ISSUES IN CONTRACEPTION
Educational Objectives
| The goal of this program is to improve hormone withdrawal symptoms in women using oral contraceptives
(OCs) and to reduce the risk for unintended pregnancy by the proper prescribing of emergency contraception
(EC). After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Cite evidence that supports modifying the conventional 21/7 OC regimen.
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| 2. Modify a patient’s OC regimen to reduce menstrual-related symptoms.
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| 3. Explain the mechanism of action of EC.
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| 4. Recognize appropriate scenarios for administering EC and prescribe the appropriate agent.
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| 5. Address reproductive health issues with adolescent patients.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts
of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health
care and not a proprietary business or commercial interest. Dr Sulak receives research grants from Organon and Warner
Chilcott, and is a consultant for Duramed and Bayer. Dr. Gibson is a senior trainer for and receives honoraria from Organon.
The planning committee reported nothing to disclose.
Acknowledgments
Dr. Sulak was recorded at Women’s Health Update 2008 sponsored by Mayo Clinic, Scottsdale, and held on April 17-
19, 2008, in Scottsdale, AZ. Dr. Gibson was recorded at Women’s Health Issues for Primary Care Providers, sponsored
by The University of Vermont College of Medicine, held on May 7-9, 2008, in Burlington, VTt. The Audio-Digest
Foundation thanks the speaker and the sponsors for their cooperation in the production of this program.
| THE REDESIGN OF CONTRACEPTION: THE DEMISE OF 21/7 REGIMENS —Patricia J. Sulak, MD, Professor, Texas
A&M University College of Medicine; Director, Scott and White Adolescent Sex Education Program; and Medical Director,
Division of Departmental Research, Department of Obstetrics and Gynecology, Scott and White Clinic and Hospital,
Temple, TX
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| Rationale for 21/7 regimen: mimics average 28-day menstrual cycle; creates artificially induced monthly bleeding (reassuring
woman not pregnant); socially acceptable; current dosage significantly reduced from earlier formulations, leading
to hormone withdrawal symptoms and incomplete pituitary-ovarian suppression; hormone withdrawal symptoms in users
of oral contraceptives (OCs)—prospective study of 262 women showed almost all symptoms assessed (eg, headaches,
cramps, bloating and swelling, breast tenderness) worse during 7-day hormone-free interval than during 21 days of hormone-containing
pills; 50% of women stop OCs in <1 yr because of side effects created by 21/7 regimen
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| Shortening hormone-free interval: prospective randomized trial of serum hormone levels in 12 patients on OCs; first cycle
21/7 regimen; second cycle abbreviated 3- or 4-day hormone-free interval; blood drawn on 9 consecutive days in both
cycles, beginning on day of pill 21 and continuing for 9 days, through hormone-free interval; follicle-stimulating hormone
(FSH) first hormone to increase during hormone-free interval, signaling ovary to make estradiol and inhibin-B; hormone
levels begin to decrease when patient starts next pack of OCs; patient begins early withdrawal bleeding before
hormone-free interval; 7-day hormone-free interval causes symptoms and interferes with menstrual cycle; with shortened
hormone-free interval, pituitary-ovarian axis suppression greater; effect of 21/7-day and 24/4-day OC regimens on ovarian
activity—data show no ovarian cysts in women using 24/4 regimen vs 6 cases of cysts in 21/7 group; OCs, tubal
sterilization, and functional ovarian cysts—data show low-dose (≤35 µg) OCs have little or no effect on functional ovarian
cysts because of 7-day hormone-free interval
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| Reasons to modify 21/7 contraception regimen: common withdrawal symptoms associated with 7-day hormone-free interval;
development of functional ovarian cysts, and possible ovulation and pregnancy; withdrawal bleeding artificial and
unnecessary; data confirm need for modification; issues in modifying—determine patient’s preference for menstrual frequency
(ie, every month? every 3 mo? never?); determines which method of modification to use (eg, hormone-free interval
shortened to <7 days, decrease in frequency of interval, addition or elimination of estrogen)
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| Methods of modifying interval
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| Shorten to <7 days: 2 OC formulations approved by Food and Drug Administration (FDA) that shorten hormone-free interval
to 4 days; 20 µg ethinyl estradiol plus 3 mg drospirenone (YAZ) and 20 µg ethinyl estradiol plus 1 mg norethindrone
