www.AJOG.org

The state of hormonal contraception today: benefitsand risks of hormonal contraceptives: combinedestrogen and progestin contraceptives

Lee P. Shulman, MD

Over the course of the past 50 years,modifications have been made to

improve the effectiveness, acceptability,and tolerability of hormonal contracep-tives. Initially, the doses of the estrogenand progestin components were loweredand formulations were developed con-taining only progestin. Subsequently,new progestins were developed to de-crease androgenic side effects, and, morerecently, alternative delivery systemswere introduced to improve tolerabilityand continuance, and convenience ofuse.1 All combination hormonal contra-ceptives are highly effective in prevent-ing pregnancy when used properly; thechanges that have been made to pill reg-imens and components along the courseof the past 5 decades have been under-taken to improve tolerability and in-crease the likelihood of consistent andcorrect use to improve overall contra-ceptive effectiveness and maximize thenoncontraceptive benefits associatedwith contraceptive use.

Benefits and risks of combinationhormonal contraceptivesUnderstanding the benefits and risks ofcontraceptive methods and being able tocommunicate those to women are criti-

From the Division of Clinical Genetics,Feinberg School of Medicine NorthwesternUniversity; Department of MedicinalChemistry and Pharmacognosy, Universityof Illinois at Chicago College of Pharmacy,Chicago, IL.

Received Feb. 15, 2011; revised June 2, 2011;accepted June 10, 2011.

Publication of this article was supported by thePotomac Center for Medical Education.

The author reports no conflict of interest.

Reprints will not be available.

0002-9378/$36.00© 2011 Mosby, Inc. All rights reserved.

doi: 10.1016/j.ajog.2011.06.057

cal to improved acceptability and appro-priate use of effective birth control. Pro-viding detailed counseling to women atthe outset that addresses the advantages,disadvantages, benefits, and risks of var-ious contraceptive methods, invariablyleads to better outcomes in the future.Frequently, misconceptions exist withregard to the safety of hormonal contra-ceptives. Clinicians must balance risksagainst the benefits of contraception inthe context of a particular women’shealth history. Unintended pregnancy isusually the result of a lack of contracep-tive use or failure of the chosen contra-ceptive method. The impact of unin-tended pregnancy can be significant andencompasses health risks as well as ad-verse social and economic consequences.Health risks usually pertain to absent orpoor prenatal care and include an in-creased risk of maternal and neonatalmorbidity and mortality. Social and eco-nomic consequences include reducedmaternal education and employmentoptions, and an increased likelihood ofwelfare dependency. As such, unin-tended pregnancies place a substantialsocial, medical and economic burden onwomen and society.

In addition to preventing unintendedpregnancy, hormonal contraceptiveshave been shown to provide numerous

Discussion of effective birth control methodbecause the adoption and consistent use ofears, myths, and misperceptions. Over thecombination contraceptives or are used alonto decrease androgenic side effects and amphoric disorder. Alternative delivery systemimprove tolerability and continuance and coand progestin combinations and their effec

Key words: androgenic effects, contraceptvenous thromboembolism

noncontraceptive benefits.2 Oral contra-

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ceptives have been shown to reduce therisk of ovarian epithelial cancer and en-dometrial cancer without increasing therisk for breast cancer.3 Combinationhormonal contraceptives generally re-duce androgenic symptoms, with severaloral contraceptive regimens having beenformally approved for the treatment ofmild to moderate acne.2 Many women ofchildbearing age experience some degreeof physical and emotional symptoms re-lated to their impending menses. Someof these menstrual-related health issuesinclude heavy menstrual bleeding, head-ache, dysmenorrhea and behavioral,emotional, and physical symptoms asso-ciated with premenstrual dysphoric dis-order. Combination hormonal contra-ceptives have been shown to ameliorateor effectively treat these problems. Re-cently, in women choosing to use oralcontraceptives for pregnancy preven-tion, the 20 mcg EE/3 mg drospirenone24/4 regimen was approved by the USFood and Drug Administration (FDA)for the treatment of the symptoms ofpremenstrual dysphoric disorder4 andthe multiphasic E2V/DNG regimen wasapproved in Europe for the treatment ofheavy menstrual bleeding in women.5

