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
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
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 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
Randomized study of 21 days +
7-day HFI or x 28 days continuous
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
Randomized study of 3- vs 4-day
Decreasing the HFI from 7 days
to 3 or 4 days provides greater
pituitary?ovarian inhibition and
suppression of hormone withdrawal
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
Evaluation of premenstrual
syndrome symptomatology in
42- to 126-day cycles (10)
Improvements in breast tenderness
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
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
who experience hormone
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
- Sulak P. Continuous oral contraception: changing times. Best Practice and Research Clinical Obstetrics and Gynecology. 2008 Apr; 22(2):355-74.
- Lin K, Barnhart K. The clinical rationale for menses free contraception. Journal of Women's Health. 2007 Oct;16(8):1171-80
- Vandever MA, Kuehl TJ, Sulak PJ, et al. Evaluation of pituitary-ovarian axis suppression with three oral contraceptive regimens. Contraception. 2008 Mar;77(3):162-70
- Baerwald, AR, Olatunbosun PA, Peirson RA. Ovarian follicular development is initiated during the hormone free interval of oral contraceptive use. Contraception. 2004 November; 70:371-377
- Mishell DR Jr. Rationale for decreasing the number of days of the hormone-free interval with use of low-dose oral contraceptive formulations. Contraception. 2005 Apr; 71:304-5.
- Schlaff WD, Lynch AM, Highes HD, Cedars MI, Smith DL. Manipulation of the pill free interval in oral contraceptive pill users: the effect on follicular suppression. American Journal of Obstetrics and Gynecology. 2004 Apr; 190(4):943-51.
- Birtch RL, Olatunbosun OA, Perison RA. Ovarian follicular dynamics during conventional vs. continuous oral contraceptive use. Contraception 2006 March; 73(7):235-43.
- Kwiecien M, Edelman A, Nichols MS, Jensen JT. Bleeding patterns and patient acceptability of standard or continuous dosing regimens of a low dose oral contraceptive: a randomized trial. Contraception. 2003 Jan;67(1):9-13.
- Willis S, Kuehl TJ, Spiekerman AM, Sulak PJ, . Greater inhibition of the pituitary--ovarian axis in oral contraceptive regimens with a shortened hormone-free interval. Contraception. 2006 Aug;74(2):100-3.
- Sillem M, Schneidereit R, Heithecker R, Mueck AO. Use of an oral contraceptive containing drospirenone in an extended regimen. European Journal of Contraception and Reproductive Health Care. 2003 Sep;8(3):162-9.
- Miller L, Hughes JP. Continuous Combination Oral Contraceptive Pills to Eliminate Withdrawal Bleeding: A Randomized Trial. Obstetrics and Gynecology. Volume 101, Number. 4, April 2003
- Spona J, Elstein M, Feichtinger W, et al. Shorter pill free interval in combined oral contraceptives decreases follicular development. Contraception 1996;54:71-7.
- Sulak P, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormone Withdrawal Symptoms in Oral Contraceptive Users. Obstetrics and Gynecology 2000 Feb; 95(2):261-6.
- Legro RS, Pauli JG, Kunselman AR, et al. Effects of continuous versus cyclic oral contraception. A randomized controlled trial. Journal of Clinical Endocrinology and Metabolism. 2008 Feb; 93(2):420-9.
- Rosenberg MJ, Meyers A< Roy V. Efficacy, cycle control and side effects of low and lower dose oral contraceptives: A randomized trial of 20 micrograms and 35 micrograms estrogen preparations. Contraception. 1999 Dec; 60(6):321-9.
- Nelson A. Communicating with patients about extended-cycle and continuous use of oral contraceptives. Journal of Women's Health. 2007 May; 16(4):463-70.
- Anderson, FD, Hait H and the Seasonale 301 Study Group. A multicenter randomized study of an extended cycle oral contraceptive. Contraception. 2003; 68:89-96
- Anderson, FD, Gibbons W, Portman D. Safety and efficacy of an extended regimen oral contraceptive utilizing continuous low dose ethinyl estradiol. Contraception. 2006 Mar; 73(3):229-34.
- Archer DF, Jensen JT, Johnson JV, et al. Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol: phase 3 results. Contraception, 2006;74:439-445.
- Bachmann G, Sulak PJ, Sampson-Landers C, Benda N, Marr J, Efficacy and safety of a low-dose 24-day combined oral contraceptive containing 20 ?g ethinylestradiol and 3 mg drosperinone. Contraception. 2004;70:191-198.
- Nakajima ST, Archer DF, Ellman H. Efficacy and safety of a new 24-day oral contraceptive regimen of norethindrone acetate 1 mg/ethinyl estradiol 20 ?g (Loestrin? 24 Fe). Contraception. 2007;75:16-22.