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REVIEW

Helping Women Choose Appropriate Hormonal

Contraception: Update on Risks, Benefits, and IndicationsAbby L. Spencer, MD, MS,a Rachel Bonnema, MD, MS,b Megan C. McNamara, MD, MScc

a Department of Medicine, Section of General Internal Medicine, Allegheny General Hospital, Pittsburgh, Pa; b Department of Medicine,

Section of General Internal Medicine, University of Nebraska Medical Center, Omaha; and c Department of Medicine, Section of

General Internal Medicine, Case Western Reserve University, Cleveland, Ohio.

ABSTRACT

Primary care physicians frequently provide contraceptive counseling to women who are interested in

family planning, have medical conditions that may be worsened by pregnancy, or have medical conditions

that necessitate the use of potentially teratogenic medications. Effective counseling requires up-to-dateknowledge about hormonal contraceptive methods that differ in hormone dosage, cycle length, and

hormone-free intervals and are delivered by oral, transdermal, transvaginal, injectable, or implantable

routes. Effective counseling also requires an understanding of a woman’s preferences and medical history

as well as the risks, benefits, side effects, and contraindications of each contraceptive method. This article

is designed to update physicians on this information.

© 2009 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2009) 122, 497-506

KEYWORDS: Contraception; Contraception counseling; Contraceptive choice; Women’s health

The rate of unintended pregnancies in the United States is

nearly 1 in 5 for women of all ages and 1 in 10 for women

aged 18-24 years.1 Because primary care physicians rou-

tinely provide treatment for a variety of medical condi-

tions, including conditions that may be adversely affected

by pregnancy and conditions that necessitate the use of

potentially teratogenic drugs,2 it is important for them to

have a thorough knowledge of contraceptive methods.

Women today have the option of using new types of oral

contraceptives that differ from traditional types in terms of

hormone dosages, cycle length, and hormone-free intervals.

They also have the option of using contraceptives with a

variety of hormone delivery systems, including transdermal,

transvaginal, injectable, and implantable devices. In this

review, we discuss newer contraceptives and give special

consideration to their use by women with medical disorders.

Intrauterine devices or systems may be appropriate for

many women seeking effective long-term contraception but

are beyond the scope of this article which focuses primarily

on newer hormonal methods. We present 3 clinical vignettes

and use the vignettes to discuss controversies about benefits

and risks associated with different contraceptive methods.

CASE 1A 27-year-old woman presents to you for advice about

contraception. She says she would be willing to take oral

contraceptive pills on a daily basis. She typically expe-

riences bloating and pain for 3 days before her menses

and reports that her menstrual flow is heavy and lasts for

6 days. She smokes a pack of cigarettes a week, and hermother had breast cancer at the age of 65 years.

How Do Oral Contraceptive Pills Work?Oral contraceptive pills are agents that contain estrogen

(ethinyl estradiol) and a progestin. They work primarily

by preventing the surge of luteinizing hormone and

thereby preventing ovulation, but they also thicken the

cervical mucus and alter the endometrial lining to help

prevent fertilization or implantation. Failure rates of oral

contraceptive pills vary from 0.3% with perfect use to 8%

Funding: None.

Conflict of Interest: None.

Authorship: Each author was involved in the conception, design, and

the writing of the manuscript, and approved the submitted version of the

manuscript.

Requests for reprints should be addressed to Abby L. Spencer, MD,

MS, Department of Medicine, Division of General Internal Medicine,

Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA

15212.

E-mail address: [email protected]

0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved.

doi:10.1016/j.amjmed.2009.01.016

mailto:[email protected]

mailto:[email protected]





Table 1 Characteristics of Contraceptive Methods

Method Description

Average Cost per

Month Failure Rate

Side Effects and

Drawbacks Special Considerations

Traditional oral

contraceptive

pills (OCPs)

Packet of 21 tabs

containing ethinyl

estradiol (20-50 g)

and progestin; 7

placebo tabs.

$20-$60 0.3% with perfect

use; 3%-8%

with typical

use.

Spotting; nausea;

headache; breast

tenderness;

breakthrough

bleeding; venous

thromboembolism(VTE); stroke;

myocardial

infarction (MI).