As with any therapeutic agent, there isinvariably an increased risk for side ef-fects and adverse events that is concom-

an be a challenging process for cliniciansntraception may be influenced by patients’ars, new progestins have been included ino provide effective contraception as well asiorate the symptoms of premenstrual dys-nd regimens have also been introduced tonience of use. This is a review of estrogen

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Clinicians are in the position to weighthe risks and benefits of hormonal con-traceptives for each individual patient soas to empower that woman to decidewhich method, if any, to use to preventpregnancy. The use of combination oralcontraceptives is associated with an in-creased risk for thromboembolic events.In addition, other cardiovascular risksare increased especially among womenwho are smokers, are obese, or have per-sonal or family histories of cardiovascu-lar and other disease. However, manywomen believe that hormonal contra-ceptives are associated with great risk totheir health and well-being. Much of thisconcern stems from women reading thelay press, which highlights women whohave experienced considerable morbid-ity or even death while using such meth-ods.6 Unfortunately, such reports rarely,if ever, present information as to the rel-ative safety of such methods, especially incomparison to unintended pregnancy,which is characterized by profoundlyhigher rates of overall morbidity andmortality. Such fears have a powerfulimpact on women and all too often leadwomen either to choose less effectivemethods of contraception or to use nomethod at all, thus placing them at amuch higher risk for pregnancy and its

FIGURE 1Percent of women discontinuing a c

Shulman. Risks and benefits of hormonal contraceptives. Am

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Eliciting a woman’s choice for contra-ception during consultation is critical tothe process of her finding a method of con-traception that she can successfully incor-porate into her lifestyle. Although somewomen may find the recommendations ofher clinician to be important, it is the pa-tient who best knows the type of contra-ceptive regimen that she is likely to use cor-rectly and gain the maximal contraceptiveand noncontraceptive benefits associatewith her choice of contraception. Indeed, astudy to determine factors associated withsustained use of contraceptives found thatwhen the choice of birth control was de-nied by providing the patient with a popu-lar method of oral contraception at thetime of the study, about 72% of womendiscontinued its use within 12 months,whereas only 8.9% of those whose pre-ferred choice was granted eventually dis-continued the contraceptive (Figure 1).7

Whereas the disparity between those whocontinued with their birth control andthose who did not is impressive, the dis-continuation rate among those denied achoice is even more remarkable.

Adoption of effective birth controlmethods can be a challenging process forclinicians because of patient barriers—fears, myths, and misperceptions. Thesecan include unrealistic expectations, me-

raceptive based on choice offered

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merous noncontraceptive benefits. Of-fering women choices, discussing benefitsand risks, engaging women in birth-con-trol decision making, and listening towomen about their concerns and needs allsupport effective use.

Nondaily, nonoral combinationhormonal contraceptivesTwo nonoral, nondaily combination con-traceptive methods are available, the vagi-nal ring and a transdermal patch.8,9 Thesemethods have a number of characteristicsthat make them especially attractive towomen: they are highly effective, conve-nient, and easy to use. Because these meth-ods require less frequent attention to themethod than other birth control, they areless likely to be subject to inconsistent use.In addition, these methods likely have thenoncontraceptive benefits associated withother hormonal methods while not requir-ing daily administration.

Vaginal ringThe vaginal ring is a flexible transparentring that is inserted like a tampon. It pro-vides steady and continuous delivery oflow-dose hormone (120 mcg/d of etono-gestrel and 15 mcg/d of ethinyl estradiol)over 3 weeks, after which it is removedfor a hormone-free week.8 Lower dosesof estrogen afforded by vaginal adminis-tration may reduce the effects associatedwith higher doses of estrogen, such asbreast tenderness, nausea, and head-ache.10 The pharmacokinetics of the ringhow that contraceptive levels of etono-estrel and ethinyl estradiol are main-ained to 35 days of use, suggesting thatomen can extend use and may experi-

nce lighter or even absent withdrawalleeding during the ring-free week.11

Efficacy, cycle control, and acceptabil-ity were studied in a population of 2322women using the vaginal ring and fol-lowed for more than 23,000 cycles.12 Ef-ficacy, measured by the Pearl Index, was0.77 in the per-protocol population and1.18 in the intent-to-treat group. Thisstudy found that the majority of com-pleters (96%) were very satisfied with thering and 90% of them indicated that theywould recommend the ring to others.

