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Clinical Reviews


OCs, breakthrough bleeding, and patients’ need to know

Managing expectations is as important as adjusting formulations

April 2007 · Vol. 19, No. 04

IN THIS ARTICLE

 

Recommendations for practice

  • Lack of adherence is a common cause of breakthrough bleeding. Focus counseling on ensuring that patients understand and can follow pill-taking instructions before switching pills or contraceptive method
  • If breakthrough bleeding extends beyond 4 cycles and a woman wishes to continue using an oral contraceptive, consider switching to a pill with a higher ethinyl estradiol:progestin ratio, either by increasing the estradiol dose or by decreasing the relative progestin dose
  • Breakthrough bleeding may be due to progestin type; switching from an estrane to a gonane may reduce it
  • Women who have breakthrough bleeding after having well-controlled menstrual cycles on an oral contraceptive should be assessed for causes not related to their birth control pills, such as pregnancy, cervicitis, smoking, or interactions with medications.

In 1982, more than 20% of women surveyed in a nationally representative sample had discontinued oral contraceptives (OCs) on their own or at the recommendation of their physician due to bleeding or spotting.1 Sadly, the percentage today has not decreased much.

Understandable concern, embarrassment, and annoyance lead these women to abandon OCs.1,2 What they often don’t know, though, is that breakthrough bleeding generally is greatest in the first 3 to 4 months after starting OCs,3 and it steadily declines and stabilizes by the end of the fourth cycle.4 Timely counsel could enable many of these women to cope with the bleeding and stick with an effective contraceptive method. Additional incentives are noncontraceptive benefits of OCs: improved menstrual regularity and decreased menstrual blood loss, dysmenorrhea, and risk of ovarian and endometrial cancer.

Women who discontinue OCs on their own switch to less effective methods of birth control or use no method.1,2 Consequences may be unexpected pregnancies and an increased abortion rate.5 With patients who are using an OC, it would be appropriate to ask periodically whether they are satisfied with OC use.

In this review, we discuss the mechanisms and management of breakthrough bleeding in women taking OCs, and provide tips for counseling that may help decrease the risk of discontinuation due to menstrual abnormalities in the initial months of use.

Breakthrough bleeding in this review refers to either unplanned spotting or bleeding, regardless of requirement for protection—unless defined otherwise by a specific study under discussion.

How is irregular bleeding defined?

For the purpose of performing studies, unplanned bleeding is classified by the World Health Organization into 2 categories:

  1. breakthrough bleeding, which requires sanitary protection, and
  2. spotting, which does not require sanitary protection.6 Despite this formal classification, trials have varied in their terminology and method of recording menstrual irregularities, making comparisons between studies difficult. In addition, there is wide variation among women in tolerance to bleeding abnormalities, perceptions of heavy vs light bleeding, as well as the need for protection.3

Nevertheless, menstrual abnormalities are consistently cited as a common reason for discontinuing OCs. A prospective US study of 1,657 women performed in the 1990s reported that 37% of OC users had stopped taking OCs by 6 months after starting a new prescription because of side effects.2 Irregular bleeding was the most common cause, cited by 12% of women, followed by nausea, weight gain, and mood changes, which ranged from 5% to 7%.

Four causes of bleeding

Breakthrough bleeding may be due to any the following variables:

  1. physiologic effects of OCs on the endometrium,
  2. OC-related parameters, including dose, formulation, and regimen,
  3. patient behavior (including compliance, using concomitant medications, and smoking),
  4. benign or malignant pathology.

OCs and the endometrium: Estrogen-progestin balance significant

Progestin and estrogen in combination OCs have profound effects on the endometrium that, although not contributing to contraception, do lead to a predictable pattern of bleeding or such problems as breakthrough bleeding or lack of withdrawal bleed.

Normally, estrogen causes the endometrium to proliferate. Progesterone stabilizes the growing uterine lining. Since the introduction of OCs in 1960, the trend in formulation has been to use the least amount of hormone necessary to inhibit ovulation. Given that the progestin is primarily responsible for the contraceptive efficacy of OCs, the risk of pregnancy is not altered with decreases in the estrogen component. However, significantly lowering the estrogen in OCs may account for breakthrough bleeding. Unplanned bleeding, though, is not dependent solely on the estrogen component, as variations in the progestin can contribute to breakthrough bleeding.7

Most OC users in the US take low-dose formulations, so designated because the estrogen component is <50 μg. this level of estrogen in combination with a progestin provides excellent contraceptive efficacy, but may be insufficient to sustain endometrial integrity in some women.8 Studies that have compared OCs containing 20 μg ethinyl estradiol (EE) with those containing 30 μg or 35 μg EE have not been very useful for judging breakthrough bleeding rates because the products often also vary in the phasing and type of progestin. Some studies show more breakthrough bleeding with 20 μg EE pills,9-11 but others show equal or improved cycle control with the lower EE dose.

