Alteration of the Hormone-free Interval in Oral Contraception

SEPTEMBER 01, 2008
Yvette C. Terrie, BSPharm, RPh

Ms. Terrie is a clinical pharmacy writer based in Haymarket, Virginia.

The majority of oral contraceptives (OCs) involve a regimen of 21 days of active pills followed by 7 days of placebo pills. The 7-day hormone-free interval (HFI) typically results in hormone withdrawal bleeding and was intended to mimic the natural menstrual cycle. In recent years, with increased recognition that the 28-day cycle is not a physiologic necessity, interest has focused on the role of the HFI in oral contraception and methods of altering it.1

Understanding the Hormone-Free Interval

No health-related or physiologic benefits are associated with monthly withdrawal bleeding in a woman taking OCs.1,2 During the 7-day HFI of a typical 28-day OC regimen, exogenous estrogen and progestin are cleared 2 to 3 days after a patient completes active pills, levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) increase, and ovarian follicular growth occurs.3,4 As a result, the possibility for ovulation during the HFI (escape ovulation) increases with each hormone-free day.4 By decreasing the HFI or by using low-dose estrogen rather than placebo, the risk for escape ovulation is reduced, possibly improving contraceptive efficacy.5

Hormone-Free Intervals: Is Shorter Better?

Studies have demonstrated that conventional 28-day OC regimens that utilize a 7-day HFI fail to induce complete ovarian suppression.3,4 Recent studies have focused on the safety and efficacy of extending active combination OC therapy and reducing or eliminating the HFI (see Table3,6-11).

Spona et al were the first to report less ovarian activity in women randomized to a shorter HFI.12 When the duration of active pills was increased to 23 and the HFI was decreased from 7 to 5 days, the risk of breakthrough ovulation when pills were omitted was decreased.12

Hormone Withdrawal Symptoms

Hormone withdrawal during the HFI may be associated with bothersome symptoms such as headaches, migraines, pelvic pain and cramping, breast tenderness, bloating, and bleeding problems.13 Sulak and colleagues evaluated the timing, frequency, and severity of hormone-related symptoms in women using OCs, in particular comparing the symptoms women experience during active pill phases with those experienced during the HFI. As many as 70% of the women experienced pelvic pain and cramping during the traditional 7-day HFI, compared with 21% of women taking active pills. In addition, more women experienced headaches and breast tenderness during the HFI, and more reported the need for analgesia. The study concluded that almost all symptoms, including headache, pain, breast tenderness, bloating, and swelling, were considerably worse during the 7-day HFI, compared with 21 days of active hormones.

Overview of Clinical Studies Evaluating Alterations to the 7-day HFI in OC Regimens

Study Design (Ref)


Randomized study of 21 days + 7-day HFI vs 21 days + 10 mcg EE x 2 days + 5-day HFI vs 28 days (6)

7-day HFI demonstrated less follicular suppression than 5-day or continuous regimens

Randomized study of 21 days + 7-day HFI or x 28 days continuous (7)

Continuous OC regimens were more effective in preventing dominant follicle development and escape ovulation

Randomized study of 168 days continuous vs 21 days + 7-day HFI x 6 cycles (8)

Continuous group reported fewer light and moderate bleeding days, and less bloating and menstrual pain

Randomized study of 3- vs 4-day HFI (9)

Decreasing the HFI from 7 days to 3 or 4 days provides greater pituitary?ovarian inhibition and suppression of hormone withdrawal symptoms

Randomized study of 21 days + 7-day HFI vs 84 days + 7-day HFI vs 84 days + 7 days EE (3)

10 mcg EE after 84 days demonstrated decreased FSH levels and a reduced number of developing follicles

Evaluation of premenstrual syndrome symptomatology in 42- to 126-day cycles (10)

Improvements in breast tenderness and dysmenorrhea

Randomized study of x 21 days + 7-day HFI vs x 336 days (11)

Continuous use resulted in significantly fewer bleeding days

EE = ethinyl estradiol; FSH = follicle-stimulating hormone;
HFI = hormone-free interval; OC = oral contraceptive.

Results from a recent study conducted by Legro et al have demonstrated that continuous OC therapy may be more effective than conventional 28-day OC regimens in reducing menstrual pain and controlling episodes of heavy bleeding and other menstrual-related symptoms.14 Continuous OC regimens provide greater suppression of activity in the ovaries and endometrium; this suppression is associated with improvement of menstrual symptoms.14 Furthermore, the researchers suggest that continuous OC therapy may be beneficial in treating chronic medical conditions (eg, polycystic ovarian syndrome and endometriosis) in which greater suppression of the ovaries and endometrium are desired.

Reducing or Eliminating the HFI

Research regarding the impact of a 7-day HFI and recent modifications to OC regimens have piqued the interest of many healthcare professionals and their patients.15,16 In April 1998, the FDA approved Mircette (Duramed) as the first OC to use a shorter HFI. Each packet of Mircette contains 21 active tablets of 0.15 mg desogestrel/20 mcg ethinyl estradiol (EE), 2 placebo tablets, and 5 tablets of 10 mcg EE. In 2003, the FDA approved Seasonale (Duramed), the first extended OC regimen, and subsequently approved other OC regimens that either reduce the number of HFI days for each cycle (Loestrin 24 Fe, Yaz) or eliminate the HFI (Seasonique, Lybrel) (Figure). These formulations may decrease the HFI withdrawal symptoms experienced by women using OCs, reduce menstrual bleeding, and maximize ovarian follicular suppression.17-21

The Pharmacist's Role

Pharmacists are in a pivotal position to provide women with the necessary information to make informed choices about OCs. Extended and continuous regimens give women more choices to accommodate their individual needs, especially those women who experience hormone withdrawal symptoms. Because many women discontinue OCs due to symptoms attributed to the typical 7-day HFI, the use of extended and continuous regimens may be an ideal choice. Patients seeking advice on OCs should be encouraged to see their gynecologists to assess if they are an appropriate candidate.

When counseling women about OCs, pharmacists should provide the patient with thorough information about proper use and adverse effects and risks associated with the use of OCs. Patients should be reminded that extended and continuous OC regimens have been associated with episodes of breakthrough bleeding and spotting during the first 3 to 4 months of therapy and that the incidence typically subsides as therapy continues. To minimize these episodes, patients should be reminded to take the pill at the same time each day.


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