to turn the tables and ask her why she feels the need to bleed every month. For women considering use of OCs, it opens up the conversation to use of regimens other than 21/7. For women who are established users of OCs, asking whether they are having symptoms every month will open up the same conversation.

DR KAUNITZ: We’re not here to suggest that women should no longer menstruate or that women should no longer experience monthly bleeding.

It’s all about choice. Using hormones not only to provide safe, effective contraception but also to allow women the option of choosing when to bleed is a second revolution in contraception.

With regard to symptoms, I ask about grouchiness. “Do you get headaches or feel grouchy or down during your HFI?” If the answer is yes, it moves the conversation in the direction of extended regimens.

MS MOORE: I agree. The extended regimen has become mainstream over the past couple of years—the only reason I can see for using 21/7 is if the patient demands it or if reimbursement drives the issue.

How important is breakthrough bleeding in OC product selection?

DR KAUNITZ: Breakthrough bleeding occurs with all OC products—it’s importance becomes a matter of how well you have prepared patients for it.

MS MOORE: I like to tell my patients that it is likely they will experience some breakthrough bleeding in the early cycles. Then they are prepared and those who do not have any are pleasantly surprised.

DR SULAK: It’s inevitable and it can be managed—to me, it’s more important to focus on eliminating hormone withdrawal symptoms.

Are all combined hormonal contraceptive products appropriate for use in extended regimens?

DR NELSON: At this time there are insufficient data regarding the safety and pharmacokinetics of extended regimen use of the transdermal patch. Until studies evaluating its use in multiple extended cycles become available, we cannot recommend its use in extended regimens.¹⁸

DR KAUNITZ: Traditional 21/7 pill packs can be used in extended regimens but I find this approach often poses challenges for the patient—from remembering not to take placebo pills to reimbursement to trips to the pharmacy every 3 weeks for a new pill pack.

DR LONDON: It seems intuitive that the multiphasic pills would not be optimal for use in extended regimens. Given the paucity of data supporting their use, I would not recommend initiating an extended regimen with a mutiphasic pill. I certainly would allow a patient who is using them successfully to continue.

What are practical options to manage breakthrough bleeding in patients taking extended regimen OCs?

DR SULAK: We find that patients usually don’t begin to have unscheduled bleeding until week 4 or later. In our prospective study, we found that women who had heavier daily flow ratings during the 21/7 lead-in cycle tended to have greater daily flow ratings and earlier occurrence of unscheduled bleeding when taking an extended regimen.¹³ We also showed that a 3-day pill holiday was helpful in managing breakthrough bleeding and/or spotting that had persisted for 7 consecutive days (TABLE 4).

MS MOORE: Essentially patients have 2 options: endure the bleeding or take a brief pill holiday. I let my patients decide—some are very bothered by even the slightest amount of breakthrough bleeding while others have no issue with it. The worse thing a patient can do is to stop taking pills without a back-up plan for contraception. It is critical that they take at least 3 weeks of active pills between drug holidays.

DR LONDON: It’s also important to remember that you cannot use a 3-day pill holiday to manage breakthrough bleeding/spotting with 21/7 regimens as the increased number of hormone-free days per cycle could lead to a greater chance of escape ovulation.

DR KAUNITZ: Let’s not forget the value of counseling. Just letting women know what to expect and what to do has certainly been proven to be valuable in improving continuation rates among women on other forms of long-term contraception^19,20 and would without doubt be beneficial for women receiving extended regimens (SIDEBAR).

DR SULAK: With the low-dose OCs, it is especially important to let the patient know at the time you write the prescription that she has to take her pills at about the same time each day. I have had patients tell me that they experience bleeding if they take their pills even a few hours late.

DR NELSON: There will be patients with breakthrough bleeding/spotting who need to be examined, such as a long-term pill user who reports it for the first time. If you can establish a history of good pill taking with no illnesses or medication interaction which might alter hormone absorption, this woman should be evaluated for infection and anatomic changes like cervical or endometrial polyps.

TABLE 4

Recommendations for Initiating Extended Regimens

Summary

DR SULAK: We are finally seeing the demise of 21/7 contraceptive regimens. Numerous studies of these regimens over the past decade have documented hormone withdrawal symptoms, inadequate pituitary-ovarian suppression, follicular development, and even ovulation. Regimens which shorten or eliminate the 7-day HFI by adding estrogen and providing greater duration of active pills will improve the side effect profile and efficacy.

Oral contraceptives first gave women control over their fertility; now, regimens that extend the cycle and eliminate the HFI give women the option of having fewer hormone withdrawal symptoms. In addition to the convenience of fewer cycles per year, women may experience further benefit from prolonged suppression of ovulation and menstruation.

While breakthrough bleeding and spotting occur with all OCs, the pattern seen with extended regimens differs. It can be managed with patient counseling and brief pill holidays. Additional strategies to manage breakthrough bleeding that should be evaluated in the future include additional estrogen only, nonsteroidal anti-inflammatory drugs, and changing the estrogen dose of the formulation (ie, increasing the dose from 20 mcg EE to 30-35 mcg EE).

Articles of interest

Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

Prospective trial of 1006 sexually active adult women of childbearing potential who received a 91-day extended regimen OC (30 mcg EE/150 mcg LNG) with continuous low-dose EE (10 mcg) during the hormone free interval. Cycle control and safety of the regimen were comparable to that reported for other OCs.

Anderson FD, Gibbons W, Portman D. Long-term safety of an extended-cycle oral contraceptive (Seasonale): a 2-year multicenter open-label extension trial. Am J Obstet Gynecol. 2006;195:92-96.

Long-term safety study of a 91-day extended cycle OC regimen. Overall rates of study discontinuation and incidence of adverse events were similar to those of an earlier Phase 3 clinical trial. The regimen was well tolerated and the numbers of reported bleeding and/or spotting days diminished during the study.

Foster DG, Parvataneni R, de Bocanegra HT, Lewis C, Bradsberry M, Darney P. Number of oral contraceptive pill packages dispensed, method continuation, and costs. Obstet Gynecol. 2006;108:1107-1114.

Evaluation of the effect of the number of cycles of OC pill packages dispensed on the method continuation, pill wastage, use of services, and health care costs among 82,319 women enrolled in the California Family PACT system. Dispensing a year’s supply of OCs during first visits was associated with a higher method continuation and lower health care costs than dispensing fewer cycles per visit.

Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.

A population-based, case-control study of 4575 women with breast cancer and 4682 controls to determine the risk of breast cancer among former and current users of OCs. The relative risk of breast cancer was 1.0 (95% CI, 0.8-1.3) for women who were currently using OCs and 0.9 (95% CI, 0.8-1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. Use of OCs by women with a family history of breast cancer was not associated with an increased risk of breast cancer nor was the initiation of OC use at a young age.

Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception. 1996;54:71-77.

Double-blind, randomized trial to determine the suppressive effect on ovarian activity of OCs administered for 21 or 23 days. Observed differences in 17β-estradiol levels and follicular development between a 21-day and 23-day preparation suggest that shortening the pill-free interval in combined OCs may increase the contraceptive safety margin in women on low-dose formulations.

Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:261-266.

Prospective evaluation to measure the timing, frequency, and severity of hormone-related symptoms in OC users. Pelvic pain, headaches, use of pain medication, bloating or swelling, and breast tenderness occurred significantly more frequently during the 7-day hormone free interval among both current users and new start users of OCs.

Sulak PJ, Kuehl TJ, Coffee A, Willis S. Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen. Am J Obstet Gynecol. 2006;195:935-941.

Single-center, prospective analysis of self-rated menstrual flow during a 21/7 regimen versus a 168-day extended OC regimen. Subjects with a heavier daily flow rating during the 21/7 day cycle tended to have greater daily flow ratings and earlier breakthrough bleeding during the 168-day extension cycle. The 168-day extended regimen had an acceptable bleeding profile with bleeding during the active pill interval effectively managed with institution of a 3-day hormone free interval.

Acknowledgment

The assistance of Kathryn Martin, PharmD, in providing background research and editorial support is acknowledged.

A roundtable discussion among key thought leaders in the area of hormonal contraception was held on October 20, 2006, in New Orleans, Louisiana. These experts addressed the critical questions regarding the practical management of extended regimen oral contraceptives based on information in the medical literature.

Oral contraceptives (OCs) have been available in the United States for nearly 50 years. It is easy to forget that the introduction of reliable oral contraception—a widely available method that allows women control of their fertility—was revolutionary at that time. The decision to use a 28-day pill regimen was not a response to a physiologic need for 13 cycles per year but was dictated by the social norms and pregnancy testing technology of the day. At a time when pregnancy testing was neither easy to perform nor highly sensitive, the 7-day hormone free interval (HFI) provided a monthly reassurance to the OC user that she was not pregnant. Over the ensuing years numerous improvements in oral contraception have taken place—lowering of estrogen content due to safety concerns, confirmation of the efficacy of low-dose pills, introduction of new progestins, and phasic regimens. These changes came about due to a large number of clinical trials and other scientific assessments of OC regimens. Now with research shifted toward reducing the HFI and maximizing ovarian follicular suppression, oral contraception is undergoing a second revolution. By altering or eliminating the HFI, the goal of reducing withdrawal bleeding and minimizing hormone withdrawal can be accomplished.

Both spontaneous menstrual bleeding associated with ovulatory cycles and iatrogenically induced scheduled bleeding associated with OCs are due to endogenous or exogenous hormone withdrawal. However, the similarity ends abruptly, as menstrual bleeding fulfills a physiologic need to slough the secretory endometrium after ovulation in preparation for a new cycle and possible pregnancy. In contrast, there is no health-related reason to bleed while taking OCs. Monthly menstruation in reproductive-age women is necessary unless the patient is pregnant, using hormonal contraception, breastfeeding, or has undergone hysterectomy. A lack of cyclical menstrual bleeding in women not taking hormonal contraception is indicative of a pathologic state, whether it is the hypoestrogenic state of premature ovarian failure or the unopposed estrogen anovulatory state characteristic of women with polycystic ovarian syndrome (TABLE 1). Conversely, the recurrent ovulation and menstruation that is common among today’s post-industrial women is associated with health risks (TABLE 2).

The focus on alteration of the HFI to further improve OC therapy began with the introduction of Mircette^® in 1998.¹ This was followed by the introduction of Seasonale^®, the first extended OC regimen² and subsequently 2 OC products, Yaz^® and Loestrin^® 24 Fe, that maintained the 28-day cycle with a shortened HFI.^3-5 A recently introduced OC product, Seasonique^®, uses an extended 91-day regimen with low-dose ethinyl estradiol (EE) during the HFI, thus eliminating the HFI completely (TABLE 3).⁶

TABLE 1

Conditions Associated With Oligomenorrhea/Amenorrhea

TABLE 2

Health Risks

TABLE 3

OC Products With Extended Regimens or Altered Hormone Free Interval

Are there specific clinical advantages to extended regimen OCs?

DR LONDON: The real advantage to the extended regimens is that they do not have the disadvantages known to exist with the 21/7 regimens.

DR KAUNITZ: There are 4 advantages to extended regimens:

• improvement in contraceptive success
• therapeutic use for hormone withdrawal symptoms
• treatment of gynecologic problems such as dysmenorrhea, endometriosis, and anemia
• accommodation of lifestyle preference

Once women understand that extending combined hormone contraceptives is safe, most will prefer fewer cycles.

DR SULAK: While we need to acknowledge that the decision to introduce the first OCs in a 21/7 regimen was a wise choice nearly 50 years ago, research has shown us that the low doses of EE and the 7-day HFI creates problems—incomplete pituitary-ovarian suppression, endogenous estradiol formation, follicular development, ovarian cyst formation, risk of escape ovulation, and hormone withdrawal symptoms. It doesn’t matter whether a pill, patch, or ring is used—a 7-day HFI is too long with today’s low-dose combined hormonal contraceptives.

Spona was the first to report greater suppression of ovarian activity with a shortened HFI.⁷ By increasing the number of active pills from 21 to 23 per cycle and decreasing the HFI from 7 to 5 days, there was lower residual ovarian activity and endogenous 17β-estradiol. The study also showed that 17β-estradiol levels began to rise during the HFI but the rise was earlier and greater in women assigned to the 21-day regimen.

DR KAUNITZ: Another fundamental issue focuses on the reason our patients use OCs—effective, convenient, and reversible contraception. Unfortunately, the current 21/7 paradigm may not be optimal. The “typical” failure rate with OCs—which is what applies to our patients—is 8%.⁸ I don’t think that is acceptable.

The HFI and the first few days of a new pill pack are the time at which women are at greatest risk for contraceptive failure and unintended pregnancy. By extending the overall duration of active pills and decreasing the duration of the HFI, we are setting our patients up for better contraceptive success.

DR SULAK: There is also the issue of symptoms during the HFI. We all recognize that menstrual symptoms—breast tenderness, headache, bloating, and cramping—increase during the HFI.⁹ Although our data reported significant hormone withdrawal symptoms in women taking OCs, women experience these symptoms with all forms of combined estrogen-progestin hormonal contraceptives regardless of route of administration.

Importantly, the study showed that the symptoms occurred consistently not only in the new start patients, but also in the established users—the women who had been on the pill for more than a year. There is a reason why so many women stop their OCs in less than a year—it’s not because they are feeling wonderful. They may stop because they feel terrible during the HFI.

DR NELSON: The symptoms are real and it is astonishing how many women experience them. Women have become so accustomed to feeling lousy once a month, whether it’s due to menstrual symptoms or hormone withdrawal, that they will not mention it.

Another advantage to extended use of combination estrogen-progestin contraception is the prolonged suppression of ovulation and menstruation, like that produced by the progestin-only regimens, without the negative effects on bone. Given the multitude of problems caused by recurrent ovulation and menstruation, it may be healthier for some women not to have periods every month.

DR KAUNITZ: There are also therapeutic uses for extended regimen OCs that we should not overlook. Decreased dysmenorrhea and menorrhagia are both included in the prescribing information for all OCs. Women suffering from these disorders will likely have additive benefit from extended regimens. In the same vein, the value of extended regimens in managing endometriosis has been known for years.¹⁰

DR SULAK: A very recent paper showed that extending the regimen can improve premenstrual symptoms.¹¹ When symptomatology was compared with that recorded during a 21/7 cycle, there was a significant improvement that was especially apparent in the women who had the greatest variability in their cycles.

Another important finding was that the greatest improvement was detected in the sixth month. That is a key counseling point—you need to stick with the regimen to see the benefits.

What practical advantages does an extended regimen offer to the patient?

DR LONDON: Convenience, convenience, convenience.

MS MOORE: The worst pill to miss in any cycle is the one that is still at the pharmacy. Once your patient has already had 7 hormone-free days, her risk of pregnancy increases with each day of delay in starting a new pack of pills.

DR LONDON: With an extended regimen, that risk occurs fewer times per year. Just as the change from 50-mcg pills to low-dose pills was an improvement, the extension of the regimen beyond 28 days is a real improvement in OC therapy.