Estrogen-progestin balance is more important than absolute level of estrogen.

Endrikat et al12 conducted a study to compare two 20 μg EE pills containing different progestins, and to compare 2 levonorgestrel-based formulations with differing EE amounts. An OC of 20 μg EE/100 μg levonorgestrel was compared with a preparation of 20 μg EE/500 μg norethisterone. A 30 μg EE/150 μg levonorgestrel pill was used as a standard reference preparation.

Overall, the 30 μg EE preparation showed a lower cumulative incidence of breakthrough bleeding compared with the 20 μg EE/100 μg levonorgestrel and 20 μg EE/500 μg norethisterone pills over 13 cycles (1.0% vs 4.1% and 11.7%, respectively). However, the 20 μg EE/500 μg norethisterone pills consistently had a higher breakthrough bleeding rate than the 20 μg EE/100 μg levonorgestrel pill. This suggests that, although the higher EE component in the 30 μg pill was important when comparing 2 formulations with the same progestin, the difference in progestins of the two 20 μg EE pills was most likely responsible for the differing rates of breakthrough bleeding.

This study highlights the ability to achieve greater cycle control by titrating the EE component of an OC in a balanced ratio with the same progestin, but suggests that the absolute quantity of EE in a given pill may be less important than maintaining a balance between the 2 hormones or less important than the impact of different progestins on breakthrough bleeding rates.

The delicate balance between estrogen and progesterone supplementation required for contraception may also lead to progestin-induced decidualization and endometrial atrophy, which can result in asynchronous, erratic bleeding.7,13 This has been primarily studied in long-acting progestin-only contraceptives such as implants. Alterations in angiogenic factors14 may play a role. Hysteroscopic studies have shown abnormalities in superficial endometrial blood vessels in terms of size, proliferation, and fragility in women using norplant.13,15,16 Abnormalities in endothelial cells and extracellular matrix proteins,17 tissue factor,18 and endometrial lymphoid cells19 may contribute to breakthrough bleeding in progestin-dominant environments.

OC formulations, doses, regimens

More than 30 formulations of combination OCs are available in the US, with different doses and types of estrogen and progestin (TABLE 1).20 Approved OCs have been studied in clinical trials to assess contraceptive efficacy and cycle control; however, comparisons between studies regarding bleeding phenomena are impaired by inconsistent terminology.3

Whereas some studies describe breakthrough bleeding and spotting according to their recognized definitions, others simply refer to intermenstrual bleeding or use spotting to refer to any unexpected bleeding. In addition, cycle control studies of OC users frequently do not account for the effects of missed pills, use of concomitant medications, or smoking. The percentage of women who experience breakthrough bleeding in a given cycle varies widely even in different trials of the same formulation.

Pay attention to progestin level. Conventional wisdom holds that OCs with the lowest doses of EE (≤20 μg) are associated with more breakthrough bleeding.11 However, even moderately low doses of either EE or progestin can increase the incidence of breakthrough bleeding. For example, when 3 pills with the same estrogen and progestin (50 μg EE/100 μg norethindrone; 35 μg EE/100 μg norethindrone; and 35 μg EE/50 μg norethindrone) were compared in 192 women over 8 cycles, the pill containing the lowest amount of norethindrone (35 μg EE/50 μg norethindrone) caused the highest rates of breakthrough bleeding (decreasing to approximately 50% by cycle 8 as compared with 35% in the 35 μg EE/100 μg norethindrone pill and 25% in the 50 μg EE/100 μg norethindrone pill).21

In addition, the number of intermenstrual bleeding days plateaued more slowly as the amount of both hormones in the OC formulations decreased. This underscores the importance of the relative proportion of estrogen and progestin contained in combination OCs and its impact on breakthrough bleeding.

Similarly, a large comprehensive study in 1,991 women compared 7 different formulations of combination OCs containing different dose combinations of EE and norgestimate—20/250, 50/250, 35/125, 20/60, 50/60, 30/90, 25/125.22 Total intermenstrual bleeding was more frequent at lower doses of either estrogen or progestin. However, as long as a similar estrogen-progestin ratio was maintained, bleeding rates were considered acceptable (approximately 10% of days per cycle with bleeding). the authors also noted that in the low-dose range of OCs, small changes in the absolute amount of either EE or norgestimate might result in noticeable changes in bleeding

TABLE 1

Available OCs by formulation and regimen

TRADE NAME

GENERIC NAME(S)

ESTROGEN (DOSE)

PROGESTIN (DOSE)

MONOPHASIC

Alesse, Levlite

Aviane, Lessina

Ethinyl estradiol (20 μg)