acetate (Loestrin 24 Fe) shown to have greater pituitary-ovarian suppression; greater number of active pills; maintains 28-
day menstrual cycle for woman desiring monthly menstrual period; YAZ only medication other than selective serotonin
reuptake inhibitors (SSRIs) FDA-approved for premenstrual dysphoric disorder (PMDD); response rate similar to that for
sertraline (Zoloft), paroxetine (eg, Paxel), and fluoxetine (eg, Prozac); although Yasmin also drospirenone plus ethinyl estradiol,
not effective for PMDD because of 21/7 regimen
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| Decrease frequency of interval: 30 µg ethinyl estradiol plus 0.15 mg levonorgestrel (Seasonale) first FDA-approved extended
regimen; regimen 84 days of combined active pills, followed by 7-day hormone-free interval (91-day cycle); during
7-day interval, ovary begins to make estrogen; ovary-made estrogen combined with estrogen from OC causes
breakthrough bleeding (BTB); less acceptable than 21/7 regimen
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| Add estrogen: 20 µg ethinyl estradiol plus 0.15 mg desogestrel (Mircette) first OC to have estrogen added to 5 of 7 hormone-
free days; results in greater pituitary-ovarian suppression; BTB rate with Mircette equal to that of most 30-µg OCs; ethinyl
estradiol plus levonorgestrel (Seasonique) has 84/7 phasic regimen (84 days of 30 µg ethinyl estradiol plus 0.15 mg
levonorgestrel, then 7 days of 10 µg ethinyl estradiol alone); Seasonique superior to 30 µg ethinyl estradiol plus 0.15 mg
levonorgestrel (Portia; Seasonale) in inhibiting pituitary gland; patients on extended-regimen OCs should not take 7 days
off
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| Entirely eliminate menstrual period: continuous estrogen and progestin regimens provide greater pituitary-ovarian suppression;
should result in reduction in premenstrual symptoms if taken correctly; data show extended placebo-free regimens
lead to decrease in headaches and symptoms of premenstrual syndrome (PMS), compared to 21/7 regimens; 20
µg ethinyl estradiol plus 0.09 mg levonorgestrel (Lybrel) FDA-approved continuous regimen; ultra–low-dose OC; BTB
reported
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| Why alter menstruation? menstrual disorders affect millions of women of reproductive age; costly in terms of time lost
from work and family; helpful to change reproductive patterns from past (eg, early menarche, late childbearing, low parity,
shortened or absent breast-feeding, increased longevity, more menses); incessant ovulation associated with health
risks; reducing frequency of menses can result in fewer health risks; data show bleeding during extended cycle well managed
with 3-day hormone-free interval; patients on continuous contraception regimens should never take 7 days off
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| Summary: ensure patient understands difference between natural ovulatory menstruation (ie, lush secretory endometrium)
and artificially induced “pill periods” (attenuated decidualized endometrium); important to know when menstruation necessary
and when not; potential for improved quality of life with modification of 21/7 regimen
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| HORMONAL EMERGENCY CONTRACEPTION —Cheryl A. Gibson, MD, Clinical Associate Professor of Obstetrics
and Gynecology, University of Vermont College of Medicine, Burlington, and Medical Director, Planned Parenthood of
Northern New England, Williston, VT
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| History: term “emergency contraception” (EC) refers to hormones used in common doses as postcoital emergency protection
against pregnancy; products not abortifacients; in 1963—first reported use (in Netherlands); Ary Hapels, MD, administered
high doses of postcoital estrogen to 13-yr-old rape victim; mid 1960s—major clinical trial at Yale University
using diethylstilbestrol (DES); no pregnancies occurred in first 100 cycles; trial abandoned due to concerns about teratogenicity
and carcinogenesis; mid 1970s—Canadian physician, Albert Yuzpe, proposed regimen of high-dose combined
OCs, leading to widespread use of estrogen-progestin (ethinyl estradiol plus norgestrel) regimen after single act of unprotected
sex; in 1970, investigators initiated studies of levonorgestrel in varying doses for routine use in postcoital contraception;
early research found single 0.75-mg dose of levonorgestrel taken soon after intercourse effective in preventing
pregnancy, but resulted in high incidence of menstrual disturbances; 1980s and 1990s—Yuzpe regimen (ethinyl estradiol
plus norgestrel) only EC option during these 2 decades; in 1996—American College of Obstetricians and Gynecologists
(ACOG) published practice bulletin supporting use of EC; in 1997—FDA declared 6 brands of OCs safe and effective