DR NELSON: Access to pills is a real issue—it’s more than having to go to the pharmacy every few weeks. A recent paper from the California Family PACT (Planning, Access, Care and Treatment) Program showed that women who were dispensed a year’s supply of OCs at their first visit were more likely to continue therapy, were more likely to receive Papanicolaou tests and Chlamydia tests, and actually had a lower annual women’s health care–related costs than women who were dispensed 3 cycles.¹²

We recently presented data that support this conclusion—hormonal method continuation rates were higher among women who received 3 pill packs than in those who received only 1. Having the supply of pills available is one more way of promoting contraceptive success.

Are there side effects that are specific to the extended regimen OCs?

DR SULAK: We are in consensus that there are no side effects that are specific to the extended regimen OCs. The only side effect found to be increased with extended regimen is unscheduled bleeding, but some studies have shown less bleeding overall.¹³ Studies have shown a decrease in many typical side effects seen with 21/7 OCs such as premenstrual syndrome and headaches.¹⁴

DR KAUNITZ: I agree. We should, however, address unscheduled bleeding and spotting. It’s something that we see with every OC, but extending the regimen changes the pattern.

A number of years ago, a randomized trial showed that addition of low-dose estrogen to the HFI provided superior cycle control to that of a 20-mcg EE OC and similar to that reported with a 35-mcg pill.¹⁵ There are more recent data that suggest that once you have passed the first cycle, addition of low-dose estrogen to the HFI also improves unscheduled bleeding in 91-day regimens.⁶

MS MOORE: Patients must understand there will be some unscheduled bleeding/spotting as their endometrium transitions from a monthly cycle or withdrawal bleed to more complete ovarian suppression, but it is manageable.

DR LONDON: Some clinicians have concerns about estrogen exposure—specifically the risk of venous thromboembolism and breast cancer. When the published data regarding extended regimens are examined in total, the safety profile is virtually the same as for 21/7. The safety of 91-day regimens have been demonstrated in both 1-year trials as well as longer-term 2-year studies.^2,6,16

The Women’s CARE (Contraceptive and Reproductive Experiences) study really put concerns about the association of OC use and breast cancer to rest.¹⁷ There was no evidence of increased risk of breast cancer in either current or past users of OCs. Given that the study included women who had taken high-dose 50-mcg EE pills, it’s very reasonable to conclude that extended OC use poses no increased risk of breast cancer.

What can be done to ensure that an extended regimen is offered to all OC-appropriate patients regardless of age or pathology?

DR KAUNITZ: We still need to work on overcoming common misconceptions. Despite more than 45 years of use, a fundamental lack of understanding of how OCs work persists among patients and health care professionals outside the field of women’s health.

MS MOORE: Many of my students are incredulous when they realize that there is no physiologic reason for the 7-day HFI and cyclical bleeding for women taking OCs.

DR LONDON: We also need to dispel the myth that women taking OCs are having periods. Remember that no women taking an OC has a period. They have withdrawal bleeding.

DR SULAK: Extended regimens set my patients up for contraceptive success and should be considered for all women who are candidates for OCs. The advantages—avoidance of monthly withdrawal symptoms, less follicular development, and, overall, less bleeding—outweigh the issues of unscheduled bleeding and spotting.

DR NELSON: We should discuss bleeding with our patients and, perhaps, it is time to turn the tables and ask her why she feels the need to bleed every month. For women considering use of OCs, it opens up the conversation to use of regimens other than 21/7. For women who are established users of OCs, asking whether they are having symptoms every month will open up the same conversation.

DR KAUNITZ: We’re not here to suggest that women should no longer menstruate or that women should no longer experience monthly bleeding.

It’s all about choice. Using hormones not only to provide safe, effective contraception but also to allow women the option of choosing when to bleed is a second revolution in contraception.

With regard to symptoms, I ask about grouchiness. “Do you get headaches or feel grouchy or down during your HFI?” If the answer is yes, it moves the conversation in the direction of extended regimens.

MS MOORE: I agree. The extended regimen has become mainstream over the past couple of years—the only reason I can see for using 21/7 is if the patient demands it or if reimbursement drives the issue.

How important is breakthrough bleeding in OC product selection?

DR KAUNITZ: Breakthrough bleeding occurs with all OC products—it’s importance becomes a matter of how well you have prepared patients for it.

MS MOORE: I like to tell my patients that it is likely they will experience some breakthrough bleeding in the early cycles. Then they are prepared and those who do not have any are pleasantly surprised.

DR SULAK: It’s inevitable and it can be managed—to me, it’s more important to focus on eliminating hormone withdrawal symptoms.

Are all combined hormonal contraceptive products appropriate for use in extended regimens?

DR NELSON: At this time there are insufficient data regarding the safety and pharmacokinetics of extended regimen use of the transdermal patch. Until studies evaluating its use in multiple extended cycles become available, we cannot recommend its use in extended regimens.¹⁸

DR KAUNITZ: Traditional 21/7 pill packs can be used in extended regimens but I find this approach often poses challenges for the patient—from remembering not to take placebo pills to reimbursement to trips to the pharmacy every 3 weeks for a new pill pack.

DR LONDON: It seems intuitive that the multiphasic pills would not be optimal for use in extended regimens. Given the paucity of data supporting their use, I would not recommend initiating an extended regimen with a mutiphasic pill. I certainly would allow a patient who is using them successfully to continue.

What are practical options to manage breakthrough bleeding in patients taking extended regimen OCs?

DR SULAK: We find that patients usually don’t begin to have unscheduled bleeding until week 4 or later. In our prospective study, we found that women who had heavier daily flow ratings during the 21/7 lead-in cycle tended to have greater daily flow ratings and earlier occurrence of unscheduled bleeding when taking an extended regimen.¹³ We also showed that a 3-day pill holiday was helpful in managing breakthrough bleeding and/or spotting that had persisted for 7 consecutive days (TABLE 4).

MS MOORE: Essentially patients have 2 options: endure the bleeding or take a brief pill holiday. I let my patients decide—some are very bothered by even the slightest amount of breakthrough bleeding while others have no issue with it. The worse thing a patient can do is to stop taking pills without a back-up plan for contraception. It is critical that they take at least 3 weeks of active pills between drug holidays.

DR LONDON: It’s also important to remember that you cannot use a 3-day pill holiday to manage breakthrough bleeding/spotting with 21/7 regimens as the increased number of hormone-free days per cycle could lead to a greater chance of escape ovulation.

DR KAUNITZ: Let’s not forget the value of counseling. Just letting women know what to expect and what to do has certainly been proven to be valuable in improving continuation rates among women on other forms of long-term contraception^19,20 and would without doubt be beneficial for women receiving extended regimens (SIDEBAR).

DR SULAK: With the low-dose OCs, it is especially important to let the patient know at the time you write the prescription that she has to take her pills at about the same time each day. I have had patients tell me that they experience bleeding if they take their pills even a few hours late.

DR NELSON: There will be patients with breakthrough bleeding/spotting who need to be examined, such as a long-term pill user who reports it for the first time. If you can establish a history of good pill taking with no illnesses or medication interaction which might alter hormone absorption, this woman should be evaluated for infection and anatomic changes like cervical or endometrial polyps.

TABLE 4

Recommendations for Initiating Extended Regimens

Summary

DR SULAK: We are finally seeing the demise of 21/7 contraceptive regimens. Numerous studies of these regimens over the past decade have documented hormone withdrawal symptoms, inadequate pituitary-ovarian suppression, follicular development, and even ovulation. Regimens which shorten or eliminate the 7-day HFI by adding estrogen and providing greater duration of active pills will improve the side effect profile and efficacy.

Oral contraceptives first gave women control over their fertility; now, regimens that extend the cycle and eliminate the HFI give women the option of having fewer hormone withdrawal symptoms. In addition to the convenience of fewer cycles per year, women may experience further benefit from prolonged suppression of ovulation and menstruation.

While breakthrough bleeding and spotting occur with all OCs, the pattern seen with extended regimens differs. It can be managed with patient counseling and brief pill holidays. Additional strategies to manage breakthrough bleeding that should be evaluated in the future include additional estrogen only, nonsteroidal anti-inflammatory drugs, and changing the estrogen dose of the formulation (ie, increasing the dose from 20 mcg EE to 30-35 mcg EE).

Articles of interest

Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

Prospective trial of 1006 sexually active adult women of childbearing potential who received a 91-day extended regimen OC (30 mcg EE/150 mcg LNG) with continuous low-dose EE (10 mcg) during the hormone free interval. Cycle control and safety of the regimen were comparable to that reported for other OCs.

Anderson FD, Gibbons W, Portman D. Long-term safety of an extended-cycle oral contraceptive (Seasonale): a 2-year multicenter open-label extension trial. Am J Obstet Gynecol. 2006;195:92-96.

Long-term safety study of a 91-day extended cycle OC regimen. Overall rates of study discontinuation and incidence of adverse events were similar to those of an earlier Phase 3 clinical trial. The regimen was well tolerated and the numbers of reported bleeding and/or spotting days diminished during the study.

Foster DG, Parvataneni R, de Bocanegra HT, Lewis C, Bradsberry M, Darney P. Number of oral contraceptive pill packages dispensed, method continuation, and costs. Obstet Gynecol. 2006;108:1107-1114.

Evaluation of the effect of the number of cycles of OC pill packages dispensed on the method continuation, pill wastage, use of services, and health care costs among 82,319 women enrolled in the California Family PACT system. Dispensing a year’s supply of OCs during first visits was associated with a higher method continuation and lower health care costs than dispensing fewer cycles per visit.

Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.

A population-based, case-control study of 4575 women with breast cancer and 4682 controls to determine the risk of breast cancer among former and current users of OCs. The relative risk of breast cancer was 1.0 (95% CI, 0.8-1.3) for women who were currently using OCs and 0.9 (95% CI, 0.8-1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. Use of OCs by women with a family history of breast cancer was not associated with an increased risk of breast cancer nor was the initiation of OC use at a young age.

Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception. 1996;54:71-77.

Double-blind, randomized trial to determine the suppressive effect on ovarian activity of OCs administered for 21 or 23 days. Observed differences in 17β-estradiol levels and follicular development between a 21-day and 23-day preparation suggest that shortening the pill-free interval in combined OCs may increase the contraceptive safety margin in women on low-dose formulations.

Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:261-266.

Prospective evaluation to measure the timing, frequency, and severity of hormone-related symptoms in OC users. Pelvic pain, headaches, use of pain medication, bloating or swelling, and breast tenderness occurred significantly more frequently during the 7-day hormone free interval among both current users and new start users of OCs.

Sulak PJ, Kuehl TJ, Coffee A, Willis S. Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen. Am J Obstet Gynecol. 2006;195:935-941.

Single-center, prospective analysis of self-rated menstrual flow during a 21/7 regimen versus a 168-day extended OC regimen. Subjects with a heavier daily flow rating during the 21/7 day cycle tended to have greater daily flow ratings and earlier breakthrough bleeding during the 168-day extension cycle. The 168-day extended regimen had an acceptable bleeding profile with bleeding during the active pill interval effectively managed with institution of a 3-day hormone free interval.

Acknowledgment

The assistance of Kathryn Martin, PharmD, in providing background research and editorial support is acknowledged.

A roundtable discussion among key thought leaders in the area of hormonal contraception was held on October 20, 2006, in New Orleans, Louisiana. These experts addressed the critical questions regarding the practical management of extended regimen oral contraceptives based on information in the medical literature.

Oral contraceptives (OCs) have been available in the United States for nearly 50 years. It is easy to forget that the introduction of reliable oral contraception—a widely available method that allows women control of their fertility—was revolutionary at that time. The decision to use a 28-day pill regimen was not a response to a physiologic need for 13 cycles per year but was dictated by the social norms and pregnancy testing technology of the day. At a time when pregnancy testing was neither easy to perform nor highly sensitive, the 7-day hormone free interval (HFI) provided a monthly reassurance to the OC user that she was not pregnant. Over the ensuing years numerous improvements in oral contraception have taken place—lowering of estrogen content due to safety concerns, confirmation of the efficacy of low-dose pills, introduction of new progestins, and phasic regimens. These changes came about due to a large number of clinical trials and other scientific assessments of OC regimens. Now with research shifted toward reducing the HFI and maximizing ovarian follicular suppression, oral contraception is undergoing a second revolution. By altering or eliminating the HFI, the goal of reducing withdrawal bleeding and minimizing hormone withdrawal can be accomplished.

Both spontaneous menstrual bleeding associated with ovulatory cycles and iatrogenically induced scheduled bleeding associated with OCs are due to endogenous or exogenous hormone withdrawal. However, the similarity ends abruptly, as menstrual bleeding fulfills a physiologic need to slough the secretory endometrium after ovulation in preparation for a new cycle and possible pregnancy. In contrast, there is no health-related reason to bleed while taking OCs. Monthly menstruation in reproductive-age women is necessary unless the patient is pregnant, using hormonal contraception, breastfeeding, or has undergone hysterectomy. A lack of cyclical menstrual bleeding in women not taking hormonal contraception is indicative of a pathologic state, whether it is the hypoestrogenic state of premature ovarian failure or the unopposed estrogen anovulatory state characteristic of women with polycystic ovarian syndrome (TABLE 1). Conversely, the recurrent ovulation and menstruation that is common among today’s post-industrial women is associated with health risks (TABLE 2).

The focus on alteration of the HFI to further improve OC therapy began with the introduction of Mircette^® in 1998.¹ This was followed by the introduction of Seasonale^®, the first extended OC regimen² and subsequently 2 OC products, Yaz^® and Loestrin^® 24 Fe, that maintained the 28-day cycle with a shortened HFI.^3-5 A recently introduced OC product, Seasonique^®, uses an extended 91-day regimen with low-dose ethinyl estradiol (EE) during the HFI, thus eliminating the HFI completely (TABLE 3).⁶

TABLE 1

Conditions Associated With Oligomenorrhea/Amenorrhea

TABLE 2

Health Risks

TABLE 3

OC Products With Extended Regimens or Altered Hormone Free Interval

Are there specific clinical advantages to extended regimen OCs?

DR LONDON: The real advantage to the extended regimens is that they do not have the disadvantages known to exist with the 21/7 regimens.

DR KAUNITZ: There are 4 advantages to extended regimens:

• improvement in contraceptive success
• therapeutic use for hormone withdrawal symptoms
• treatment of gynecologic problems such as dysmenorrhea, endometriosis, and anemia
• accommodation of lifestyle preference

Once women understand that extending combined hormone contraceptives is safe, most will prefer fewer cycles.

DR SULAK: While we need to acknowledge that the decision to introduce the first OCs in a 21/7 regimen was a wise choice nearly 50 years ago, research has shown us that the low doses of EE and the 7-day HFI creates problems—incomplete pituitary-ovarian suppression, endogenous estradiol formation, follicular development, ovarian cyst formation, risk of escape ovulation, and hormone withdrawal symptoms. It doesn’t matter whether a pill, patch, or ring is used—a 7-day HFI is too long with today’s low-dose combined hormonal contraceptives.

Spona was the first to report greater suppression of ovarian activity with a shortened HFI.⁷ By increasing the number of active pills from 21 to 23 per cycle and decreasing the HFI from 7 to 5 days, there was lower residual ovarian activity and endogenous 17β-estradiol. The study also showed that 17β-estradiol levels began to rise during the HFI but the rise was earlier and greater in women assigned to the 21-day regimen.