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factors, key among which is cycle con-trol. The Dieben et al12 study reportedood cycle control among the ring users.lmost all women experienced with-rawal bleeding, which did not generallyccur outside the ring-free week, and,hen it did, it was mainly spotting rather

han bleeding.12 In another study, therofile of irregular bleeding was more fa-orable with the ring than with an oralevonorgestrel/ethinyl estradiol contra-eptive.10 In this study and in clinical ob-

servation, the incidence of irregularbleeding in the combination oral contra-ceptive (COC) group was particularlyhigh during the first cycle.10 This was notthe experience among women using thering, although this may be attributed tothe fact that women starting the pill usu-ally do so on day 1 of the cycle, whereasthe ring users started on day 5.10

Transdermal patchThe transdermal patch contains 6.00 mgnorelgestromin and 0.75 mg ethinyl es-tradiol and is a highly effective method ofcontraception, applied weekly for 3weeks with a fourth week off.13 An anal-sis of pooled data from 3 open-labeltudies reported a Pearl Index of 0.88nd a low failure probability of 0.6%ith the patch.14

The patch is also well accepted bywomen, and it may offer advantages overCOCs, including convenience and bettercontinuance of use. Using data pooledfrom 3 studies, researchers assessed com-pliance patterns of the patch comparedwith those of an established oral contra-ceptive.15 For all cycles, adherence to theweekly dosing schedule of the patch wassignificantly better than that of the oralcontraceptive regardless of age of thewomen (P � .001) (Figure 2).15

A pharmacokinetic study showed meansteady-state concentrations ranged from0.305–1.53 ng/mL for the progestin com-ponent and from 11.2-137 pg/mL for theestrogen component of the patch.13 In astudy that compared the patch with a COCcontaining 250 mcg norelgestromin and35 mcg ethinyl estradiol, the overall expo-sure to these steroids (area under thecurve) was greater with the patch.13 A

tudy examining the pharmacokinetic y

roperties of 3 hormonal contraceptiveormulations (a vaginal ring, the transder-

al patch, and a COC containing 30 mcgthinyl estradiol) found that the maximallood level of ethinyl estradiol with theatch was about 60% less than that of theOC.16,17 A case-controlled study com-

pared the risk of nonfatal venous throm-boembolism (VTE) in women using thetransdermal patch to that of women usinga COC containing 35 mcg of ethinyl estra-diol. The study found that the odds ratiofor VTE for transdermal patch users was0.9, representing no increased risk for VTEand similar to the risk observed in new us-ers of the COC comparator.17 Anothertudy found a 2-fold increased risk for VTEith the patch.18 Based on this negative in-

ormation, the US FDA issued a warningoncerning the possible increased risk ofTE with patch use. Since then, a third re-ort of a case-controlled study using post-arketing data found that in women un-

er 40 years of age, there was no increasedisk of VTE with the transdermal patch,ompared with a levonorgestrel-contain-ng COC.19 The authors concluded thathe risk of idiopathic VTE in users of theransdermal patch was not different fromhat of users of levonorgestrel-containingOCs in women 39 years of age or

FIGURE 2Percent of women adherent to theiregimen (transdermal patch or ora

NG, levonorgestrel.9

hulman. Risks and benefits of hormonal contraceptives. Am

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Combination oral contraceptivesThe daily COC remains the most com-monly used nonbarrier method of re-versible contraception. When properlyused, it is more than 99% effective.20 Ineality, about half of women use COCsorrectly and consistently,21 a study of

use patterns showed that 37% of womenreported that they discontinued theirCOC because of side effects.21 Seriousomplications, like deep vein thrombo-is or pulmonary embolism, are rare, andside from a few persistent intolerableide effects— breast tenderness, spot-ing—the pill has few absolute contrain-ications and several noncontraceptiveenefits. Refer to the package insert toeview the complete list of contraindica-ions and special considerations. Recentevelopments in OCs have focused on:

● The development of a pill or pill regi-men that improves tolerability and ac-ceptability.

● Lowering doses and altering deliverypatterns of estrogen and progestins.

● The development of new progestins.