Consider for women with

dysmenorrhea,

menorrhagia, irregular

menstrual periods,

acne, hirsutism, or

polycystic ovarysyndrome (PCOS).

Women can expect

rapid resolution of

fertility after stopping

OCPs.

Extended-cycle

OCPs

Yasmin Packet of 28 tabs

containing ethinyl

estradiol (20 g)

and drospirenone (3mg); 7 placebo tabs.

$ϳ60 Similar to rates of

traditional

OCPs.

Spotting; nausea;

VTE; stroke; MI.

Same as traditional OCPs.

Might be safer for

women with mild

hypertension givenmodest reductions in

SBP seen with

drospirenone. Might

offer particular benefit

to women with acne,

hirsutism, and

evidence of PCOS.

Yaz Packet of 24 tabs

containing ethinyl

estradiol (20 g)

and drospirenone (3

mg); 4 placebo tabs.


traditional

OCPs.

Spotting; nausea;

VTE; stroke; MI.

Same as Yasmin. Shorter

HFI may offer

particular benefit for

women with estrogen

withdrawal symptoms.

Particular benefit inwomen with

premenstrual dysphoric

disorder.

Loestrin 24 Packet of 24 tabs

containing ethinyl

estradiol (20 g)

and norethindrone (1

mg); 4 placebo tabs.


traditional

OCPs.

Spotting; nausea;

VTE; stroke; MI.


Shorter HFI may offer


women with estrogen

withdrawal symptoms.



Table 1 Continued

Method Description

Average Cost per

Month Failure Rate

Side Effects and


Seasonale Packet of 84 tabs

containing ethinyl

estradiol (30 g)

and levonorgestrel

(0.15 mg); 7 placebo

tabs.


traditional

OCPs.

Spotting; nausea;

VTE; stroke; MI.

Unknown if

additional days of

estrogen exposure

increases risk.


Fewer withdrawal

bleeds per year and

shorter HFI may offer


women with estrogenwithdrawal symptoms,

dysmenorrhea or

endometriosis.

Withdrawal bleed is

once every 3 months

or once/season.

Seasonique Packet of 84 tabs

containing ethinyl

estradiol (30 g)

and levonorgestrel

(0.15 mg); 7 tabs

containing ethinyl

estradiol (10 g); 0placebo tabs.


traditional

OCPs.

Spotting; nausea;

VTE; stroke; MI.

Unknown if

additional days of

estrogen exposure

increases risk.

Same as Seasonale. Might

be more helpful for

women with

dysmenorrhea or

endometriosis.

Withdrawal bleed is

once every 3 monthsor once/season,

shorter HFI than

Seasonale.

Lybrel Packet of 28 tabs

containing ethinyl

estradiol (20 g)

and levonorgestrel

(0.09 mg); 0 placebo

tabs.


traditional

OCPs.

Spotting; nausea;

VTE; stroke; MI.


Shorter HFI can offer


women with estrogen

withdrawal symptoms,

dysmenorrhea, or

endometriosis. Option

for women who do not

desire monthly periods.

Ortho Evra Transdermal patch thatis applied once a

week and releases

ethinyl estradiol (75

g) and

norelgestromin (6

mg) during the week.

$50-$60 0.3% with perfectuse; 8% with

typical use.

Efficacy may be

reduced in

obese women.

VTE; stroke; MI;reaction at site of

application.

Consider for women whoare unable to take pills

on a daily basis but

would benefit from

combined estrogen and

progestin

contraceptive. Might

have increased risk of

VTE as compared with

OCPs.



Table 1 Continued

Method Description

Average Cost per

Month Failure Rate

Side Effects and


NuvaRing Soft plastic ring that is

inserted vaginally

and releases ethinyl

estradiol (15 g)and etonogestrel

(0.12 mg) each day

for at least 3 weeks.

$50-$60 0.3% with perfect

use; 8% with

typical use.

Leukorrhea; VTE;

stroke; MI;

vaginal

discomfort. Rarerisk of ring falling

out.

Consider for women who

would benefit from a

combined estrogen and

progestin contraceptivebut who are either

obese or unable to

take pills on a daily

basis.

