No question: The estrogen–progestin oral contraceptive (OC) developed by physician John Rock and biologist Gregory Pincus was one of the great inventions of the 20th century. Their 21-7 short-cycle OC regimen recapitulated the idealized 28-day menstrual cycle.
But, over the past 10 years, contraceptive experts have increasingly, and more fiercely, questioned the soundness of a formulation that contains only 21 hormone pills and produces a monthly withdrawal bleed. Now, we are at a tipping point in OC prescribing practice, where use of the classic 21-7 formulation is likely to decline, significantly. Why? And what will come next for our patients?
21-7 formulations can cause problems
The standard OC formulation, with 21 low-dose estrogen–progestin hormone pills and 7 inert pills, contains too few hormone pills and too many inert pills. The serum follicle-stimulating hormone (FSH) level rises significantly during the 7-day hormone-free interval—an effect that may stimulate follicle growth.
For example, in two studies, the serum FSH level rose from approximately 1.0 mIU/mL during the hormone interval to 5 to 8 mIU/mL during the hormone-free interval.1,2 Of even greater concern, at least one study3 reported that the rise in FSH and stimulation of ovarian follicles during the hormone-free interval are sufficient to result in intermittent luteinization of a follicle, demonstrated by a rise in a urinary progesterone metabolite.
These findings suggest that intermittent ovulation occurs in women who take the standard 21-7 regimen. Compounding this problem is the fact that, if a woman forgets to restart the hormone pills at the end of the 7-day hormone-free interval, ovarian follicle growth progresses and ovulation occurs more frequently. The 7-day pill-free interval, combined with a delay in restarting the next phase of the pill regimen, is the likely cause of some of the unintended pregnancies reported in pill users.
24-4 formulations carry advantages…
Some OC users strongly prefer to have a monthly withdrawal bleed. For them, the main OC formulations are 21-7, 24-4, and 21-2-5 (TABLE).
The 24-4 formulation (24 estrogen–progestin pills and 4 inert pills) results in greater suppression of FSH, luteinizing hormone, and estradiol than does a standard 21-7 formulation. This indicates more complete pituitary–ovarian suppression that, likely, results in fewer episodes of ovulation.4
In addition, some 24-4 formulations have been reported effective in treating acne and premenstrual dysphoric disorder.5,6
TABLE
Sorting among the short-cycle 21-7 OC formulation and its alternatives
| Regimen | Pill tally | Comments on formulation |
|---|---|---|
| 21-7 (SHORT-CYCLE) FORMULATION | ||
| Standard 21-day estrogen–progestin (EP)–7-day inert (I) formulations | 21 EP pills, 7 I pills | |
| 28-DAY FORMULATIONS WITH REDUCED HORMONE-FREE INTERVAL | ||
| Use any standard 21-7 OC; take 3 additional EP pills and 3 fewer I pills to extend cycle to 24-4 | 24 EP pills, 4 I pills | |
| Lo Estrin 24 Fe | 24 EP pills, 4 iron pills | EP pills contain 20 μg ethinyl estradiol (EE) and 1 mg norethindrone acetate; iron (Fe) pill contains ferrous fumarate |
| Yaz | 24 EP pills, 4 I pills | EP pills contain 20 μg EE and 3 mg drospirenone |
| Mircette, Kariva | 21 EP pills, 2 I pills, 5 EE pills | EP pills contain 20 μg EE and 0.15 mg desogestrel; EE pills contain 10 μg EE |
| 49-DAY CYCLES | ||
| Use any standard 21-7 OC and combine the EP pills from two packs; take as 42 EP pills followed by 7 I pills | 42 EP pills, 7 I pills | |
| 84-7 FORMULATIONS | ||
| Use any standard 21-7 OC and combine the EP pills from four packs; take as 84 EP pills followed by 7 I pills | 84 EP pills, 7 I pills | |
| Seasonale | 84 EP pills, 7 I pills | EP pills contain 30 μg EE and 0.15 mg levonorgestrel |
| Seasonique | 84 EP pills, 7 EE pills | EP pills contain 30 μg EE and 0.15 mg levonorgestrel; EE pills contain 10 mcg |
| CONTINUOUS FORMULATIONS | ||
| Use any standard 21-7 OC continuously; take hormone pills only | Daily EP pills | |
| Lybrel | Daily EP pills | EP pills contain 20 μg EE and 0.09 mg levonorgestrel |
…and so do extended-cycle formulations
Many women are willing to consider using an extended-cycle OC regimen that is designed to reduce the frequency of withdrawal bleeding.7 With an 84-7I formulation, which contains 7 inert (I) pills, there are only 7 hormone-free days during 91 days of therapy. The 84-7I formulation is associated with fewer intervals during which the FSH level rises and follicle growth resumes. Furthermore, the 84-7I formulation may also be associated with fewer days of heavy menstrual bleeding than are 21-7 regimens.3,8
A further evolution in extended-cycle formulations is to provide zero hormone-free days by following 84 days of estrogen–progestin with 7 days of ethinyl estradiol (EE). The 84-7EE regimen continually suppresses FSH and estradiol levels during the 7 days between estrogen–progestin pills, and may help reduce the risk of breakthrough bleeding.