for EC; 1998—0.05 mg ethinyl estradiol plus 0.25 mg levonorgestrel (Preven) approved by FDA; no longer marketed;
also, large multicenter study by World Health Organization shows 0.75-mg dose of levonorgestrel (Plan B; 2 doses, 12 hr
apart) at least as effective as Yuzpe regimen and better tolerated
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| Safety issues: combined hormonal OCs for EC—nearly all women who have known contraindications to ongoing use of
combined OCs candidates for use of combined OC as EC; contraindicated in women with history of deep venous thrombosis
or pulmonary embolism, women currently under treatment for ischemic stroke or myocardial infarction, those with
estrogen-dependent neoplasm, or women who are pregnant (however, data show no increase in adverse pregnancy outcomes
in women exposed to EC); data from British Medicines Control Agency report only 3 cases of thromboembolism
and 3 cases of stroke in >4 million cycles of EC given over 13 yr; only 1 of these 6 cases occurred close enough to time of
administration to be considered drug-related; combined estrogen plus progestin—Yuzpe did not find any effect on clotting
factors in study of 11 healthy volunteers; progestin-only EC—any woman with any medical diagnosis can be given 2
doses without concern; no reported cases of significant adverse events reported; contraindications include confirmed or
suspected pregnancy, undiagnosed abnormal uterine bleeding, or hypersensitivity to component of product
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| Efficacy: Yuzpe published 2 studies; failure rates in both studies ≈2%; study published in Lancet—showed combined regimen
slightly less effective than levonorgestrel regimen; risk for failure of treatment increases as interval between coitus
and treatment increases; efficacy dependent on timing of use of medication and when in cycle woman engaged in unprotected
sexual intercourse; medication cannot interrupt impending ovulation; wide range of efficacy (56%-98%) reported;
effectiveness dependent on where in cycle woman is when EC administered; published expert in field states 85% efficacy;
patient prescribing information states Plan B reduces average risk for pregnancy among users from ≈8% to ≈1%; EC most
effective when administered ≤ 72 hr after unprotected intercourse, but data support use ≤ 120 hr after unprotected intercourse
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| Mechanism of action: Yuzpe regimen—primarily by inhibition of both follicular development and ovulation; Chilean
study involving 29 women showed that in 82% of levonorgestrel EC cycles, patients failed to ovulate within 5 days of
treatment, and luteinizing hormone (LH) surge suppressed in all patients on active drug if given before start of LH surge;
concluded that Yuzpe regimen has positive effect on fertilization; progestins are progestational agents; have no effect on
fertilized ovum or established implanted pregnancy; Durand et al showed EC administered in preovulatory phase inhibited
ovulation in 42 of 45 women, with no effect on endometrium; multistudy analysis supports concept that levonorgestrel
EC has little or no effect after ovulation; editorial review published in Contraception—no clinical evidence to
support theories that altered sperm motility, alteration in tubal transport of embryos, or inhibition of fertilization or implantation
responsible for contraceptive effect of EC; only clinical or study evidence for mechanism of action of hormonal
EC is inhibition or delay of ovulation
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| Difference between EC and medical abortion: WHO study showed single 10-mg dose of mifepristone or two 0.75-mg
doses of levonorgestrel 12 hr apart effective for EC; 200 mg or 600 mg of mifepristone (RU-486) current regimen for
medical abortion; clinician should clarify distinction between low-dose mifepristone used for EC and high-dose mifepristone
used for medical abortion, ie, mifepristone in dose of 10 mg works as EC
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| When to use EC: when condom breaks; when no contraception used; when woman misses 2 consecutive oral contraceptive
pills in pill pack, forgets to start new pill pack for >1 day, or forgets to change contraceptive patch or ring; when woman
>2 wk late for depomedroxyprogesterone acetate (DMPA) injection; in cases of sexual assault
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| Current dosing recommendations for EC: levonorgestrel 0.75 mg (Plan B), 2 pills as soon after unprotected sexual intercourse
as possible, or any combination of OCs that provides dose of 100 to 120 µg ethinyl estradiol and 1.0 to 1.5 mg
levonorgestrel; effectiveness of OCs containing norgestimate unknown, levonorgestrel-containing OCs recommended
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| Adverse events: nausea primary side effect; pretreatment to prevent nausea appropriate; cramping (gastrointestinal or uterine