Drospirenone-containing COCDrospirenone is a novel progestin notderived from 19-nortestosterone butrather from 17alpha-spirolactone and

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drogenic activity.22 Combined with ethi-yl estradiol, it is an effective oral contra-eptive23,24 and has favorable effects in

women who have premenstrual dys-phoric disorder (PMDD).22 In addition,ts antimineralocorticoid properties havehe potential to lower body weight (throughater weight change and not loss of fat)

nd blood pressure.22

Two prospective studies have been un-dertaken to examine the cardiovasculareffects of the drospirenone-containingCOC— one conducted in Europe25 andthe other in an American population.26

Both studies found that deep veinthrombosis and pulmonary embolismoccurred with equal frequency in theethinyl estradiol/drospirenone COC andother COC users (Figure 3).25,26 The USstudy observed that a clinician can ex-pect to find one case of thromboembo-lism among 769 women over the courseof 1 year if they were prescribed the dro-spirenone-containing COC.26

Two more-recent studies, both usingEuropean populations, have also exam-ined thrombotic events in users ofCOCs.27,28 The Dutch study found anincreased risk of venous thrombosis,which differed by type of progestin and

FIGURE 3Comparison of risk for venous throcomparing oral contraceptives with

CI, confidence interval; DVT, deep vein thrombosis; EURAS, Europmbolism; TE, thromboembolism; VTE, venous thromboembolism

Shulman. Risks and benefits of hormonal contraceptives. Am

dose of estrogen, with all of the COCs.28

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The Danish study also found an increasedrisk, which differed by type of progestin,that decreased with duration of use and de-creasing estrogen dose.27 All of the studyresults are now included in the prescribinginformation for the drospirenone-con-taining COCs; however, the FDA alsoadded a statement that the results of theDutch and Danish studies do not provideconvincing evidence of an increased riskfor VTE, given the relatively few number ofVTE cases among drospirenone users inthe Dutch study and a likelihood of ascer-tainment bias in the Danish study.

The rationale for shortening the hor-mone-free interval in women usingCOCs was improvement in ovarian sup-pression as well as reduction of adversesymptoms experienced during the hor-mone-free interval.29-31 An early studyound that by adding 2 days to the COCegimen, ovarian suppression improvedontraceptive efficacy.32 This was testedn the extended use of a low-dose 20-mcgthinyl estradiol COC, and results showedhat the efficacy of the 24-day low-doseOC improved efficacy.33

The COCS of the futureTwo COCs in development are a 26-day

oembolism in 2 prospective trialsnd without drospirenone

Active Surveillance Study; OC, oral contraceptive; PE, pulmonary9

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multiphasic regimen of estradiol valerate

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and dienogest and a COC containing 17beta-estradiol and nomegestrol ace-tate.34-36 Although the use of estradiol val-erate may have some advantages over ethi-nyl estradiol, there are no head-to-headstudies of ethinyl estradiol and estradiol-containing pills to date. The 26-day multi-phasic combination of estradiol valerateand dienogest provides reliable contracep-tion and, with only 2 days off, may providelighter withdrawal bleeding than does atraditional pill containing ethinyl estradioland levonorgestrel.34

The other new pill contains 17 beta-estradiol and nomegestrol acetate in amonophasic regimen. A recent pharma-cologic and pharmacokinetic study indi-cates good ovulation suppression withthis combination, with mean maximumfollicular diameter decreased from 19.3mm before treatment to between 6.9 and8.2 mm during treatment.36 The findingsfrom this study are consistent with ovu-lation inhibition produced by oral con-traceptives containing ethinyl estradioland drospirenone.

As the investigation of new com-pounds continues, it will add to the arrayof effective combination hormonal con-traceptives available to women. The ex-pansion of contraceptive choice can onlyimprove the likelihood that a womanwill find a method of contraception thatshe will successfully incorporate into herlifestyle and use consistently and cor-rectly for as long as she chooses not to bepregnant. As many hormonal methodscarry similar capabilities to prevent preg-nancy, it will be the availability of meth-ods with unique noncontraceptive ben-efits that will help women find a methodthat is right for them. It is important thatresearch continues to improve tolerabil-ity and acceptability of contraceptive op-tions, preserve efficacy, and delineatenoncontraceptive benefits, while lower-ing hormone exposure and improvingthe safety profile. f

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