Depo-Provera Injectable formula of

medroxyprogesterone

acetate that is

administered

intramuscularly (150

mg) or

subcutaneously (104

mg) every 12 weeks.

$16-$20 ($50-

$90 per

injection)

0.3% with perfect

use; 3% with

typical use.

Irregular bleeding;

transient decrease

in bone mineral

density; may have

delayed

reversibility.

Consider for women who

have dysmenorrhea,

seizure disorder,

hemoglobinopathies,

migraine headache

with aura, or a history

of cardiovascular

disease, stroke,

thromboembolism, orperipheral vascular

disorder. Consider for

women who are unable

to use products

containing estrogen or

have a desire for long-

term contraception.

Does not increase the

risk of VTE, stroke, MI,

breast cancer, or bone

fracture.

Implanon Single-rod device that

is implantedsubdermally in the

upper arm, releases

etonogestrel, active

for 3 years.

$15 ($500-$750

per implant)

0.05% with

perfect ortypical use.

Irregular bleeding. Consider for women who

have dysmenorrhea,are unable to use

products containing

estrogen, or have a

desire for long-term

contraception. Is safe

for women who are

breastfeeding.



and antimineralocorticoid activity of Yasmin causes less

weight gain and water retention and may offer a greater

reduction in acne and hirsutism than that offered by tradi-

tional oral contraceptive pills.20 Additionally, Yasmin can

lower systolic and diastolic blood pressure up to 4 mm

Hg.20,21 Although potassium retention is a potential side

effect of Yasmin use, this problem has not been found in

clinical trials. Nevertheless, Yasmin is contraindicated inpatients with renal, hepatic, or adrenal insufficiency.22

During the standard 7-day hormone-free interval that

occurs with use of low-dose estrogen formulations, the

function of the hypothalamic-pituitary-ovarian axis recovers

rapidly, and this increases the risk of ovarian follicle devel-

opment, ovulation with unintended pregnancy, and in-

creased spotting due to endogenous estradiol produc-

tion.23-27 Fluctuating hormone levels allow endometrial

buildup and can exacerbate premenstrual symptoms and

menstrual headaches by creating hormone excess and with-

drawal states.24-27 The newer extended-cycle oral contra-

ceptive pills with a shorter or eliminated hormone-free in-terval reduce the risk of these unwanted effects by

preventing endogenous estradiol production while still pro-

viding highly effective and safe contraception.13,16-18,27

Discussing a patient’s preferences for menstrual frequency

and tolerance for scheduled and unscheduled bleeding will

be important in deciding which contraceptive will best fit

her needs. For example, Lybrel, the first Food and Drug

Administration (FDA)-approved oral contraceptive pill

taken 365 days per year, is an option for women with

hormone withdrawal symptoms who do not desire sched-

uled monthly periods, as there is no hormone-free interval.

Safety, efficacy, and resolution of fertility are similar toother oral contraceptive pills.18,19

If a woman is having difficulty remembering to take a

daily pill but would like to have the benefits of a combined

estrogen-progestin contraceptive, there are two options

available: the Ortho Evra patch and the NuvaRing.

The Ortho Evra patch is a thin transdermal patch con-

taining 75 g of ethinyl estradiol and 6 mg of

norelgestromin. Although the patch is generally as effective

as oral contraceptive pills (Table 1), studies have shown that

it has decreased efficacy in women who are obese (Ͼ90

kg).28 Most of the side effects, cardiovascular risks, and

contraindications are similar to those of other combined-hormone contraceptives. While one study showed no dif-

ference in the risk of venous thromboembolism with use of

the patch versus oral contraceptive pills, other studies

showed that the risk was twice as high with the patch as

compared with oral contraceptive pills containing norgesti-

mate or levonorgestrel.29 These studies were the basis for

updating the Ortho Evra label to indicate a higher risk of

venous thromboembolism.29 Of note, the venous thrombo-

embolism risk associated with patch use is lower than the

venous thromboembolism risk associated with pregnancy.30

NuvaRing is a soft plastic ring that is inserted vaginally,

usually for 3 weeks, and then removed for 1 week (thehormone-free interval). The ring releases 15 g of ethinyl

estradiol and 0.12 mg of etonogestrel daily for 3-5 weeks, so

it can be kept in longer than 3 weeks. Each ring releases

about half the level of hormones as the average oral con-

traceptive pill without affecting efficacy. If the ring falls out

(as occurs in 2.5% of women per year), it can be rinsed and

reinserted without a change in efficacy. Unlike the patch,

the ring is not affected by excess weight. Most women find

the ring easy to insert and remove and comfortable to retainduring intercourse.31 NuvaRing has been associated with an

increase in leukorrhea. Otherwise, its side effects, cardio-

vascular risks, and contraindications are similar to those of

other combined-hormone contraceptives (Table 2).