pain); transient (≤24 hr) headache; follow-up care—necessary if patient has not menstruated ≤3 wk after treatment
(conception may have occurred); no concern about breast-feeding (small amount of progestin passes into breast milk, but
no effect on growth or development of infant); repeated use of EC—no evidence that repeated use of EC (progestin-only
EC) causes significant medical concerns; issues—expense (cost $45-$50); abnormal uterine bleeding; less effective than
conventional contraceptives; effectiveness after multiple acts of unprotected intercourse unknown
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| EC in promoting teen sex: data show young adolescents who had improved access to EC used method more frequently
when needed; however, this did not compromise use of routine contraception or increase risky sexual behavior; tolerability
of EC in adolescents same as in adults
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| Recommendations for gynecologic care of adolescents: establish care between 13 and 15 yr of age; “clothes-on, risk assessment
visit”; attend to health concerns appropriate to developmental stage; physical examination limited to body mass
index (BMI) and blood pressure; urine sample for chlamydia screen; oral fluid specimen for HIV (Orasure) and human
papillomavirus (HPV) vaccine
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| Quick-start contraception: check for possible pregnancy; administer hormonal contraceptive or other form of contraception
while patient in office; if EC necessary, start hormonal contraception next day; no evidence showing medical concerns
about using quick-start approach to hormonal contraception; patient using hormonal cyclic contraception should
have normal withdrawal bleeding at end of first cycle (if not, schedule pregnancy test); see patient in 3 wk for pregnancy
test if using continuous-cycling birth control rings
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| Hormonal EC and risk for ectopic pregnancy: 3 case reports in United States (1982 to 2002) of ectopic pregnancy occurring
after use of hormonal EC; 8 reported ectopic pregnancies in 4.4 million units sold in European Union from 2000 to
2004; multicenter clinical study of 2712 women showed 44 pregnancies (only 1 ectopic); incidence rate equivalent to
spontaneous ectopic pregnancy rate
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| Reasons for lack of use: data show <30% of women who became pregnant used EC in cycle in which conception occurred;
reasons include failure to recognize pregnancy risk, dismissal of such risk, perceived stigma associated with
EC, and misunderstanding of what EC is and how it works; include discussion about EC at routine well-woman
visit; data show advance provision of EC increased its use, and decreased length of time between unprotected intercourse
and use of EC; advance provision did not increase rates of sexually transmitted diseases, did not decrease use
of condoms, and did not increase use of less reliable contraception; advance provision did not reduce unintended
pregnancy on population level, when compared with standard- access use
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| Collaborative practice with pharmacists: allows pharmacist to dispense EC without written prescription (may provide
strategy for obtaining for patient <18 yr of age) pharmacists must have signed collaborative agreement with
provider; 9 states currently have pharmacy laws allowing collaborative practice; barriers to access—providers concerned
about safety issues, Medicaid and private payor reimbursement issues, and pharmacy politics (conscientious
objection)
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Suggested Reading
Coffee AL et al: Long-term assessment of symptomatology and satisfaction of an extended oral contraceptive regimen.
Contraception 75:449, 2007; Durand M et al: On the mechanisms of action of short-term levonorgestrel administration
in emergency contraception. Contraception 64:227, 2001; Holt VL et al: Oral contraceptives, tubal
sterilization, and functional ovarian cyst risk. Obstet Gynecol 102:252, 2003; Killick SR et al: Ovarian activity in
women taking an oral contraceptive containing 20 microg ethinyl estradiol and 150 microg desogestrel: effects of
low estrogen doses during the hormone-free interval. Am J Obstet Gynecol 179):S18, 1998; Novikova N et al: Effectiveness
of levonorgestrel emergency contraception given before or after ovulation—a pilot study. Contraception
75:112, 2007; Sulak PJ et al: Hormone withdrawal symptoms in oral contraceptive users. Obstet Gynecol 95:261,
2000; Swahn ML et al: Baillieres Clin Obstet Gynaecol 10:43, 1996; Vandever MA et al: Evaluation of pituitary-
ovarian axis suppression with three oral contraceptives regimens. Contraception 77:162, 2008.
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