Levonorgestrel (0.1 mg)

Mircette

Kariva

Ethinyl estradiol (20 μg × 21 days + 10 μg × 5 days during placebo week)

Desogestrel (0.15 mg)

Loestrin FE

Microgestin FE 1/20, June FE 1/20

Ethinyl estradiol (20 μg)

Norethindrone acetate (1 mg)

Yaz

 

Ethinyl estradiol (20 μg)

Drospirenone (3 mg)

Levlen, Nordette

Levora, Portia

Ethinyl estradiol (30 μg)

Levonorgestrel (0.15 mg)

Lo/Ovral

Low-ogestrel, Cryselle

Ethinyl estradiol (30 μg)

Norgestrel (0.3 mg)

Desogen, Ortho-cept

Apri

Ethinyl estradiol (30 μg)

Desogestrel (0.15 mg)

Loestrin 21 1/5/30

Microgestin, Junel Fe

Ethinyl estradiol (30 μg)

Norethindrone acetate (1.5 mg)

Yasmin

 

Ethinyl estradiol (30 μg)

Drospirenone (3 mg)

Ovcon 35

 

Ethinyl estradiol (35 μg)

Norethindrone (0.4 mg)

Ortho-Cyclen

Mononesessa, Sprintec

Ethinyl estradiol (35 μg)

Norgestimate (0.25 mg)

Brevicon, Modicon

Nortrel, Necon 0.5/35

Ethinyl estradiol (35 μg)

Norethindrone (0.5 mg)

Demulen 1/35

Zovia 1/35

Ethinyl estradiol (35 μg)

Ethynodiol diacetate (1 mg)

Ortho-Novum 1/35, Norinyl 1+35

Necon 1/35, Nortrel

Ethinyl estradiol (35 μg)

Norethindrone (1 mg)

Ortho-Novum 1/50

Necon 1/50

Ethinyl estradiol (50 μg)

Norethindrone (1 mg)

Ovral

Ogestrel

Ethinyl estradiol (50 μg)

Norgestrel (0.5 mg)

Ovcon 50

 

Ethinyl estradiol (50 μg)

Norethindrone (1 mg)

Demulen 1/50

Zovia 1/50

Ethinyl estradiol (50 μg)

Ethynodiol diacetate (1 mg)

Norinyl 1/50

 

Mestranol (50 μg)

Norethindrone (1 mg)

BIPHASIC

Ortho-Novum 10/11, Jenest

Necon 10/11, Nelova 10/11

Ethinyl estradiol (35 μg)

Norethindrone (0.5 mg × 10 days, 1 mg × 11 days)

TRIPHASIC

Ortho Tri-Cyclen Lo

 

Ethinyl estradiol (25 μg)

Norgestimate (0.18 mg × 7 days, 0.215 mg × 7 days, 0.25 mg × 7 days)

Cyclessa

Velivet

Ethinyl estradiol (25 μg)

Desogestrel (0.1 mg × 7 days, 0.125 mg × 7 days, 0.15 mg × 7 days)

Triphasil, Tri-Levlen

Trivora, Enpresse

Ethinyl estradiol (30 μg × 6 days, 40 μg × 5 days, 30 μg × 10 days)

Levonorgestrel (0.05 mg × 6 days, 0.075 mg × 5 days, 0.125 mg × 10 days)

Tri-Norinyl

 

Ethinyl estradiol (35 μg)

Norethindrone (0.5 mg × 7 days, 1 mg × 9 days, 0.5 mg × 5 days)

Ortho Tri-Cyclen

Tri-Sprintec, TriNessa

Ethinyl estradiol (35 μg)

Norgestimate (0.18 mg × 7 days, 0.215 mg × 7 days, 0.25 mg × 7 days)

Ortho-Novum 7/7/7

Nortrel 7/7/7, Necon 7/7/7

Ethinyl estradiol (35 μg)

Norethindrone (0.5 mg × 7 days, 0.75 mg × 7 days, 1 mg × 7 days)

Estrostep FE

 

Ethinyl estradiol (20 μg × 5 days, 30 μg × 7 days, 35 μg × 9 days)

Norethindrone acetate (1 mg)

EXTENDED CYCLE

Seasonale

 

Ethinyl estradiol (30 μg × 84 days followed by 7 placebo pills)

Levonorgestrel (0.15 mg)

Seasonique

 

Ethinyl estradiol (30 μg × 84 days followed by 10 μg × 7 days)

Levonorgestrel (0.15 mg)

Type of progestin may affect breakthrough bleeding.

All combination OCs contain either EE or mestranol. However, a variety of progestins have come into use. The 2 most common contraceptive progestins are derived from 19-nortestosterone, and are classified as gonanes or estranes.23

Continued...
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