CASE 2A 31-year-old woman with a history of seizure disorder

presents to your office to discuss Depo-Provera (Pfizer, New

York, NY). She has been using this injectable contraceptive

for 2 years. She likes not having to take a daily pill and is

pleased that her menstrual cycles have lightened substan-tially. However, she read some recent reports about the

effects of Depo-Provera on “bone strength” and wonders if

it is still safe for her to use.

How Does Depo-Provera Work?Depo-Provera (depot medroxyprogesterone acetate) is a

progestin-only contraceptive that was approved by the FDA

more than 15 years ago.32 Depo-Provera can be given in-

tramuscularly (150-mg dose) or subcutaneously (104-mg

Table 2 Take-Home Points: Case 1

Oral contraceptive pills (OCPs) are comprised of varying doses of

estrogen and progesterone, which prevent pregnancy by

inhibiting ovulation, thickening cervical mucus, and altering

the endometrial lining.

Common side effects of OCPs include nausea, headaches, breast

tenderness, and breakthrough bleeding.

More rare but serious side effects include VTE, stroke, and

myocardial infarction. These risks are increased in women

with migraines with aura, uncontrolled hypertension, diabetes

with complications, and in women aged Ͼ35 years who

smoke. Drosperinone-containing OCPs or progestin-only

contraceptives may be safer options for women with mild

hypertension.

OCPs are not associated with an increased risk of breast cancer

in non-mutation carriers.

Extended-cycle OCPs may reduce unwanted menstrual symptoms

by preventing endogenous estradiol production with shorter

hormone-free intervals.

Discussing your patients’ preferences for menstrual frequency

and tolerance for scheduled and unscheduled bleeding will be

important in deciding whether a traditional or extended-cycle

OCP will best fit her needs.

Ortho Evra patch and NuvaRing are combined-hormonal options

if a woman can not take a daily pill; OrthoEvra may be less

effective in obese women (Ͼ90 kg).

OCPsϭ oral contraceptive pills; VTEϭ venous thromboembolism.

502 The American Journal of Medicine, Vol 122, No 6, June 2009



dose). It is highly effective and works by thickening the

cervical mucus, preventing ovulation through suppression

of the luteinizing hormone surge, and altering the endome-

trial lining.33 Its slow absorption through the subcutaneous

tissues provides adequate systemic levels of progesterone

for at least 14 weeks, although women are instructed to

return in 12 weeks to ensure timely administration.33

Who Are Good Candidates for Depo-Provera?Depo-Provera is safe for women with a history of cardio-

vascular disease, stroke, thromboembolism, or peripheral

vascular disease.6 It is ideal for women with hemoglobinop-

athies, such as sickle cell disease, because these women will

likely notice a decrease in painful hemolytic crises.34 Women

with seizure disorder are especially good candidates for Depo-

Provera. Anticonvulsants can increase hepatic metabolism of

estrogen and progesterone in oral contraceptive pills, thereby

lowering contraceptive efficacy.6,32,33 However, Depo-Provera

is effective in women taking these medications, presumably

secondary to its high progesterone levels;33,35 moreover, Depo-

Provera can decrease the frequency of seizures.35

What Are the Side Effects of andContraindications for Depo-Provera?Commonly reported side effects associated with Depo-