DR KAUNITZ: Another fundamental issue focuses on the reason our patients use OCs—effective, convenient, and reversible contraception. Unfortunately, the current 21/7 paradigm may not be optimal. The “typical” failure rate with OCs—which is what applies to our patients—is 8%.⁸ I don’t think that is acceptable.

The HFI and the first few days of a new pill pack are the time at which women are at greatest risk for contraceptive failure and unintended pregnancy. By extending the overall duration of active pills and decreasing the duration of the HFI, we are setting our patients up for better contraceptive success.

DR SULAK: There is also the issue of symptoms during the HFI. We all recognize that menstrual symptoms—breast tenderness, headache, bloating, and cramping—increase during the HFI.⁹ Although our data reported significant hormone withdrawal symptoms in women taking OCs, women experience these symptoms with all forms of combined estrogen-progestin hormonal contraceptives regardless of route of administration.

Importantly, the study showed that the symptoms occurred consistently not only in the new start patients, but also in the established users—the women who had been on the pill for more than a year. There is a reason why so many women stop their OCs in less than a year—it’s not because they are feeling wonderful. They may stop because they feel terrible during the HFI.

DR NELSON: The symptoms are real and it is astonishing how many women experience them. Women have become so accustomed to feeling lousy once a month, whether it’s due to menstrual symptoms or hormone withdrawal, that they will not mention it.

Another advantage to extended use of combination estrogen-progestin contraception is the prolonged suppression of ovulation and menstruation, like that produced by the progestin-only regimens, without the negative effects on bone. Given the multitude of problems caused by recurrent ovulation and menstruation, it may be healthier for some women not to have periods every month.

DR KAUNITZ: There are also therapeutic uses for extended regimen OCs that we should not overlook. Decreased dysmenorrhea and menorrhagia are both included in the prescribing information for all OCs. Women suffering from these disorders will likely have additive benefit from extended regimens. In the same vein, the value of extended regimens in managing endometriosis has been known for years.¹⁰

DR SULAK: A very recent paper showed that extending the regimen can improve premenstrual symptoms.¹¹ When symptomatology was compared with that recorded during a 21/7 cycle, there was a significant improvement that was especially apparent in the women who had the greatest variability in their cycles.

Another important finding was that the greatest improvement was detected in the sixth month. That is a key counseling point—you need to stick with the regimen to see the benefits.

What practical advantages does an extended regimen offer to the patient?

DR LONDON: Convenience, convenience, convenience.

MS MOORE: The worst pill to miss in any cycle is the one that is still at the pharmacy. Once your patient has already had 7 hormone-free days, her risk of pregnancy increases with each day of delay in starting a new pack of pills.

DR LONDON: With an extended regimen, that risk occurs fewer times per year. Just as the change from 50-mcg pills to low-dose pills was an improvement, the extension of the regimen beyond 28 days is a real improvement in OC therapy.

DR NELSON: Access to pills is a real issue—it’s more than having to go to the pharmacy every few weeks. A recent paper from the California Family PACT (Planning, Access, Care and Treatment) Program showed that women who were dispensed a year’s supply of OCs at their first visit were more likely to continue therapy, were more likely to receive Papanicolaou tests and Chlamydia tests, and actually had a lower annual women’s health care–related costs than women who were dispensed 3 cycles.¹²

We recently presented data that support this conclusion—hormonal method continuation rates were higher among women who received 3 pill packs than in those who received only 1. Having the supply of pills available is one more way of promoting contraceptive success.

Are there side effects that are specific to the extended regimen OCs?

DR SULAK: We are in consensus that there are no side effects that are specific to the extended regimen OCs. The only side effect found to be increased with extended regimen is unscheduled bleeding, but some studies have shown less bleeding overall.¹³ Studies have shown a decrease in many typical side effects seen with 21/7 OCs such as premenstrual syndrome and headaches.¹⁴

DR KAUNITZ: I agree. We should, however, address unscheduled bleeding and spotting. It’s something that we see with every OC, but extending the regimen changes the pattern.

A number of years ago, a randomized trial showed that addition of low-dose estrogen to the HFI provided superior cycle control to that of a 20-mcg EE OC and similar to that reported with a 35-mcg pill.¹⁵ There are more recent data that suggest that once you have passed the first cycle, addition of low-dose estrogen to the HFI also improves unscheduled bleeding in 91-day regimens.⁶

MS MOORE: Patients must understand there will be some unscheduled bleeding/spotting as their endometrium transitions from a monthly cycle or withdrawal bleed to more complete ovarian suppression, but it is manageable.

DR LONDON: Some clinicians have concerns about estrogen exposure—specifically the risk of venous thromboembolism and breast cancer. When the published data regarding extended regimens are examined in total, the safety profile is virtually the same as for 21/7. The safety of 91-day regimens have been demonstrated in both 1-year trials as well as longer-term 2-year studies.^2,6,16

The Women’s CARE (Contraceptive and Reproductive Experiences) study really put concerns about the association of OC use and breast cancer to rest.¹⁷ There was no evidence of increased risk of breast cancer in either current or past users of OCs. Given that the study included women who had taken high-dose 50-mcg EE pills, it’s very reasonable to conclude that extended OC use poses no increased risk of breast cancer.

What can be done to ensure that an extended regimen is offered to all OC-appropriate patients regardless of age or pathology?

DR KAUNITZ: We still need to work on overcoming common misconceptions. Despite more than 45 years of use, a fundamental lack of understanding of how OCs work persists among patients and health care professionals outside the field of women’s health.

MS MOORE: Many of my students are incredulous when they realize that there is no physiologic reason for the 7-day HFI and cyclical bleeding for women taking OCs.

DR LONDON: We also need to dispel the myth that women taking OCs are having periods. Remember that no women taking an OC has a period. They have withdrawal bleeding.

DR SULAK: Extended regimens set my patients up for contraceptive success and should be considered for all women who are candidates for OCs. The advantages—avoidance of monthly withdrawal symptoms, less follicular development, and, overall, less bleeding—outweigh the issues of unscheduled bleeding and spotting.

DR NELSON: We should discuss bleeding with our patients and, perhaps, it is time to turn the tables and ask her why she feels the need to bleed every month. For women considering use of OCs, it opens up the conversation to use of regimens other than 21/7. For women who are established users of OCs, asking whether they are having symptoms every month will open up the same conversation.

DR KAUNITZ: We’re not here to suggest that women should no longer menstruate or that women should no longer experience monthly bleeding.

It’s all about choice. Using hormones not only to provide safe, effective contraception but also to allow women the option of choosing when to bleed is a second revolution in contraception.

With regard to symptoms, I ask about grouchiness. “Do you get headaches or feel grouchy or down during your HFI?” If the answer is yes, it moves the conversation in the direction of extended regimens.

MS MOORE: I agree. The extended regimen has become mainstream over the past couple of years—the only reason I can see for using 21/7 is if the patient demands it or if reimbursement drives the issue.

How important is breakthrough bleeding in OC product selection?

DR KAUNITZ: Breakthrough bleeding occurs with all OC products—it’s importance becomes a matter of how well you have prepared patients for it.

MS MOORE: I like to tell my patients that it is likely they will experience some breakthrough bleeding in the early cycles. Then they are prepared and those who do not have any are pleasantly surprised.

DR SULAK: It’s inevitable and it can be managed—to me, it’s more important to focus on eliminating hormone withdrawal symptoms.

Are all combined hormonal contraceptive products appropriate for use in extended regimens?

DR NELSON: At this time there are insufficient data regarding the safety and pharmacokinetics of extended regimen use of the transdermal patch. Until studies evaluating its use in multiple extended cycles become available, we cannot recommend its use in extended regimens.¹⁸

DR KAUNITZ: Traditional 21/7 pill packs can be used in extended regimens but I find this approach often poses challenges for the patient—from remembering not to take placebo pills to reimbursement to trips to the pharmacy every 3 weeks for a new pill pack.

DR LONDON: It seems intuitive that the multiphasic pills would not be optimal for use in extended regimens. Given the paucity of data supporting their use, I would not recommend initiating an extended regimen with a mutiphasic pill. I certainly would allow a patient who is using them successfully to continue.

What are practical options to manage breakthrough bleeding in patients taking extended regimen OCs?

DR SULAK: We find that patients usually don’t begin to have unscheduled bleeding until week 4 or later. In our prospective study, we found that women who had heavier daily flow ratings during the 21/7 lead-in cycle tended to have greater daily flow ratings and earlier occurrence of unscheduled bleeding when taking an extended regimen.¹³ We also showed that a 3-day pill holiday was helpful in managing breakthrough bleeding and/or spotting that had persisted for 7 consecutive days (TABLE 4).

MS MOORE: Essentially patients have 2 options: endure the bleeding or take a brief pill holiday. I let my patients decide—some are very bothered by even the slightest amount of breakthrough bleeding while others have no issue with it. The worse thing a patient can do is to stop taking pills without a back-up plan for contraception. It is critical that they take at least 3 weeks of active pills between drug holidays.

DR LONDON: It’s also important to remember that you cannot use a 3-day pill holiday to manage breakthrough bleeding/spotting with 21/7 regimens as the increased number of hormone-free days per cycle could lead to a greater chance of escape ovulation.

DR KAUNITZ: Let’s not forget the value of counseling. Just letting women know what to expect and what to do has certainly been proven to be valuable in improving continuation rates among women on other forms of long-term contraception^19,20 and would without doubt be beneficial for women receiving extended regimens (SIDEBAR).

DR SULAK: With the low-dose OCs, it is especially important to let the patient know at the time you write the prescription that she has to take her pills at about the same time each day. I have had patients tell me that they experience bleeding if they take their pills even a few hours late.

DR NELSON: There will be patients with breakthrough bleeding/spotting who need to be examined, such as a long-term pill user who reports it for the first time. If you can establish a history of good pill taking with no illnesses or medication interaction which might alter hormone absorption, this woman should be evaluated for infection and anatomic changes like cervical or endometrial polyps.

TABLE 4

Recommendations for Initiating Extended Regimens

Summary

DR SULAK: We are finally seeing the demise of 21/7 contraceptive regimens. Numerous studies of these regimens over the past decade have documented hormone withdrawal symptoms, inadequate pituitary-ovarian suppression, follicular development, and even ovulation. Regimens which shorten or eliminate the 7-day HFI by adding estrogen and providing greater duration of active pills will improve the side effect profile and efficacy.

Oral contraceptives first gave women control over their fertility; now, regimens that extend the cycle and eliminate the HFI give women the option of having fewer hormone withdrawal symptoms. In addition to the convenience of fewer cycles per year, women may experience further benefit from prolonged suppression of ovulation and menstruation.

While breakthrough bleeding and spotting occur with all OCs, the pattern seen with extended regimens differs. It can be managed with patient counseling and brief pill holidays. Additional strategies to manage breakthrough bleeding that should be evaluated in the future include additional estrogen only, nonsteroidal anti-inflammatory drugs, and changing the estrogen dose of the formulation (ie, increasing the dose from 20 mcg EE to 30-35 mcg EE).

Articles of interest

Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

Prospective trial of 1006 sexually active adult women of childbearing potential who received a 91-day extended regimen OC (30 mcg EE/150 mcg LNG) with continuous low-dose EE (10 mcg) during the hormone free interval. Cycle control and safety of the regimen were comparable to that reported for other OCs.

Anderson FD, Gibbons W, Portman D. Long-term safety of an extended-cycle oral contraceptive (Seasonale): a 2-year multicenter open-label extension trial. Am J Obstet Gynecol. 2006;195:92-96.

Long-term safety study of a 91-day extended cycle OC regimen. Overall rates of study discontinuation and incidence of adverse events were similar to those of an earlier Phase 3 clinical trial. The regimen was well tolerated and the numbers of reported bleeding and/or spotting days diminished during the study.

Foster DG, Parvataneni R, de Bocanegra HT, Lewis C, Bradsberry M, Darney P. Number of oral contraceptive pill packages dispensed, method continuation, and costs. Obstet Gynecol. 2006;108:1107-1114.

Evaluation of the effect of the number of cycles of OC pill packages dispensed on the method continuation, pill wastage, use of services, and health care costs among 82,319 women enrolled in the California Family PACT system. Dispensing a year’s supply of OCs during first visits was associated with a higher method continuation and lower health care costs than dispensing fewer cycles per visit.

Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.

A population-based, case-control study of 4575 women with breast cancer and 4682 controls to determine the risk of breast cancer among former and current users of OCs. The relative risk of breast cancer was 1.0 (95% CI, 0.8-1.3) for women who were currently using OCs and 0.9 (95% CI, 0.8-1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. Use of OCs by women with a family history of breast cancer was not associated with an increased risk of breast cancer nor was the initiation of OC use at a young age.

Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception. 1996;54:71-77.

Double-blind, randomized trial to determine the suppressive effect on ovarian activity of OCs administered for 21 or 23 days. Observed differences in 17β-estradiol levels and follicular development between a 21-day and 23-day preparation suggest that shortening the pill-free interval in combined OCs may increase the contraceptive safety margin in women on low-dose formulations.

Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:261-266.

Prospective evaluation to measure the timing, frequency, and severity of hormone-related symptoms in OC users. Pelvic pain, headaches, use of pain medication, bloating or swelling, and breast tenderness occurred significantly more frequently during the 7-day hormone free interval among both current users and new start users of OCs.

Sulak PJ, Kuehl TJ, Coffee A, Willis S. Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen. Am J Obstet Gynecol. 2006;195:935-941.

Single-center, prospective analysis of self-rated menstrual flow during a 21/7 regimen versus a 168-day extended OC regimen. Subjects with a heavier daily flow rating during the 21/7 day cycle tended to have greater daily flow ratings and earlier breakthrough bleeding during the 168-day extension cycle. The 168-day extended regimen had an acceptable bleeding profile with bleeding during the active pill interval effectively managed with institution of a 3-day hormone free interval.

Acknowledgment

The assistance of Kathryn Martin, PharmD, in providing background research and editorial support is acknowledged.

A roundtable discussion among key thought leaders in the area of hormonal contraception was held on October 20, 2006, in New Orleans, Louisiana. These experts addressed the critical questions regarding the practical management of extended regimen oral contraceptives based on information in the medical literature.

Oral contraceptives (OCs) have been available in the United States for nearly 50 years. It is easy to forget that the introduction of reliable oral contraception—a widely available method that allows women control of their fertility—was revolutionary at that time. The decision to use a 28-day pill regimen was not a response to a physiologic need for 13 cycles per year but was dictated by the social norms and pregnancy testing technology of the day. At a time when pregnancy testing was neither easy to perform nor highly sensitive, the 7-day hormone free interval (HFI) provided a monthly reassurance to the OC user that she was not pregnant. Over the ensuing years numerous improvements in oral contraception have taken place—lowering of estrogen content due to safety concerns, confirmation of the efficacy of low-dose pills, introduction of new progestins, and phasic regimens. These changes came about due to a large number of clinical trials and other scientific assessments of OC regimens. Now with research shifted toward reducing the HFI and maximizing ovarian follicular suppression, oral contraception is undergoing a second revolution. By altering or eliminating the HFI, the goal of reducing withdrawal bleeding and minimizing hormone withdrawal can be accomplished.