Provera include menstrual irregularities, weight gain, and

mood changes.32,33 Approximately 40% of women receiv-

ing Depo-Provera will experience amenorrhea within the

first 3 months of use;33 this may be considered a desirable

side effect for many users.32 About 2% of women will

discontinue Depo-Provera within the first 2 years due toweight gain, although studies are conflicting about whether

there is a true causal relationship.32

Several studies also have examined the risk of more

serious health consequences associated with Depo-Provera

use. According to the findings of an international, multi-

center, case-control study published by the World Health

Organization (WHO),36 Depo-Provera users were not more

likely than nonusers to experience stroke, acute myocardial

infarction, or venous thromboembolism, and the overall

combined risk for cardiovascular disease was similar in

users and nonusers. Pooled results from the WHO trial and

a similar trial conducted in New Zealand indicated that therelative risk for breast cancer among women who used

Depo-Provera sometime during their life was 1.1 (confi-

dence interval 0.97-1.40) and there was no increased risk

with longer durations of use.37

Depo-Provera reduces serum estradiol levels, and this

can adversely affect bone health. In 2004, the FDA issued a

black box warning that women who use Depo-Provera may

lose significant bone mineral density and recommended that

use be limited toϽ2 years.38 In 2006, a 7-year, prospective,

matched cohort study among young women showed that

Depo-Provera users had substantial bone mineral density

loss but that the loss was reversible with discontinuation of use.39 In 2006 and again in 2008, systematic reviews of

various studies reached the same conclusion about revers-

ibility of bone mineral density loss.40,41 The authors of the

2006 review identified only one study that evaluated the risk

of fracture among Depo-Provera users, and this study sug-

gested no association between stress fracture occurrence

and Depo-Provera use.40

The WHO has recommended that there be no restriction

on the use of Depo-Provera.42

Practitioners should advisepatients about the risk of bone mineral density loss but

reassure them about reversibility with discontinuation. They

also should recommend that Depo-Provera users exercise

regularly and increase their intake of calcium and vitamin D

(Table 3).

CASE 3A 31-year-old woman presents to your office to establish

care. She underwent 2 laparoscopies to treat severe endo-

metriosis more than 10 years ago. She is currently using an

extended-cycle oral contraceptive pill but has severe symp-toms every 3 months with menses. She previously tried

Norplant, which best controlled her symptoms but is no

longer available. She also tried Depo-Provera, which she

did not tolerate well. She is currently sexually active and in

a monogamous relationship. Results of her annual Pap

smears have been normal. You counsel her about various

methods of contraception, including Implanon (Organon

USA Inc., Roseland, NJ).

How Does Implanon Work?Implanon is a contraceptive device that is implanted sub-

dermally in the upper arm and remains active for 3 years. Itconsists of a single rod that contains etonogestrel, which is

the same progestin used in the NuvaRing. Implanon has

been available for more than 10 years but has been widely

marketed in the United States only since 2007.

Like other progestin-only contraceptives, Implanon works

by blocking the luteinizing hormone surge and thereby

preventing ovulation. It also thickens the cervical mucus

and thins the endometrial lining. Unlike other progestin-

only methods, Implanon causes estradiol to gradually in-

crease to normal endogenous levels after an initial de-

crease.43,44 Implanon is extremely effective in preventing

pregnancy and has an efficacy rate similar to that associa-ted with sterilization or use of an intrauterine device.43,45


Depo-Provera is a progesterone-only contraceptive method that

is safe in women with a variety of medical conditions

Depo-Provera does not increase the risk of stroke, myocardial

infarction, VTE, or breast cancer

Users of Depo-Provera may experience a decrease in bone

mineral density that is reversible with discontinuation and is

not associated with increased fracture risk

VTEϭ venous thromboembolism.

503Spencer et al Update on Contraception



Women experience a quick return to normal cycles after

implant removal, and there have been no reports of infer-

tility after removal.46 The cost of implantation is typically

$500-$750 and is often covered by health insurance.

Implantation and removal of Implanon require training

but can be performed as simple office procedures. For im-

plantation, the clinician gives the patient a local anesthetic

and then uses a preloaded, disposable applicator supplied bythe manufacturer to insert the rod about 3 fingerbreadths

above the medial epicondyle of the humerus. The correct

placement is confirmed by palpation. Difficulty with re-

moval is experienced in only 2%-3% of patients, and the

usual cause is that the implant was placed too deep in

the arm.47

How Does Implanon Differ from Norplant?Norplant was a highly effective implant system that con-

sisted of 6 rods containing levonorgestrel.43 In 2002, Nor-

plant production was halted in the United States after clini-cians and patients complained about difficulty in removing the

device and after the manufacturer found it necessary to

recall a single lot of the implant devices because they

released lower-than-expected levels of hormone.