Both spontaneous menstrual bleeding associated with ovulatory cycles and iatrogenically induced scheduled bleeding associated with OCs are due to endogenous or exogenous hormone withdrawal. However, the similarity ends abruptly, as menstrual bleeding fulfills a physiologic need to slough the secretory endometrium after ovulation in preparation for a new cycle and possible pregnancy. In contrast, there is no health-related reason to bleed while taking OCs. Monthly menstruation in reproductive-age women is necessary unless the patient is pregnant, using hormonal contraception, breastfeeding, or has undergone hysterectomy. A lack of cyclical menstrual bleeding in women not taking hormonal contraception is indicative of a pathologic state, whether it is the hypoestrogenic state of premature ovarian failure or the unopposed estrogen anovulatory state characteristic of women with polycystic ovarian syndrome (TABLE 1). Conversely, the recurrent ovulation and menstruation that is common among today’s post-industrial women is associated with health risks (TABLE 2).

The focus on alteration of the HFI to further improve OC therapy began with the introduction of Mircette^® in 1998.¹ This was followed by the introduction of Seasonale^®, the first extended OC regimen² and subsequently 2 OC products, Yaz^® and Loestrin^® 24 Fe, that maintained the 28-day cycle with a shortened HFI.^3-5 A recently introduced OC product, Seasonique^®, uses an extended 91-day regimen with low-dose ethinyl estradiol (EE) during the HFI, thus eliminating the HFI completely (TABLE 3).⁶

TABLE 1

Conditions Associated With Oligomenorrhea/Amenorrhea

TABLE 2

Health Risks

TABLE 3

OC Products With Extended Regimens or Altered Hormone Free Interval

Are there specific clinical advantages to extended regimen OCs?

DR LONDON: The real advantage to the extended regimens is that they do not have the disadvantages known to exist with the 21/7 regimens.

DR KAUNITZ: There are 4 advantages to extended regimens:

• improvement in contraceptive success
• therapeutic use for hormone withdrawal symptoms
• treatment of gynecologic problems such as dysmenorrhea, endometriosis, and anemia
• accommodation of lifestyle preference

Once women understand that extending combined hormone contraceptives is safe, most will prefer fewer cycles.

DR SULAK: While we need to acknowledge that the decision to introduce the first OCs in a 21/7 regimen was a wise choice nearly 50 years ago, research has shown us that the low doses of EE and the 7-day HFI creates problems—incomplete pituitary-ovarian suppression, endogenous estradiol formation, follicular development, ovarian cyst formation, risk of escape ovulation, and hormone withdrawal symptoms. It doesn’t matter whether a pill, patch, or ring is used—a 7-day HFI is too long with today’s low-dose combined hormonal contraceptives.

Spona was the first to report greater suppression of ovarian activity with a shortened HFI.⁷ By increasing the number of active pills from 21 to 23 per cycle and decreasing the HFI from 7 to 5 days, there was lower residual ovarian activity and endogenous 17β-estradiol. The study also showed that 17β-estradiol levels began to rise during the HFI but the rise was earlier and greater in women assigned to the 21-day regimen.

DR KAUNITZ: Another fundamental issue focuses on the reason our patients use OCs—effective, convenient, and reversible contraception. Unfortunately, the current 21/7 paradigm may not be optimal. The “typical” failure rate with OCs—which is what applies to our patients—is 8%.⁸ I don’t think that is acceptable.

The HFI and the first few days of a new pill pack are the time at which women are at greatest risk for contraceptive failure and unintended pregnancy. By extending the overall duration of active pills and decreasing the duration of the HFI, we are setting our patients up for better contraceptive success.

DR SULAK: There is also the issue of symptoms during the HFI. We all recognize that menstrual symptoms—breast tenderness, headache, bloating, and cramping—increase during the HFI.⁹ Although our data reported significant hormone withdrawal symptoms in women taking OCs, women experience these symptoms with all forms of combined estrogen-progestin hormonal contraceptives regardless of route of administration.

Importantly, the study showed that the symptoms occurred consistently not only in the new start patients, but also in the established users—the women who had been on the pill for more than a year. There is a reason why so many women stop their OCs in less than a year—it’s not because they are feeling wonderful. They may stop because they feel terrible during the HFI.

DR NELSON: The symptoms are real and it is astonishing how many women experience them. Women have become so accustomed to feeling lousy once a month, whether it’s due to menstrual symptoms or hormone withdrawal, that they will not mention it.

Another advantage to extended use of combination estrogen-progestin contraception is the prolonged suppression of ovulation and menstruation, like that produced by the progestin-only regimens, without the negative effects on bone. Given the multitude of problems caused by recurrent ovulation and menstruation, it may be healthier for some women not to have periods every month.

DR KAUNITZ: There are also therapeutic uses for extended regimen OCs that we should not overlook. Decreased dysmenorrhea and menorrhagia are both included in the prescribing information for all OCs. Women suffering from these disorders will likely have additive benefit from extended regimens. In the same vein, the value of extended regimens in managing endometriosis has been known for years.¹⁰

DR SULAK: A very recent paper showed that extending the regimen can improve premenstrual symptoms.¹¹ When symptomatology was compared with that recorded during a 21/7 cycle, there was a significant improvement that was especially apparent in the women who had the greatest variability in their cycles.

Another important finding was that the greatest improvement was detected in the sixth month. That is a key counseling point—you need to stick with the regimen to see the benefits.

What practical advantages does an extended regimen offer to the patient?

DR LONDON: Convenience, convenience, convenience.

MS MOORE: The worst pill to miss in any cycle is the one that is still at the pharmacy. Once your patient has already had 7 hormone-free days, her risk of pregnancy increases with each day of delay in starting a new pack of pills.

DR LONDON: With an extended regimen, that risk occurs fewer times per year. Just as the change from 50-mcg pills to low-dose pills was an improvement, the extension of the regimen beyond 28 days is a real improvement in OC therapy.

DR NELSON: Access to pills is a real issue—it’s more than having to go to the pharmacy every few weeks. A recent paper from the California Family PACT (Planning, Access, Care and Treatment) Program showed that women who were dispensed a year’s supply of OCs at their first visit were more likely to continue therapy, were more likely to receive Papanicolaou tests and Chlamydia tests, and actually had a lower annual women’s health care–related costs than women who were dispensed 3 cycles.¹²

We recently presented data that support this conclusion—hormonal method continuation rates were higher among women who received 3 pill packs than in those who received only 1. Having the supply of pills available is one more way of promoting contraceptive success.

Are there side effects that are specific to the extended regimen OCs?

DR SULAK: We are in consensus that there are no side effects that are specific to the extended regimen OCs. The only side effect found to be increased with extended regimen is unscheduled bleeding, but some studies have shown less bleeding overall.¹³ Studies have shown a decrease in many typical side effects seen with 21/7 OCs such as premenstrual syndrome and headaches.¹⁴

DR KAUNITZ: I agree. We should, however, address unscheduled bleeding and spotting. It’s something that we see with every OC, but extending the regimen changes the pattern.

A number of years ago, a randomized trial showed that addition of low-dose estrogen to the HFI provided superior cycle control to that of a 20-mcg EE OC and similar to that reported with a 35-mcg pill.¹⁵ There are more recent data that suggest that once you have passed the first cycle, addition of low-dose estrogen to the HFI also improves unscheduled bleeding in 91-day regimens.⁶

MS MOORE: Patients must understand there will be some unscheduled bleeding/spotting as their endometrium transitions from a monthly cycle or withdrawal bleed to more complete ovarian suppression, but it is manageable.

DR LONDON: Some clinicians have concerns about estrogen exposure—specifically the risk of venous thromboembolism and breast cancer. When the published data regarding extended regimens are examined in total, the safety profile is virtually the same as for 21/7. The safety of 91-day regimens have been demonstrated in both 1-year trials as well as longer-term 2-year studies.^2,6,16

The Women’s CARE (Contraceptive and Reproductive Experiences) study really put concerns about the association of OC use and breast cancer to rest.¹⁷ There was no evidence of increased risk of breast cancer in either current or past users of OCs. Given that the study included women who had taken high-dose 50-mcg EE pills, it’s very reasonable to conclude that extended OC use poses no increased risk of breast cancer.

What can be done to ensure that an extended regimen is offered to all OC-appropriate patients regardless of age or pathology?

DR KAUNITZ: We still need to work on overcoming common misconceptions. Despite more than 45 years of use, a fundamental lack of understanding of how OCs work persists among patients and health care professionals outside the field of women’s health.

MS MOORE: Many of my students are incredulous when they realize that there is no physiologic reason for the 7-day HFI and cyclical bleeding for women taking OCs.

DR LONDON: We also need to dispel the myth that women taking OCs are having periods. Remember that no women taking an OC has a period. They have withdrawal bleeding.

DR SULAK: Extended regimens set my patients up for contraceptive success and should be considered for all women who are candidates for OCs. The advantages—avoidance of monthly withdrawal symptoms, less follicular development, and, overall, less bleeding—outweigh the issues of unscheduled bleeding and spotting.

DR NELSON: We should discuss bleeding with our patients and, perhaps, it is time to turn the tables and ask her why she feels the need to bleed every month. For women considering use of OCs, it opens up the conversation to use of regimens other than 21/7. For women who are established users of OCs, asking whether they are having symptoms every month will open up the same conversation.

DR KAUNITZ: We’re not here to suggest that women should no longer menstruate or that women should no longer experience monthly bleeding.

It’s all about choice. Using hormones not only to provide safe, effective contraception but also to allow women the option of choosing when to bleed is a second revolution in contraception.

With regard to symptoms, I ask about grouchiness. “Do you get headaches or feel grouchy or down during your HFI?” If the answer is yes, it moves the conversation in the direction of extended regimens.

MS MOORE: I agree. The extended regimen has become mainstream over the past couple of years—the only reason I can see for using 21/7 is if the patient demands it or if reimbursement drives the issue.

How important is breakthrough bleeding in OC product selection?

DR KAUNITZ: Breakthrough bleeding occurs with all OC products—it’s importance becomes a matter of how well you have prepared patients for it.

MS MOORE: I like to tell my patients that it is likely they will experience some breakthrough bleeding in the early cycles. Then they are prepared and those who do not have any are pleasantly surprised.

DR SULAK: It’s inevitable and it can be managed—to me, it’s more important to focus on eliminating hormone withdrawal symptoms.

Are all combined hormonal contraceptive products appropriate for use in extended regimens?

DR NELSON: At this time there are insufficient data regarding the safety and pharmacokinetics of extended regimen use of the transdermal patch. Until studies evaluating its use in multiple extended cycles become available, we cannot recommend its use in extended regimens.¹⁸

DR KAUNITZ: Traditional 21/7 pill packs can be used in extended regimens but I find this approach often poses challenges for the patient—from remembering not to take placebo pills to reimbursement to trips to the pharmacy every 3 weeks for a new pill pack.

DR LONDON: It seems intuitive that the multiphasic pills would not be optimal for use in extended regimens. Given the paucity of data supporting their use, I would not recommend initiating an extended regimen with a mutiphasic pill. I certainly would allow a patient who is using them successfully to continue.

What are practical options to manage breakthrough bleeding in patients taking extended regimen OCs?

DR SULAK: We find that patients usually don’t begin to have unscheduled bleeding until week 4 or later. In our prospective study, we found that women who had heavier daily flow ratings during the 21/7 lead-in cycle tended to have greater daily flow ratings and earlier occurrence of unscheduled bleeding when taking an extended regimen.¹³ We also showed that a 3-day pill holiday was helpful in managing breakthrough bleeding and/or spotting that had persisted for 7 consecutive days (TABLE 4).

MS MOORE: Essentially patients have 2 options: endure the bleeding or take a brief pill holiday. I let my patients decide—some are very bothered by even the slightest amount of breakthrough bleeding while others have no issue with it. The worse thing a patient can do is to stop taking pills without a back-up plan for contraception. It is critical that they take at least 3 weeks of active pills between drug holidays.

DR LONDON: It’s also important to remember that you cannot use a 3-day pill holiday to manage breakthrough bleeding/spotting with 21/7 regimens as the increased number of hormone-free days per cycle could lead to a greater chance of escape ovulation.

DR KAUNITZ: Let’s not forget the value of counseling. Just letting women know what to expect and what to do has certainly been proven to be valuable in improving continuation rates among women on other forms of long-term contraception^19,20 and would without doubt be beneficial for women receiving extended regimens (SIDEBAR).

DR SULAK: With the low-dose OCs, it is especially important to let the patient know at the time you write the prescription that she has to take her pills at about the same time each day. I have had patients tell me that they experience bleeding if they take their pills even a few hours late.

DR NELSON: There will be patients with breakthrough bleeding/spotting who need to be examined, such as a long-term pill user who reports it for the first time. If you can establish a history of good pill taking with no illnesses or medication interaction which might alter hormone absorption, this woman should be evaluated for infection and anatomic changes like cervical or endometrial polyps.

TABLE 4

Recommendations for Initiating Extended Regimens

Summary

DR SULAK: We are finally seeing the demise of 21/7 contraceptive regimens. Numerous studies of these regimens over the past decade have documented hormone withdrawal symptoms, inadequate pituitary-ovarian suppression, follicular development, and even ovulation. Regimens which shorten or eliminate the 7-day HFI by adding estrogen and providing greater duration of active pills will improve the side effect profile and efficacy.

Oral contraceptives first gave women control over their fertility; now, regimens that extend the cycle and eliminate the HFI give women the option of having fewer hormone withdrawal symptoms. In addition to the convenience of fewer cycles per year, women may experience further benefit from prolonged suppression of ovulation and menstruation.

While breakthrough bleeding and spotting occur with all OCs, the pattern seen with extended regimens differs. It can be managed with patient counseling and brief pill holidays. Additional strategies to manage breakthrough bleeding that should be evaluated in the future include additional estrogen only, nonsteroidal anti-inflammatory drugs, and changing the estrogen dose of the formulation (ie, increasing the dose from 20 mcg EE to 30-35 mcg EE).

Articles of interest

Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

Prospective trial of 1006 sexually active adult women of childbearing potential who received a 91-day extended regimen OC (30 mcg EE/150 mcg LNG) with continuous low-dose EE (10 mcg) during the hormone free interval. Cycle control and safety of the regimen were comparable to that reported for other OCs.

Anderson FD, Gibbons W, Portman D. Long-term safety of an extended-cycle oral contraceptive (Seasonale): a 2-year multicenter open-label extension trial. Am J Obstet Gynecol. 2006;195:92-96.

Long-term safety study of a 91-day extended cycle OC regimen. Overall rates of study discontinuation and incidence of adverse events were similar to those of an earlier Phase 3 clinical trial. The regimen was well tolerated and the numbers of reported bleeding and/or spotting days diminished during the study.

Foster DG, Parvataneni R, de Bocanegra HT, Lewis C, Bradsberry M, Darney P. Number of oral contraceptive pill packages dispensed, method continuation, and costs. Obstet Gynecol. 2006;108:1107-1114.

Evaluation of the effect of the number of cycles of OC pill packages dispensed on the method continuation, pill wastage, use of services, and health care costs among 82,319 women enrolled in the California Family PACT system. Dispensing a year’s supply of OCs during first visits was associated with a higher method continuation and lower health care costs than dispensing fewer cycles per visit.

Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.

A population-based, case-control study of 4575 women with breast cancer and 4682 controls to determine the risk of breast cancer among former and current users of OCs. The relative risk of breast cancer was 1.0 (95% CI, 0.8-1.3) for women who were currently using OCs and 0.9 (95% CI, 0.8-1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. Use of OCs by women with a family history of breast cancer was not associated with an increased risk of breast cancer nor was the initiation of OC use at a young age.

Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception. 1996;54:71-77.

Double-blind, randomized trial to determine the suppressive effect on ovarian activity of OCs administered for 21 or 23 days. Observed differences in 17β-estradiol levels and follicular development between a 21-day and 23-day preparation suggest that shortening the pill-free interval in combined OCs may increase the contraceptive safety margin in women on low-dose formulations.

Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:261-266.

Prospective evaluation to measure the timing, frequency, and severity of hormone-related symptoms in OC users. Pelvic pain, headaches, use of pain medication, bloating or swelling, and breast tenderness occurred significantly more frequently during the 7-day hormone free interval among both current users and new start users of OCs.

Sulak PJ, Kuehl TJ, Coffee A, Willis S. Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen. Am J Obstet Gynecol. 2006;195:935-941.

Single-center, prospective analysis of self-rated menstrual flow during a 21/7 regimen versus a 168-day extended OC regimen. Subjects with a heavier daily flow rating during the 21/7 day cycle tended to have greater daily flow ratings and earlier breakthrough bleeding during the 168-day extension cycle. The 168-day extended regimen had an acceptable bleeding profile with bleeding during the active pill interval effectively managed with institution of a 3-day hormone free interval.

Acknowledgment

The assistance of Kathryn Martin, PharmD, in providing background research and editorial support is acknowledged.

A roundtable discussion among key thought leaders in the area of hormonal contraception was held on October 20, 2006, in New Orleans, Louisiana. These experts addressed the critical questions regarding the practical management of extended regimen oral contraceptives based on information in the medical literature.

Oral contraceptives (OCs) have been available in the United States for nearly 50 years. It is easy to forget that the introduction of reliable oral contraception—a widely available method that allows women control of their fertility—was revolutionary at that time. The decision to use a 28-day pill regimen was not a response to a physiologic need for 13 cycles per year but was dictated by the social norms and pregnancy testing technology of the day. At a time when pregnancy testing was neither easy to perform nor highly sensitive, the 7-day hormone free interval (HFI) provided a monthly reassurance to the OC user that she was not pregnant. Over the ensuing years numerous improvements in oral contraception have taken place—lowering of estrogen content due to safety concerns, confirmation of the efficacy of low-dose pills, introduction of new progestins, and phasic regimens. These changes came about due to a large number of clinical trials and other scientific assessments of OC regimens. Now with research shifted toward reducing the HFI and maximizing ovarian follicular suppression, oral contraception is undergoing a second revolution. By altering or eliminating the HFI, the goal of reducing withdrawal bleeding and minimizing hormone withdrawal can be accomplished.

Both spontaneous menstrual bleeding associated with ovulatory cycles and iatrogenically induced scheduled bleeding associated with OCs are due to endogenous or exogenous hormone withdrawal. However, the similarity ends abruptly, as menstrual bleeding fulfills a physiologic need to slough the secretory endometrium after ovulation in preparation for a new cycle and possible pregnancy. In contrast, there is no health-related reason to bleed while taking OCs. Monthly menstruation in reproductive-age women is necessary unless the patient is pregnant, using hormonal contraception, breastfeeding, or has undergone hysterectomy. A lack of cyclical menstrual bleeding in women not taking hormonal contraception is indicative of a pathologic state, whether it is the hypoestrogenic state of premature ovarian failure or the unopposed estrogen anovulatory state characteristic of women with polycystic ovarian syndrome (TABLE 1). Conversely, the recurrent ovulation and menstruation that is common among today’s post-industrial women is associated with health risks (TABLE 2).

The focus on alteration of the HFI to further improve OC therapy began with the introduction of Mircette^® in 1998.¹ This was followed by the introduction of Seasonale^®, the first extended OC regimen² and subsequently 2 OC products, Yaz^® and Loestrin^® 24 Fe, that maintained the 28-day cycle with a shortened HFI.^3-5 A recently introduced OC product, Seasonique^®, uses an extended 91-day regimen with low-dose ethinyl estradiol (EE) during the HFI, thus eliminating the HFI completely (TABLE 3).⁶

TABLE 1

Conditions Associated With Oligomenorrhea/Amenorrhea

TABLE 2

Health Risks

TABLE 3

OC Products With Extended Regimens or Altered Hormone Free Interval

Are there specific clinical advantages to extended regimen OCs?

DR LONDON: The real advantage to the extended regimens is that they do not have the disadvantages known to exist with the 21/7 regimens.

DR KAUNITZ: There are 4 advantages to extended regimens:

• improvement in contraceptive success
• therapeutic use for hormone withdrawal symptoms
• treatment of gynecologic problems such as dysmenorrhea, endometriosis, and anemia
• accommodation of lifestyle preference

Once women understand that extending combined hormone contraceptives is safe, most will prefer fewer cycles.

DR SULAK: While we need to acknowledge that the decision to introduce the first OCs in a 21/7 regimen was a wise choice nearly 50 years ago, research has shown us that the low doses of EE and the 7-day HFI creates problems—incomplete pituitary-ovarian suppression, endogenous estradiol formation, follicular development, ovarian cyst formation, risk of escape ovulation, and hormone withdrawal symptoms. It doesn’t matter whether a pill, patch, or ring is used—a 7-day HFI is too long with today’s low-dose combined hormonal contraceptives.

Spona was the first to report greater suppression of ovarian activity with a shortened HFI.⁷ By increasing the number of active pills from 21 to 23 per cycle and decreasing the HFI from 7 to 5 days, there was lower residual ovarian activity and endogenous 17β-estradiol. The study also showed that 17β-estradiol levels began to rise during the HFI but the rise was earlier and greater in women assigned to the 21-day regimen.

DR KAUNITZ: Another fundamental issue focuses on the reason our patients use OCs—effective, convenient, and reversible contraception. Unfortunately, the current 21/7 paradigm may not be optimal. The “typical” failure rate with OCs—which is what applies to our patients—is 8%.⁸ I don’t think that is acceptable.

The HFI and the first few days of a new pill pack are the time at which women are at greatest risk for contraceptive failure and unintended pregnancy. By extending the overall duration of active pills and decreasing the duration of the HFI, we are setting our patients up for better contraceptive success.

DR SULAK: There is also the issue of symptoms during the HFI. We all recognize that menstrual symptoms—breast tenderness, headache, bloating, and cramping—increase during the HFI.⁹ Although our data reported significant hormone withdrawal symptoms in women taking OCs, women experience these symptoms with all forms of combined estrogen-progestin hormonal contraceptives regardless of route of administration.

Importantly, the study showed that the symptoms occurred consistently not only in the new start patients, but also in the established users—the women who had been on the pill for more than a year. There is a reason why so many women stop their OCs in less than a year—it’s not because they are feeling wonderful. They may stop because they feel terrible during the HFI.

DR NELSON: The symptoms are real and it is astonishing how many women experience them. Women have become so accustomed to feeling lousy once a month, whether it’s due to menstrual symptoms or hormone withdrawal, that they will not mention it.

Another advantage to extended use of combination estrogen-progestin contraception is the prolonged suppression of ovulation and menstruation, like that produced by the progestin-only regimens, without the negative effects on bone. Given the multitude of problems caused by recurrent ovulation and menstruation, it may be healthier for some women not to have periods every month.

DR KAUNITZ: There are also therapeutic uses for extended regimen OCs that we should not overlook. Decreased dysmenorrhea and menorrhagia are both included in the prescribing information for all OCs. Women suffering from these disorders will likely have additive benefit from extended regimens. In the same vein, the value of extended regimens in managing endometriosis has been known for years.¹⁰

DR SULAK: A very recent paper showed that extending the regimen can improve premenstrual symptoms.¹¹ When symptomatology was compared with that recorded during a 21/7 cycle, there was a significant improvement that was especially apparent in the women who had the greatest variability in their cycles.

Another important finding was that the greatest improvement was detected in the sixth month. That is a key counseling point—you need to stick with the regimen to see the benefits.

What practical advantages does an extended regimen offer to the patient?

DR LONDON: Convenience, convenience, convenience.

MS MOORE: The worst pill to miss in any cycle is the one that is still at the pharmacy. Once your patient has already had 7 hormone-free days, her risk of pregnancy increases with each day of delay in starting a new pack of pills.

DR LONDON: With an extended regimen, that risk occurs fewer times per year. Just as the change from 50-mcg pills to low-dose pills was an improvement, the extension of the regimen beyond 28 days is a real improvement in OC therapy.

DR NELSON: Access to pills is a real issue—it’s more than having to go to the pharmacy every few weeks. A recent paper from the California Family PACT (Planning, Access, Care and Treatment) Program showed that women who were dispensed a year’s supply of OCs at their first visit were more likely to continue therapy, were more likely to receive Papanicolaou tests and Chlamydia tests, and actually had a lower annual women’s health care–related costs than women who were dispensed 3 cycles.¹²

We recently presented data that support this conclusion—hormonal method continuation rates were higher among women who received 3 pill packs than in those who received only 1. Having the supply of pills available is one more way of promoting contraceptive success.

Are there side effects that are specific to the extended regimen OCs?

DR SULAK: We are in consensus that there are no side effects that are specific to the extended regimen OCs. The only side effect found to be increased with extended regimen is unscheduled bleeding, but some studies have shown less bleeding overall.¹³ Studies have shown a decrease in many typical side effects seen with 21/7 OCs such as premenstrual syndrome and headaches.¹⁴

DR KAUNITZ: I agree. We should, however, address unscheduled bleeding and spotting. It’s something that we see with every OC, but extending the regimen changes the pattern.

A number of years ago, a randomized trial showed that addition of low-dose estrogen to the HFI provided superior cycle control to that of a 20-mcg EE OC and similar to that reported with a 35-mcg pill.¹⁵ There are more recent data that suggest that once you have passed the first cycle, addition of low-dose estrogen to the HFI also improves unscheduled bleeding in 91-day regimens.⁶

MS MOORE: Patients must understand there will be some unscheduled bleeding/spotting as their endometrium transitions from a monthly cycle or withdrawal bleed to more complete ovarian suppression, but it is manageable.

DR LONDON: Some clinicians have concerns about estrogen exposure—specifically the risk of venous thromboembolism and breast cancer. When the published data regarding extended regimens are examined in total, the safety profile is virtually the same as for 21/7. The safety of 91-day regimens have been demonstrated in both 1-year trials as well as longer-term 2-year studies.^2,6,16

The Women’s CARE (Contraceptive and Reproductive Experiences) study really put concerns about the association of OC use and breast cancer to rest.¹⁷ There was no evidence of increased risk of breast cancer in either current or past users of OCs. Given that the study included women who had taken high-dose 50-mcg EE pills, it’s very reasonable to conclude that extended OC use poses no increased risk of breast cancer.

What can be done to ensure that an extended regimen is offered to all OC-appropriate patients regardless of age or pathology?

DR KAUNITZ: We still need to work on overcoming common misconceptions. Despite more than 45 years of use, a fundamental lack of understanding of how OCs work persists among patients and health care professionals outside the field of women’s health.

MS MOORE: Many of my students are incredulous when they realize that there is no physiologic reason for the 7-day HFI and cyclical bleeding for women taking OCs.

DR LONDON: We also need to dispel the myth that women taking OCs are having periods. Remember that no women taking an OC has a period. They have withdrawal bleeding.

DR SULAK: Extended regimens set my patients up for contraceptive success and should be considered for all women who are candidates for OCs. The advantages—avoidance of monthly withdrawal symptoms, less follicular development, and, overall, less bleeding—outweigh the issues of unscheduled bleeding and spotting.

DR NELSON: We should discuss bleeding with our patients and, perhaps, it is time to turn the tables and ask her why she feels the need to bleed every month. For women considering use of OCs, it opens up the conversation to use of regimens other than 21/7. For women who are established users of OCs, asking whether they are having symptoms every month will open up the same conversation.

DR KAUNITZ: We’re not here to suggest that women should no longer menstruate or that women should no longer experience monthly bleeding.

It’s all about choice. Using hormones not only to provide safe, effective contraception but also to allow women the option of choosing when to bleed is a second revolution in contraception.

With regard to symptoms, I ask about grouchiness. “Do you get headaches or feel grouchy or down during your HFI?” If the answer is yes, it moves the conversation in the direction of extended regimens.

MS MOORE: I agree. The extended regimen has become mainstream over the past couple of years—the only reason I can see for using 21/7 is if the patient demands it or if reimbursement drives the issue.

How important is breakthrough bleeding in OC product selection?

DR KAUNITZ: Breakthrough bleeding occurs with all OC products—it’s importance becomes a matter of how well you have prepared patients for it.

MS MOORE: I like to tell my patients that it is likely they will experience some breakthrough bleeding in the early cycles. Then they are prepared and those who do not have any are pleasantly surprised.

DR SULAK: It’s inevitable and it can be managed—to me, it’s more important to focus on eliminating hormone withdrawal symptoms.

Are all combined hormonal contraceptive products appropriate for use in extended regimens?

DR NELSON: At this time there are insufficient data regarding the safety and pharmacokinetics of extended regimen use of the transdermal patch. Until studies evaluating its use in multiple extended cycles become available, we cannot recommend its use in extended regimens.¹⁸

DR KAUNITZ: Traditional 21/7 pill packs can be used in extended regimens but I find this approach often poses challenges for the patient—from remembering not to take placebo pills to reimbursement to trips to the pharmacy every 3 weeks for a new pill pack.

DR LONDON: It seems intuitive that the multiphasic pills would not be optimal for use in extended regimens. Given the paucity of data supporting their use, I would not recommend initiating an extended regimen with a mutiphasic pill. I certainly would allow a patient who is using them successfully to continue.

What are practical options to manage breakthrough bleeding in patients taking extended regimen OCs?

DR SULAK: We find that patients usually don’t begin to have unscheduled bleeding until week 4 or later. In our prospective study, we found that women who had heavier daily flow ratings during the 21/7 lead-in cycle tended to have greater daily flow ratings and earlier occurrence of unscheduled bleeding when taking an extended regimen.¹³ We also showed that a 3-day pill holiday was helpful in managing breakthrough bleeding and/or spotting that had persisted for 7 consecutive days (TABLE 4).