Serum etonogestrel levels in Implanon users have been

shown to have less variability than levonorgestrel levels

in Norplant users.48 After removal of the etonogestrel

implant, etonogestrel levels fall quickly. Within a week,

etonogestrel becomes undetectable and ovulation quickly

follows.45

What Are the Side Effects and BeneficialNoncontraceptive Effects of Implanon?Like other progestin-only contraceptives, Implanon may

cause irregular bleeding. During the first 3 months of use,

about 50% of women experience infrequent bleeding. At 6

months, about 30%-40% have amenorrhea, 30% have in-

frequent bleeding, and the remainder experience frequent or

prolonged bleeding.49 Discontinuation of use usually occurs

during the first 8-9 months and is generally due to frequent

or prolonged bleeding.49

Implanon has other effects to consider. One study indi-

cated that its use was associated with a decrease in symp-toms of dysmenorrhea in 80% of women with a history of

this disorder. Although many progestin-only contraceptives

are associated with an increase in weight, the increase with

Implanon is relatively low (about 0.7 kg/m2) and only about

3%-7% of Implanon users have their implant removed be-

cause of weight gain.43 Implanon has mixed effects on acne,

but about 70% of women with acne experience no change in

their condition.50 There have been no long-term studies

about Implanon, bone mineral density, and fractures. How-

ever, a study that followed Implanon users and nonhor-

monal intrauterine device users for 2 years showed no

clinically significant difference in the bone mineral densitylevels of these 2 groups.44

What Are the Contraindications for Implanon?Implanon is contraindicated in women being treated with

CYP3A-inducing or CYP3A-inhibiting medications. While

inducers of CYP3A might decrease the efficacy of Implanon

and lead to unintended pregnancy, inhibitors of CYP3A might

increase serum etonogestrel levels and cause toxicity.6

Implanon is contraindicated in women with active liver

disease or active venous thromboembolism, but these con-

traindications are controversial. Some studies indicate that

etonogestrel causes mild abnormalities in results of liver

function tests, but the abnormalities are thought to be of

minimal clinical significance.43,49 Progestin-only methods

of contraception have long been considered safe to use in

women with an increased risk of venous thromboembolism

(eg, women who smoke or have hypertension, diabetes

mellitus, migraine headaches, or a history of venous throm-

boembolism).6,51,52 However, active venous thromboem-

bolic disease is listed as a contraindication in the packaging

information for several progestin-only methods, including

Implanon. Unfortunately, there are no data available on the

association between Implanon use and venous thromboem-

bolism, and only one small study has examined the effect of

Implanon on hemostatic elements. In this open-label study,

there was no change in prothrombin time, partial prothrom-

bin time, or levels of fibrinogen or other coagulation vari-

ables over a 6-month period.53 Therefore, most experts

consider Implanon to be an acceptable choice for women

who have venous thromboembolism and cannot use contra-

ceptives that contain estrogen (Table 4).43

SUMMARYPhysicians need up-do-date information to help each patient

choose a contraceptive that is appropriate based on her

medical history and preferences for a pill, implant, or other

method. If a woman’s medical condition requires treatment

with a potentially teratogenic drug, it is imperative that her

physician counsel her about the wide range of contraceptive

methods that are available. If estrogen is contraindicated,

progestin-only methods can be used in most cases. The

newer formulations and extended-cycle regimens reviewed


Implanon is a highly effective, quickly reversible, long-term

contraceptive using a single rod subdermal implant containing

the progestin etonogestrel.

Implanon is an alternative for women who cannot use estrogen-

based contraceptives and is safe to use during breastfeeding.

Most important preimplantation counseling point is the

possibility of irregularly irregular bleeding patterns, although

many women experience infrequent bleeding or amenorrhea.

80% of women with dysmenorrhea at baseline will have an

improvement in symptoms with no major effects on weight,

acne, or bone mineral density.




here are attractive options that offer both contraceptive and

noncontraceptive benefits.

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