MS MOORE: Essentially patients have 2 options: endure the bleeding or take a brief pill holiday. I let my patients decide—some are very bothered by even the slightest amount of breakthrough bleeding while others have no issue with it. The worse thing a patient can do is to stop taking pills without a back-up plan for contraception. It is critical that they take at least 3 weeks of active pills between drug holidays.

DR LONDON: It’s also important to remember that you cannot use a 3-day pill holiday to manage breakthrough bleeding/spotting with 21/7 regimens as the increased number of hormone-free days per cycle could lead to a greater chance of escape ovulation.

DR KAUNITZ: Let’s not forget the value of counseling. Just letting women know what to expect and what to do has certainly been proven to be valuable in improving continuation rates among women on other forms of long-term contraception^19,20 and would without doubt be beneficial for women receiving extended regimens (SIDEBAR).

DR SULAK: With the low-dose OCs, it is especially important to let the patient know at the time you write the prescription that she has to take her pills at about the same time each day. I have had patients tell me that they experience bleeding if they take their pills even a few hours late.

DR NELSON: There will be patients with breakthrough bleeding/spotting who need to be examined, such as a long-term pill user who reports it for the first time. If you can establish a history of good pill taking with no illnesses or medication interaction which might alter hormone absorption, this woman should be evaluated for infection and anatomic changes like cervical or endometrial polyps.

TABLE 4

Recommendations for Initiating Extended Regimens

Summary

DR SULAK: We are finally seeing the demise of 21/7 contraceptive regimens. Numerous studies of these regimens over the past decade have documented hormone withdrawal symptoms, inadequate pituitary-ovarian suppression, follicular development, and even ovulation. Regimens which shorten or eliminate the 7-day HFI by adding estrogen and providing greater duration of active pills will improve the side effect profile and efficacy.

Oral contraceptives first gave women control over their fertility; now, regimens that extend the cycle and eliminate the HFI give women the option of having fewer hormone withdrawal symptoms. In addition to the convenience of fewer cycles per year, women may experience further benefit from prolonged suppression of ovulation and menstruation.

While breakthrough bleeding and spotting occur with all OCs, the pattern seen with extended regimens differs. It can be managed with patient counseling and brief pill holidays. Additional strategies to manage breakthrough bleeding that should be evaluated in the future include additional estrogen only, nonsteroidal anti-inflammatory drugs, and changing the estrogen dose of the formulation (ie, increasing the dose from 20 mcg EE to 30-35 mcg EE).

Articles of interest

Anderson FD, Gibbons W, Portman D. Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol. Contraception. 2006;73:229-234.

Prospective trial of 1006 sexually active adult women of childbearing potential who received a 91-day extended regimen OC (30 mcg EE/150 mcg LNG) with continuous low-dose EE (10 mcg) during the hormone free interval. Cycle control and safety of the regimen were comparable to that reported for other OCs.

Anderson FD, Gibbons W, Portman D. Long-term safety of an extended-cycle oral contraceptive (Seasonale): a 2-year multicenter open-label extension trial. Am J Obstet Gynecol. 2006;195:92-96.

Long-term safety study of a 91-day extended cycle OC regimen. Overall rates of study discontinuation and incidence of adverse events were similar to those of an earlier Phase 3 clinical trial. The regimen was well tolerated and the numbers of reported bleeding and/or spotting days diminished during the study.

Foster DG, Parvataneni R, de Bocanegra HT, Lewis C, Bradsberry M, Darney P. Number of oral contraceptive pill packages dispensed, method continuation, and costs. Obstet Gynecol. 2006;108:1107-1114.

Evaluation of the effect of the number of cycles of OC pill packages dispensed on the method continuation, pill wastage, use of services, and health care costs among 82,319 women enrolled in the California Family PACT system. Dispensing a year’s supply of OCs during first visits was associated with a higher method continuation and lower health care costs than dispensing fewer cycles per visit.

Marchbanks PA, McDonald JA, Wilson HG, et al. Oral contraceptives and the risk of breast cancer. N Engl J Med. 2002;346:2025-2032.

A population-based, case-control study of 4575 women with breast cancer and 4682 controls to determine the risk of breast cancer among former and current users of OCs. The relative risk of breast cancer was 1.0 (95% CI, 0.8-1.3) for women who were currently using OCs and 0.9 (95% CI, 0.8-1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. Use of OCs by women with a family history of breast cancer was not associated with an increased risk of breast cancer nor was the initiation of OC use at a young age.

Spona J, Elstein M, Feichtinger W, et al. Shorter pill-free interval in combined oral contraceptives decreases follicular development. Contraception. 1996;54:71-77.

Double-blind, randomized trial to determine the suppressive effect on ovarian activity of OCs administered for 21 or 23 days. Observed differences in 17β-estradiol levels and follicular development between a 21-day and 23-day preparation suggest that shortening the pill-free interval in combined OCs may increase the contraceptive safety margin in women on low-dose formulations.

Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol. 2000;95:261-266.

Prospective evaluation to measure the timing, frequency, and severity of hormone-related symptoms in OC users. Pelvic pain, headaches, use of pain medication, bloating or swelling, and breast tenderness occurred significantly more frequently during the 7-day hormone free interval among both current users and new start users of OCs.

Sulak PJ, Kuehl TJ, Coffee A, Willis S. Prospective analysis of occurrence and management of breakthrough bleeding during an extended oral contraceptive regimen. Am J Obstet Gynecol. 2006;195:935-941.

Single-center, prospective analysis of self-rated menstrual flow during a 21/7 regimen versus a 168-day extended OC regimen. Subjects with a heavier daily flow rating during the 21/7 day cycle tended to have greater daily flow ratings and earlier breakthrough bleeding during the 168-day extension cycle. The 168-day extended regimen had an acceptable bleeding profile with bleeding during the active pill interval effectively managed with institution of a 3-day hormone free interval.

Acknowledgment

The assistance of Kathryn Martin, PharmD, in providing background research and editorial support is acknowledged.

Compared with today’s women, who have access to effective birth control, past generations had earlier and more frequent childbearing, longer periods of breastfeeding, later menarche, and earlier menopause. During their reproductive years, they were more likely than today’s women to be pregnant or breast-feeding than to be menstruating, and they had far fewer total menstrual episodes during their lifetimes.

As a result, today’s woman is more likely to have menstruation-related gynecologic complaints, which lead to diagnostic tests and surgical procedures. Indeed, as Ob/Gyns are all too aware, menstrual disorders and premenstrual symptoms account for a significant proportion of office visits. Furthermore, when these problems recur month after month for years, ovulation and menstruation may be associated with anemia, endometriosis, ovarian cysts, and increased risk of ovarian cancer.

Survey: Most women prefer less-frequent periods

Although some women like having a period each month, most would prefer less-frequent periods to prevent the problems associated with monthly menstruation, according to a recent investigation.¹ These findings were similar to those of other studies.

Active pills can be extended by a specific number of consecutive weeks or by continuous days until breakthrough bleeding occurs.

In a telephone survey of more than 1,300 women in The Netherlands, 80% of currently menstruating women said they would prefer 1 or more changes in bleeding patterns, including less-painful menses, shorter menses, lighter menses, and even no menses.¹ The majority (about 70% on average across 3 age groups: 15 to 19 years, 25 to 34 years, and 45 to 49 years) selected bleeding intervals ranging from every 3 months to never, and the remaining 30% said they would prefer monthly menses (TABLE 1). Told that menstruation can be manipulated by OCs, women expressed similar bleeding-frequency preferences.

TABLE 1

Preferred frequency of menses¹

Effects of contraceptives on menses

Among the contraceptives that can significantly alter menstruation patterns are depot medroxyprogesterone acetate (DMPA), levonorgestrel implants, oral contraceptives (OCs), and the levonorgestrel intrauterine device (IUD). Which of these methods is best for an individual woman depends on her bleeding preferences, as well as traditional considerations such as efficacy, convenience, cost, health status, and side effects. Counseling women about alterations in menstruation is a critical component of initiating and continuing contraception. Attitudes about menstruation greatly influence contraceptive choices and affect a woman’s adherence to a particular method.

DMPA, which must be injected every 3 months, causes menstrual changes in almost all users. In most women, bleeding patterns are unpredictable in the first few months of use; the frequency and length of bleeding episodes then decrease, with most patients becoming amenorrheic over time.

Levonorgestrel implants, which are inserted subcutaneously in the upper arm, cause irregular bleeding in about two thirds of women during the first year of use. About a quarter continue to have regular menses, and a minority (about 10%) have no menses at all. After 5 years, most women resume a regular bleeding pattern.

Levonorgestrel IUDs reduce menstrual bleeding because the levonorgestrel released from the device inhibits the endometrial proliferation that normally would occur during the ovulatory cycle. This endometrial suppression is a local effect and is not immediate. The uterine lining thins only after several months. As a result, the user spots frequently during the first 4 months of use. After 12 months, bleeding is greatly diminished in about 80% of women and is completely lacking in the remaining 20%. The levonorgestrel IUD is one of the most effective means available for reducing menstrual blood loss.

OCs, the most popular form of reversible contraception in the United States, help regulate cycle length, making the timing of menses more predictable. Bleeding duration and volume are decreased in most users, as is dysmenorrhea.

Troublesome symptoms during the hormone-free interval can be alleviated by reducing that interval to 4 days.

Until recently, OCs typically contained 21 days of estrogen plus a progestin and 7 hormone-free days. The rationale for this design was to mimic an average cycle length of 28 days. Also, by limiting active pills to 21 days, spotting and breakthrough bleeding were minimal after several months of use. The drawback of this design is its association with monthly hormone-withdrawal symptoms. A study of these symptoms in OC users confirmed that pelvic pain, headaches, breast tenderness, bloating, swelling, and the use of pain medicines were more common during the 7-day hormone-free interval, compared with the 21 active days (TABLE 2).²

TABLE 2

Hormone withdrawal symptoms in oral contraceptive users²

Extending active pills delays menses

Extending the duration of active OC pills delays menses and reduces hormone-withdrawal symptoms.

• In a series of 50 patients with menstrual disorders who were offered extension of their active tablets to delay menses, 75% were stabilized on an extended regimen, with the most common pattern being 12 weeks of active pills.³ About one quarter of the patients discontinued OCs or returned to the standard regimen—3 weeks of active pills.
  
• In a follow-up study of 292 patients on OCs who experienced hormone-withdrawal symptoms, 92% of women who were offered extension of their active pills agreed to try the lengthened pattern.⁴ Of the women who accepted the extended regimen, 19% discontinued OCs, and 13% extended active pills but then returned to a standard regimen. One hundred seventy-two patients (59%) maintained the extended pattern. The typical pattern was 12±12 weeks of active pills, with a median of 9 weeks and a range of up to 104 consecutive weeks. Patients also were given the option of decreasing the number of hormone-free days. The typical hormone-free interval was 6±2 days, with a median of 5 days and a range of 0 to 7 days.
  

Factors to consider for extended OC regimens

When extending OC regimens, clinicians need to consider several factors.

If patients are taking OCs for the first time, the best course may be to rely on the standard regimen for the first 2 months because of the high incidence of breakthrough bleeding and spotting when OCs are initiated. After this time, if the patient has hormone-withdrawal symptoms or simply wants to delay menses, she can try extending the active pills.

The patient must be warned that although she can go off pills for up to 7 days, the hormone-free interval should never be any longer.

Active pills can be extended in several ways. The patient can take pills for a specific number of consecutive weeks (such as 6, 9, or 12 weeks). Or, she can simply continue taking consecutive active pills until breakthrough bleeding occurs. She then should observe a 7-day (or shorter) hormone-free interval and restart the OCs.

Troublesome symptoms during the hormone-free interval can be alleviated by reducing that interval to 4 days. The patient must be warned, however, that although she can go off pills for up to 7 days, the hormone-free interval should never be any longer.

Making sure the patient understands and is comfortable with this extended regimen is extremely important.

Future options

Although current contraceptive methods allow clinicians to address patient preferences about menstrual patterns, even more options may well be available in the future. Studies of an 84-day/7-day OC regimen are underway.

Dr. Sulak has served on the speaker’s bureau for and received research support from Berlex, Eli Lilly, Organon, Ortho, and Wyeth.

Compared with today’s women, who have access to effective birth control, past generations had earlier and more frequent childbearing, longer periods of breastfeeding, later menarche, and earlier menopause. During their reproductive years, they were more likely than today’s women to be pregnant or breast-feeding than to be menstruating, and they had far fewer total menstrual episodes during their lifetimes.

As a result, today’s woman is more likely to have menstruation-related gynecologic complaints, which lead to diagnostic tests and surgical procedures. Indeed, as Ob/Gyns are all too aware, menstrual disorders and premenstrual symptoms account for a significant proportion of office visits. Furthermore, when these problems recur month after month for years, ovulation and menstruation may be associated with anemia, endometriosis, ovarian cysts, and increased risk of ovarian cancer.

Survey: Most women prefer less-frequent periods

Although some women like having a period each month, most would prefer less-frequent periods to prevent the problems associated with monthly menstruation, according to a recent investigation.¹ These findings were similar to those of other studies.

Active pills can be extended by a specific number of consecutive weeks or by continuous days until breakthrough bleeding occurs.

In a telephone survey of more than 1,300 women in The Netherlands, 80% of currently menstruating women said they would prefer 1 or more changes in bleeding patterns, including less-painful menses, shorter menses, lighter menses, and even no menses.¹ The majority (about 70% on average across 3 age groups: 15 to 19 years, 25 to 34 years, and 45 to 49 years) selected bleeding intervals ranging from every 3 months to never, and the remaining 30% said they would prefer monthly menses (TABLE 1). Told that menstruation can be manipulated by OCs, women expressed similar bleeding-frequency preferences.

TABLE 1

Preferred frequency of menses¹

Effects of contraceptives on menses

Among the contraceptives that can significantly alter menstruation patterns are depot medroxyprogesterone acetate (DMPA), levonorgestrel implants, oral contraceptives (OCs), and the levonorgestrel intrauterine device (IUD). Which of these methods is best for an individual woman depends on her bleeding preferences, as well as traditional considerations such as efficacy, convenience, cost, health status, and side effects. Counseling women about alterations in menstruation is a critical component of initiating and continuing contraception. Attitudes about menstruation greatly influence contraceptive choices and affect a woman’s adherence to a particular method.

DMPA, which must be injected every 3 months, causes menstrual changes in almost all users. In most women, bleeding patterns are unpredictable in the first few months of use; the frequency and length of bleeding episodes then decrease, with most patients becoming amenorrheic over time.

Levonorgestrel implants, which are inserted subcutaneously in the upper arm, cause irregular bleeding in about two thirds of women during the first year of use. About a quarter continue to have regular menses, and a minority (about 10%) have no menses at all. After 5 years, most women resume a regular bleeding pattern.

Levonorgestrel IUDs reduce menstrual bleeding because the levonorgestrel released from the device inhibits the endometrial proliferation that normally would occur during the ovulatory cycle. This endometrial suppression is a local effect and is not immediate. The uterine lining thins only after several months. As a result, the user spots frequently during the first 4 months of use. After 12 months, bleeding is greatly diminished in about 80% of women and is completely lacking in the remaining 20%. The levonorgestrel IUD is one of the most effective means available for reducing menstrual blood loss.

OCs, the most popular form of reversible contraception in the United States, help regulate cycle length, making the timing of menses more predictable. Bleeding duration and volume are decreased in most users, as is dysmenorrhea.

Troublesome symptoms during the hormone-free interval can be alleviated by reducing that interval to 4 days.

Until recently, OCs typically contained 21 days of estrogen plus a progestin and 7 hormone-free days. The rationale for this design was to mimic an average cycle length of 28 days. Also, by limiting active pills to 21 days, spotting and breakthrough bleeding were minimal after several months of use. The drawback of this design is its association with monthly hormone-withdrawal symptoms. A study of these symptoms in OC users confirmed that pelvic pain, headaches, breast tenderness, bloating, swelling, and the use of pain medicines were more common during the 7-day hormone-free interval, compared with the 21 active days (TABLE 2).²

TABLE 2

Hormone withdrawal symptoms in oral contraceptive users²

Extending active pills delays menses

Extending the duration of active OC pills delays menses and reduces hormone-withdrawal symptoms.

• In a series of 50 patients with menstrual disorders who were offered extension of their active tablets to delay menses, 75% were stabilized on an extended regimen, with the most common pattern being 12 weeks of active pills.³ About one quarter of the patients discontinued OCs or returned to the standard regimen—3 weeks of active pills.
  
• In a follow-up study of 292 patients on OCs who experienced hormone-withdrawal symptoms, 92% of women who were offered extension of their active pills agreed to try the lengthened pattern.⁴ Of the women who accepted the extended regimen, 19% discontinued OCs, and 13% extended active pills but then returned to a standard regimen. One hundred seventy-two patients (59%) maintained the extended pattern. The typical pattern was 12±12 weeks of active pills, with a median of 9 weeks and a range of up to 104 consecutive weeks. Patients also were given the option of decreasing the number of hormone-free days. The typical hormone-free interval was 6±2 days, with a median of 5 days and a range of 0 to 7 days.
  

Factors to consider for extended OC regimens

When extending OC regimens, clinicians need to consider several factors.

If patients are taking OCs for the first time, the best course may be to rely on the standard regimen for the first 2 months because of the high incidence of breakthrough bleeding and spotting when OCs are initiated. After this time, if the patient has hormone-withdrawal symptoms or simply wants to delay menses, she can try extending the active pills.

The patient must be warned that although she can go off pills for up to 7 days, the hormone-free interval should never be any longer.

Active pills can be extended in several ways. The patient can take pills for a specific number of consecutive weeks (such as 6, 9, or 12 weeks). Or, she can simply continue taking consecutive active pills until breakthrough bleeding occurs. She then should observe a 7-day (or shorter) hormone-free interval and restart the OCs.

Troublesome symptoms during the hormone-free interval can be alleviated by reducing that interval to 4 days. The patient must be warned, however, that although she can go off pills for up to 7 days, the hormone-free interval should never be any longer.

Making sure the patient understands and is comfortable with this extended regimen is extremely important.

Future options

Although current contraceptive methods allow clinicians to address patient preferences about menstrual patterns, even more options may well be available in the future. Studies of an 84-day/7-day OC regimen are underway.

Dr. Sulak has served on the speaker’s bureau for and received research support from Berlex, Eli Lilly, Organon, Ortho, and Wyeth.

Compared with today’s women, who have access to effective birth control, past generations had earlier and more frequent childbearing, longer periods of breastfeeding, later menarche, and earlier menopause. During their reproductive years, they were more likely than today’s women to be pregnant or breast-feeding than to be menstruating, and they had far fewer total menstrual episodes during their lifetimes.

As a result, today’s woman is more likely to have menstruation-related gynecologic complaints, which lead to diagnostic tests and surgical procedures. Indeed, as Ob/Gyns are all too aware, menstrual disorders and premenstrual symptoms account for a significant proportion of office visits. Furthermore, when these problems recur month after month for years, ovulation and menstruation may be associated with anemia, endometriosis, ovarian cysts, and increased risk of ovarian cancer.

Survey: Most women prefer less-frequent periods

Although some women like having a period each month, most would prefer less-frequent periods to prevent the problems associated with monthly menstruation, according to a recent investigation.¹ These findings were similar to those of other studies.

Active pills can be extended by a specific number of consecutive weeks or by continuous days until breakthrough bleeding occurs.

In a telephone survey of more than 1,300 women in The Netherlands, 80% of currently menstruating women said they would prefer 1 or more changes in bleeding patterns, including less-painful menses, shorter menses, lighter menses, and even no menses.¹ The majority (about 70% on average across 3 age groups: 15 to 19 years, 25 to 34 years, and 45 to 49 years) selected bleeding intervals ranging from every 3 months to never, and the remaining 30% said they would prefer monthly menses (TABLE 1). Told that menstruation can be manipulated by OCs, women expressed similar bleeding-frequency preferences.

TABLE 1

Preferred frequency of menses¹

Effects of contraceptives on menses

Among the contraceptives that can significantly alter menstruation patterns are depot medroxyprogesterone acetate (DMPA), levonorgestrel implants, oral contraceptives (OCs), and the levonorgestrel intrauterine device (IUD). Which of these methods is best for an individual woman depends on her bleeding preferences, as well as traditional considerations such as efficacy, convenience, cost, health status, and side effects. Counseling women about alterations in menstruation is a critical component of initiating and continuing contraception. Attitudes about menstruation greatly influence contraceptive choices and affect a woman’s adherence to a particular method.

DMPA, which must be injected every 3 months, causes menstrual changes in almost all users. In most women, bleeding patterns are unpredictable in the first few months of use; the frequency and length of bleeding episodes then decrease, with most patients becoming amenorrheic over time.

Levonorgestrel implants, which are inserted subcutaneously in the upper arm, cause irregular bleeding in about two thirds of women during the first year of use. About a quarter continue to have regular menses, and a minority (about 10%) have no menses at all. After 5 years, most women resume a regular bleeding pattern.

Levonorgestrel IUDs reduce menstrual bleeding because the levonorgestrel released from the device inhibits the endometrial proliferation that normally would occur during the ovulatory cycle. This endometrial suppression is a local effect and is not immediate. The uterine lining thins only after several months. As a result, the user spots frequently during the first 4 months of use. After 12 months, bleeding is greatly diminished in about 80% of women and is completely lacking in the remaining 20%. The levonorgestrel IUD is one of the most effective means available for reducing menstrual blood loss.

OCs, the most popular form of reversible contraception in the United States, help regulate cycle length, making the timing of menses more predictable. Bleeding duration and volume are decreased in most users, as is dysmenorrhea.

Troublesome symptoms during the hormone-free interval can be alleviated by reducing that interval to 4 days.

Until recently, OCs typically contained 21 days of estrogen plus a progestin and 7 hormone-free days. The rationale for this design was to mimic an average cycle length of 28 days. Also, by limiting active pills to 21 days, spotting and breakthrough bleeding were minimal after several months of use. The drawback of this design is its association with monthly hormone-withdrawal symptoms. A study of these symptoms in OC users confirmed that pelvic pain, headaches, breast tenderness, bloating, swelling, and the use of pain medicines were more common during the 7-day hormone-free interval, compared with the 21 active days (TABLE 2).²

TABLE 2

Hormone withdrawal symptoms in oral contraceptive users²

Extending active pills delays menses

Extending the duration of active OC pills delays menses and reduces hormone-withdrawal symptoms.

• In a series of 50 patients with menstrual disorders who were offered extension of their active tablets to delay menses, 75% were stabilized on an extended regimen, with the most common pattern being 12 weeks of active pills.³ About one quarter of the patients discontinued OCs or returned to the standard regimen—3 weeks of active pills.
  
• In a follow-up study of 292 patients on OCs who experienced hormone-withdrawal symptoms, 92% of women who were offered extension of their active pills agreed to try the lengthened pattern.⁴ Of the women who accepted the extended regimen, 19% discontinued OCs, and 13% extended active pills but then returned to a standard regimen. One hundred seventy-two patients (59%) maintained the extended pattern. The typical pattern was 12±12 weeks of active pills, with a median of 9 weeks and a range of up to 104 consecutive weeks. Patients also were given the option of decreasing the number of hormone-free days. The typical hormone-free interval was 6±2 days, with a median of 5 days and a range of 0 to 7 days.
  

Factors to consider for extended OC regimens

When extending OC regimens, clinicians need to consider several factors.

If patients are taking OCs for the first time, the best course may be to rely on the standard regimen for the first 2 months because of the high incidence of breakthrough bleeding and spotting when OCs are initiated. After this time, if the patient has hormone-withdrawal symptoms or simply wants to delay menses, she can try extending the active pills.

The patient must be warned that although she can go off pills for up to 7 days, the hormone-free interval should never be any longer.

Active pills can be extended in several ways. The patient can take pills for a specific number of consecutive weeks (such as 6, 9, or 12 weeks). Or, she can simply continue taking consecutive active pills until breakthrough bleeding occurs. She then should observe a 7-day (or shorter) hormone-free interval and restart the OCs.

Troublesome symptoms during the hormone-free interval can be alleviated by reducing that interval to 4 days. The patient must be warned, however, that although she can go off pills for up to 7 days, the hormone-free interval should never be any longer.

Making sure the patient understands and is comfortable with this extended regimen is extremely important.

Future options

Although current contraceptive methods allow clinicians to address patient preferences about menstrual patterns, even more options may well be available in the future. Studies of an 84-day/7-day OC regimen are underway.

Dr. Sulak has served on the speaker’s bureau for and received research support from Berlex, Eli Lilly, Organon, Ortho, and Wyeth.

A 37-year-old patient who has been taking oral contraceptives (OCs) for several years announces during her annual exam that she wishes to discontinue them. Since she is nearing perimenopause—the 2 to 8 years leading up to the cessation of menses—she is concerned about adverse effects with long-term OC use. To prevent pregnancy, she plans to undergo tubal ligation.

With the new formulations available, women can safely take OCs until menopause occurs.

When you point out that she is stopping OCs just when they have the potential to be most beneficial, the patient appears quite surprised. You explain that, as women approach perimenopause—which can begin as early as the late 30s—they tend to become hyperestrogenic, with reduced luteal-phase progesterone levels. These changes can lead to menorrhagia, anemia, hyperplasia, or growth of fibroids. Because oral contraceptives suppress ovarian hormone production, they help treat and prevent these conditions.

Positive effects

OCs have so many beneficial effects, I often recommend them as a patient’s primary preventive strategy during the perimenopausal years. I encourage women who are doing well on OCs to stay on them, and I search for reasons to initiate them in women who are having any menstrual difficulties. As indicated in Table 1, they serve as effective contraception, help stabilize the menstrual cycle, protect against ovarian and endometrial cancers, ease vasomotor symptoms, and prevent bone loss.^1-3

If a woman continues taking OCs until menopause, she need not resort to sterilization for birth control, as many perimenopausal women do. Further, since OCs do not increase the growth of fibroids, they can be used even by women with this pathology.^3-5

With OCs, women’s premenstrual symptoms generally ease.¹ Because they inhibit ovulation, the pills also reduce the incidence of functional ovarian cysts and ovarian cancer, as well as the rate of endometrial cancer and menstrual-related pelvic pain.^6-11 Indeed, with perimenopausal OC use, the need for further diagnostic and therapeutic interventions is greatly diminished, since the pills are so effective in preventing and treating a range of gynecologic problems involving the endometrium, myometrium, and ovary, including abnormal uterine bleeding and ectopic pregnancy.

In the breast, OCs reduce the incidence of fibrocystic lesions and fibroadenomas.¹² In bone, they increase bone mineral density (BMD) and lower the hip-fracture rate during menopause in women who use them after the age of 40.^13-19 There also is evidence that OC users have a lower incidence of arthritis and a diminished risk of colorectal cancer.^20-25

TABLE 1

Beneficial effects of perimenopausal OC use

Contraindications and other barriers to use

Contraindications to OC use—for women of all ages—include a history of myocardial infarction (MI), thromboembolism, stroke, breast cancer, or serious liver disease. Women over 35 who have risk factors for cardiovascular disease also should be discouraged from taking the pills. When in doubt, limit OC use among perimenopausal women to healthy nonsmokers.

There are a number of reasons perimenopausal women elect not to use OCs, and they need to be considered when counseling patients. For example, in some cases, cost may be an issue, while side effects discourage many other women. Fortunately, the low-dose formulations available today carry fewer side effects than in years past. They also may be administered in a number of different ways to further reduce the likelihood of adverse effects. For example, my colleagues and I found that some effects, e.g., headache, pelvic pain, breast tenderness, and bloating, occur more frequently during the 7 days when no pills are taken than during the 21 days when they are.²⁶ Many Ob/Gyns now extend the “active” phase of OC regimens while reducing the pill-free interval. In fact, a formulation is now available that includes only 2 pill-free days (Mircette; Organon, Inc, West Orange, NJ), and an OC with 12 weeks of active pills is currently under investigation (Seasonale; Barr Labs, Pomona, NY).

This strategy may be advisable for all perimenopausal women who take OCs, which can be extended for 12 active weeks or longer, if necessary. (In one investigation, older women preferred menstruating every 3 months to never.²⁷) In this regard, triphasic pills have no advantages over monophasic formulations. If a patient taking a triphasic OC wants to try continuous dosing, I generally switch her to a monophasic equivalent. If breakthrough bleeding occurs on a 20-mcg OC, I prescribe a 30-mcg formulation. Hopefully, further research will elucidate the best way of extending OC dosing.

It is important to advise new OC users that, while they are likely to experience at least 1 side effect, most ease spontaneously within 1 to 3 cycles. It also is important to probe for any unsubstantiated fears the patient may have about OC use (see sidebar), as misconceptions are common.

Dispelling myths

Like their patients, some health-care providers have unfounded concerns about the use of OCs in women over 40. But the evidence indicates that complications are highly unlikely in healthy nonsmokers and that the benefits far outweigh the risks.^1,13,28 OCs do increase the risk of venous thrombosis from a baseline risk of less than 1 per 10,000 person-years in nonusers to 3 to 4 per 10,000 person-years in OC users.^29,30 Rarely are these venous thrombolic events fatal, however. In addition, the World Health Organization (WHO) recently found that nonsmoking, normotensive, nondiabetic women of any age who use OCs face no increased risk of MI compared with nonusers.³⁰ In another study, the risk of MI increased among women using second-generation OCs (those containing levonorgestrel) but not third-generation formulations (those containing desogestrel).³¹ Although the relative risk of ischemic or hemorrhagic stroke does not appear to rise in healthy nonsmoking OC users, it does increase in women who smoke, are hypertensive, or have a history of migraine headaches.^30,32-34

Patients also may need to be reassured that long-term use is safe. As mentioned earlier, some of the benefits of long-term use are a reduction in the incidence of ovarian and endometrial cancers, stable or enhanced bone density, and a lower occurrence of menstrual disorders. By emphasizing these benefits, the health-care provider may improve compliance.

OCs to HRT

Women reach menopause at an average age of almost 52. However, if all patients were to stop taking OCs by the age of 52, half of them would still experience menses.³⁵ As long as the patient has remained a healthy nonsmoker and is doing well on OCs, it is safe for her to continue until the age of 55. Most women will have become menopausal by then, at which time hormone replacement therapy (HRT) can be initiated. If the patient continues to menstruate after discontinuing OCs at age 55, she can reinitiate them for an additional year. Another option is to measure follicle-stimulating hormone (FSH) levels at the end of the patient’s last pill-free interval.^36-38 Levels exceeding 20 mIU/mL suggest—but do not confirm—that menopause has occurred.

Conclusion

As ovarian function becomes increasingly erratic during the perimenopausal years, a number of gynecologic disorders may occur that have both a physical and an emotional impact. These include menorrhagia or other abnormal uterine bleeding, fibroid growth, ovarian cysts, sleep disruption, depression, and vasomotor symptoms. For this reason, I recommend OC therapy for healthy nonsmokers as they enter this transition and look for any disorder that may be alleviated by oral contraceptives.

Before initiating OC therapy, it is important to ascertain what misconceptions—if any—the patient has about their use and to counsel her about their likely side effects. Scheduling a follow-up visit at the end of the second cycle of pills is a good way of ensuring compliance and tailoring the therapy to the patient’s needs. Among the ways OC regimens can be adjusted is by extending the number of days that pills are taken—while reducing the pill-free interval to less than 7 days—to diminish side effects.

A 37-year-old patient who has been taking oral contraceptives (OCs) for several years announces during her annual exam that she wishes to discontinue them. Since she is nearing perimenopause—the 2 to 8 years leading up to the cessation of menses—she is concerned about adverse effects with long-term OC use. To prevent pregnancy, she plans to undergo tubal ligation.

With the new formulations available, women can safely take OCs until menopause occurs.

When you point out that she is stopping OCs just when they have the potential to be most beneficial, the patient appears quite surprised. You explain that, as women approach perimenopause—which can begin as early as the late 30s—they tend to become hyperestrogenic, with reduced luteal-phase progesterone levels. These changes can lead to menorrhagia, anemia, hyperplasia, or growth of fibroids. Because oral contraceptives suppress ovarian hormone production, they help treat and prevent these conditions.

Positive effects

OCs have so many beneficial effects, I often recommend them as a patient’s primary preventive strategy during the perimenopausal years. I encourage women who are doing well on OCs to stay on them, and I search for reasons to initiate them in women who are having any menstrual difficulties. As indicated in Table 1, they serve as effective contraception, help stabilize the menstrual cycle, protect against ovarian and endometrial cancers, ease vasomotor symptoms, and prevent bone loss.^1-3

If a woman continues taking OCs until menopause, she need not resort to sterilization for birth control, as many perimenopausal women do. Further, since OCs do not increase the growth of fibroids, they can be used even by women with this pathology.^3-5

With OCs, women’s premenstrual symptoms generally ease.¹ Because they inhibit ovulation, the pills also reduce the incidence of functional ovarian cysts and ovarian cancer, as well as the rate of endometrial cancer and menstrual-related pelvic pain.^6-11 Indeed, with perimenopausal OC use, the need for further diagnostic and therapeutic interventions is greatly diminished, since the pills are so effective in preventing and treating a range of gynecologic problems involving the endometrium, myometrium, and ovary, including abnormal uterine bleeding and ectopic pregnancy.

In the breast, OCs reduce the incidence of fibrocystic lesions and fibroadenomas.¹² In bone, they increase bone mineral density (BMD) and lower the hip-fracture rate during menopause in women who use them after the age of 40.^13-19 There also is evidence that OC users have a lower incidence of arthritis and a diminished risk of colorectal cancer.^20-25

TABLE 1

Beneficial effects of perimenopausal OC use

Contraindications and other barriers to use

Contraindications to OC use—for women of all ages—include a history of myocardial infarction (MI), thromboembolism, stroke, breast cancer, or serious liver disease. Women over 35 who have risk factors for cardiovascular disease also should be discouraged from taking the pills. When in doubt, limit OC use among perimenopausal women to healthy nonsmokers.

There are a number of reasons perimenopausal women elect not to use OCs, and they need to be considered when counseling patients. For example, in some cases, cost may be an issue, while side effects discourage many other women. Fortunately, the low-dose formulations available today carry fewer side effects than in years past. They also may be administered in a number of different ways to further reduce the likelihood of adverse effects. For example, my colleagues and I found that some effects, e.g., headache, pelvic pain, breast tenderness, and bloating, occur more frequently during the 7 days when no pills are taken than during the 21 days when they are.²⁶ Many Ob/Gyns now extend the “active” phase of OC regimens while reducing the pill-free interval. In fact, a formulation is now available that includes only 2 pill-free days (Mircette; Organon, Inc, West Orange, NJ), and an OC with 12 weeks of active pills is currently under investigation (Seasonale; Barr Labs, Pomona, NY).

This strategy may be advisable for all perimenopausal women who take OCs, which can be extended for 12 active weeks or longer, if necessary. (In one investigation, older women preferred menstruating every 3 months to never.²⁷) In this regard, triphasic pills have no advantages over monophasic formulations. If a patient taking a triphasic OC wants to try continuous dosing, I generally switch her to a monophasic equivalent. If breakthrough bleeding occurs on a 20-mcg OC, I prescribe a 30-mcg formulation. Hopefully, further research will elucidate the best way of extending OC dosing.

It is important to advise new OC users that, while they are likely to experience at least 1 side effect, most ease spontaneously within 1 to 3 cycles. It also is important to probe for any unsubstantiated fears the patient may have about OC use (see sidebar), as misconceptions are common.

Dispelling myths

Like their patients, some health-care providers have unfounded concerns about the use of OCs in women over 40. But the evidence indicates that complications are highly unlikely in healthy nonsmokers and that the benefits far outweigh the risks.^1,13,28 OCs do increase the risk of venous thrombosis from a baseline risk of less than 1 per 10,000 person-years in nonusers to 3 to 4 per 10,000 person-years in OC users.^29,30 Rarely are these venous thrombolic events fatal, however. In addition, the World Health Organization (WHO) recently found that nonsmoking, normotensive, nondiabetic women of any age who use OCs face no increased risk of MI compared with nonusers.³⁰ In another study, the risk of MI increased among women using second-generation OCs (those containing levonorgestrel) but not third-generation formulations (those containing desogestrel).³¹ Although the relative risk of ischemic or hemorrhagic stroke does not appear to rise in healthy nonsmoking OC users, it does increase in women who smoke, are hypertensive, or have a history of migraine headaches.^30,32-34

Patients also may need to be reassured that long-term use is safe. As mentioned earlier, some of the benefits of long-term use are a reduction in the incidence of ovarian and endometrial cancers, stable or enhanced bone density, and a lower occurrence of menstrual disorders. By emphasizing these benefits, the health-care provider may improve compliance.

OCs to HRT

Women reach menopause at an average age of almost 52. However, if all patients were to stop taking OCs by the age of 52, half of them would still experience menses.³⁵ As long as the patient has remained a healthy nonsmoker and is doing well on OCs, it is safe for her to continue until the age of 55. Most women will have become menopausal by then, at which time hormone replacement therapy (HRT) can be initiated. If the patient continues to menstruate after discontinuing OCs at age 55, she can reinitiate them for an additional year. Another option is to measure follicle-stimulating hormone (FSH) levels at the end of the patient’s last pill-free interval.^36-38 Levels exceeding 20 mIU/mL suggest—but do not confirm—that menopause has occurred.

Conclusion

As ovarian function becomes increasingly erratic during the perimenopausal years, a number of gynecologic disorders may occur that have both a physical and an emotional impact. These include menorrhagia or other abnormal uterine bleeding, fibroid growth, ovarian cysts, sleep disruption, depression, and vasomotor symptoms. For this reason, I recommend OC therapy for healthy nonsmokers as they enter this transition and look for any disorder that may be alleviated by oral contraceptives.

Before initiating OC therapy, it is important to ascertain what misconceptions—if any—the patient has about their use and to counsel her about their likely side effects. Scheduling a follow-up visit at the end of the second cycle of pills is a good way of ensuring compliance and tailoring the therapy to the patient’s needs. Among the ways OC regimens can be adjusted is by extending the number of days that pills are taken—while reducing the pill-free interval to less than 7 days—to diminish side effects.

A 37-year-old patient who has been taking oral contraceptives (OCs) for several years announces during her annual exam that she wishes to discontinue them. Since she is nearing perimenopause—the 2 to 8 years leading up to the cessation of menses—she is concerned about adverse effects with long-term OC use. To prevent pregnancy, she plans to undergo tubal ligation.

With the new formulations available, women can safely take OCs until menopause occurs.

When you point out that she is stopping OCs just when they have the potential to be most beneficial, the patient appears quite surprised. You explain that, as women approach perimenopause—which can begin as early as the late 30s—they tend to become hyperestrogenic, with reduced luteal-phase progesterone levels. These changes can lead to menorrhagia, anemia, hyperplasia, or growth of fibroids. Because oral contraceptives suppress ovarian hormone production, they help treat and prevent these conditions.

Positive effects

OCs have so many beneficial effects, I often recommend them as a patient’s primary preventive strategy during the perimenopausal years. I encourage women who are doing well on OCs to stay on them, and I search for reasons to initiate them in women who are having any menstrual difficulties. As indicated in Table 1, they serve as effective contraception, help stabilize the menstrual cycle, protect against ovarian and endometrial cancers, ease vasomotor symptoms, and prevent bone loss.^1-3

If a woman continues taking OCs until menopause, she need not resort to sterilization for birth control, as many perimenopausal women do. Further, since OCs do not increase the growth of fibroids, they can be used even by women with this pathology.^3-5

With OCs, women’s premenstrual symptoms generally ease.¹ Because they inhibit ovulation, the pills also reduce the incidence of functional ovarian cysts and ovarian cancer, as well as the rate of endometrial cancer and menstrual-related pelvic pain.^6-11 Indeed, with perimenopausal OC use, the need for further diagnostic and therapeutic interventions is greatly diminished, since the pills are so effective in preventing and treating a range of gynecologic problems involving the endometrium, myometrium, and ovary, including abnormal uterine bleeding and ectopic pregnancy.

In the breast, OCs reduce the incidence of fibrocystic lesions and fibroadenomas.¹² In bone, they increase bone mineral density (BMD) and lower the hip-fracture rate during menopause in women who use them after the age of 40.^13-19 There also is evidence that OC users have a lower incidence of arthritis and a diminished risk of colorectal cancer.^20-25

TABLE 1

Beneficial effects of perimenopausal OC use

Contraindications and other barriers to use

Contraindications to OC use—for women of all ages—include a history of myocardial infarction (MI), thromboembolism, stroke, breast cancer, or serious liver disease. Women over 35 who have risk factors for cardiovascular disease also should be discouraged from taking the pills. When in doubt, limit OC use among perimenopausal women to healthy nonsmokers.

There are a number of reasons perimenopausal women elect not to use OCs, and they need to be considered when counseling patients. For example, in some cases, cost may be an issue, while side effects discourage many other women. Fortunately, the low-dose formulations available today carry fewer side effects than in years past. They also may be administered in a number of different ways to further reduce the likelihood of adverse effects. For example, my colleagues and I found that some effects, e.g., headache, pelvic pain, breast tenderness, and bloating, occur more frequently during the 7 days when no pills are taken than during the 21 days when they are.²⁶ Many Ob/Gyns now extend the “active” phase of OC regimens while reducing the pill-free interval. In fact, a formulation is now available that includes only 2 pill-free days (Mircette; Organon, Inc, West Orange, NJ), and an OC with 12 weeks of active pills is currently under investigation (Seasonale; Barr Labs, Pomona, NY).

This strategy may be advisable for all perimenopausal women who take OCs, which can be extended for 12 active weeks or longer, if necessary. (In one investigation, older women preferred menstruating every 3 months to never.²⁷) In this regard, triphasic pills have no advantages over monophasic formulations. If a patient taking a triphasic OC wants to try continuous dosing, I generally switch her to a monophasic equivalent. If breakthrough bleeding occurs on a 20-mcg OC, I prescribe a 30-mcg formulation. Hopefully, further research will elucidate the best way of extending OC dosing.

It is important to advise new OC users that, while they are likely to experience at least 1 side effect, most ease spontaneously within 1 to 3 cycles. It also is important to probe for any unsubstantiated fears the patient may have about OC use (see sidebar), as misconceptions are common.

Dispelling myths

Like their patients, some health-care providers have unfounded concerns about the use of OCs in women over 40. But the evidence indicates that complications are highly unlikely in healthy nonsmokers and that the benefits far outweigh the risks.^1,13,28 OCs do increase the risk of venous thrombosis from a baseline risk of less than 1 per 10,000 person-years in nonusers to 3 to 4 per 10,000 person-years in OC users.^29,30 Rarely are these venous thrombolic events fatal, however. In addition, the World Health Organization (WHO) recently found that nonsmoking, normotensive, nondiabetic women of any age who use OCs face no increased risk of MI compared with nonusers.³⁰ In another study, the risk of MI increased among women using second-generation OCs (those containing levonorgestrel) but not third-generation formulations (those containing desogestrel).³¹ Although the relative risk of ischemic or hemorrhagic stroke does not appear to rise in healthy nonsmoking OC users, it does increase in women who smoke, are hypertensive, or have a history of migraine headaches.^30,32-34

Patients also may need to be reassured that long-term use is safe. As mentioned earlier, some of the benefits of long-term use are a reduction in the incidence of ovarian and endometrial cancers, stable or enhanced bone density, and a lower occurrence of menstrual disorders. By emphasizing these benefits, the health-care provider may improve compliance.

OCs to HRT

Women reach menopause at an average age of almost 52. However, if all patients were to stop taking OCs by the age of 52, half of them would still experience menses.³⁵ As long as the patient has remained a healthy nonsmoker and is doing well on OCs, it is safe for her to continue until the age of 55. Most women will have become menopausal by then, at which time hormone replacement therapy (HRT) can be initiated. If the patient continues to menstruate after discontinuing OCs at age 55, she can reinitiate them for an additional year. Another option is to measure follicle-stimulating hormone (FSH) levels at the end of the patient’s last pill-free interval.^36-38 Levels exceeding 20 mIU/mL suggest—but do not confirm—that menopause has occurred.

Conclusion

As ovarian function becomes increasingly erratic during the perimenopausal years, a number of gynecologic disorders may occur that have both a physical and an emotional impact. These include menorrhagia or other abnormal uterine bleeding, fibroid growth, ovarian cysts, sleep disruption, depression, and vasomotor symptoms. For this reason, I recommend OC therapy for healthy nonsmokers as they enter this transition and look for any disorder that may be alleviated by oral contraceptives.

Before initiating OC therapy, it is important to ascertain what misconceptions—if any—the patient has about their use and to counsel her about their likely side effects. Scheduling a follow-up visit at the end of the second cycle of pills is a good way of ensuring compliance and tailoring the therapy to the patient’s needs. Among the ways OC regimens can be adjusted is by extending the number of days that pills are taken—while reducing the pill-free interval to less than 7 days—to diminish side effects.