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Oral Contraceptives: Noncontraceptive Benefits
Leigh Ann Ramsey, Pharm.D.,
BCPS
Assistant Professor, Department of Pharmacy
Practice
Director, Pharmaceutical Care Clinics
University of Mississippi School of Pharmacy
2500 North State Street
Jackson, Mississippi 39216
and
Tasha M. Fillingane, Pharm.D. Candidate
University of Mississippi School of Pharmacy
Contact Author: Leigh Ann Ramsey, Pharm.D.
Needs Statement: Though primarily used to prevent pregnancy, oral contraceptives possess effects that may prove beneficial in preventing or treating other conditions. This lesson examines the utility of these agents in such conditions.
Intended Audience: Pharmacists
Goal: The goal of this lesson is to increase pharmacist's awareness of the potential non-contraceptive benefits of oral contraceptives
Objectives: Upon successful completion of this lesson, the participant should be able to:
Special note for on-line version of the lesson: As you read the lesson, you will encounter hyperlinked terms. Clicking on these links will take you to web sites that provide more information on the terms. In all instances, you will be leaving the CE lesson to view material that is not considered part of the CE lesson, but nevertheless constitute information that should be helpful to you in understanding the lesson's topic.
Introduction: Throughout the early twentieth century, our understanding of hormones and their respective roles in the body evolved. Based on the initial discovery in the 1950’s that the corpus luteum secreted substances capable of suppressing ovulation during pregnancy, exogenous hormonal administration for the purpose of contraception was derived.
In 1956, the first oral agent, or “pill”, approved by the United States Food and Drug Administration (FDA) as a contraceptive was branded Enovid® and contained the progestin norethynodrel plus an estrogen component, mestranol. This was followed in 1962 by the approval of Ortho-Novum ® , norethindrone plus mestranol. Thereafter, a number of combination products, containing either mestranol or ethinyl estradiol and one of various progestins, were developed, and the cadre of “first generation” oral contraceptives became well established. Although the progestin-only minipill and injectable formulations were developed around this same time and used in other parts of the world, these products were not approved for use in the United States until almost 30 years later.
Types of
Contraceptives:
Table
1
summarizes
the oral contraceptive products currently
available.
Combination
Products
Combination oral
contraceptives contain an estrogen and a progestin component,
which work synergistically to suppress Luteinizing Hormone
(LH) and Follicle Stimulating Hormone (FSH), the hormones
responsible for
ovulation.
In addition to
ovulation blockade, it is thought that oral contraceptives
possess the ability to affect transport of the sperm, egg, and
fertilized ovum to the fallopian tube, decrease sperm
penetration in the cervix, and inhibit implantation in the
endometrium.
Combination oral contraceptives may be monophasic, containing a constant amount of estrogen and progestin in each pill throughout the 21-day regimen, biphasic, or triphasic. The latter options provide two or three pill intervals with varying amounts of estrogen and progestin to be administered at different times over the course of the month in an attempt to more closely mimic the endogenous ratios of these hormones and decrease potential adverse effects associated with higher daily doses.
Progestin-Only
Contraceptives
Oral
progestin-only contraceptives, or “minipills”, may demonstrate
decreased efficacy when compared to combination
products.
The mechanisms of
oral progestins are thought to involve thickening of the
cervical mucus, thus decreasing sperm penetration, and
changing the endometrium such that implantation is
inhibited.
For optimal
effectiveness, “minipills” require administration without
interruption, with a window of only a few
hours.
From a patient
perspective, such stringent dosing recommendations make
appropriate compliance quite difficult.
Depot injections of progestin are now available and offer an option for patients unable to take an estrogen-containing product, but are concerned about compliance with oral progestin products. Effectiveness in preventing pregnancy with one injection of this formulation lasts three months.
Long-term contraception is available through a subdermal progestin implant, the Norplant System. The active ingredient is released slowly over time and confers contraceptive efficacy for as long as five years. More recently available is a combination matrix-type transdermal patch containing 0.75 mg EE and 6.0 mg norelgestromin (Ortho Evra® ). A final alternative to oral contraceptives is NuvaRing® (11.7 mg etonogestrel/ 2/7 mg ethinyl estradiol. NuvaRing ® is a combination contraceptive vaginal ring which, when placed, releases the active ingredients over a three-week period of use.
Traditional Use: Oral contraceptives are highly effective in the prevention of pregnancy, with a contraceptive failure rate of 0.1% with perfect use. Given the reliability and ease of administration, the popularity of these agents soared soon after initial marketing. It was not until a decade later that the untoward effects of oral contraceptives were elucidated.
Limitations of Oral Contraceptive Use: As more women began to use oral contraceptives and utilized them for prolonged periods of time, the adverse effects associated with their use became more evident. Unwanted effects commonly experienced with estrogen use include nausea, edema, and headache. These are dose-dependent effects and are less problematic with the newer preparations which contain lower daily doses of estrogen. Progestins are notorious for weight gain, acne, and hirsuitism, all of which are likely due to the androgenic activity of the progestin.
Cardiovascular effects, such as increased blood pressure, myocardial infarction, stroke, and venous thromboembolism, became evident with the initial oral contraceptive preparations marketed. This has more recently been evaluated in the low-dose estrogen formulations. If the patient does not smoke and has no risk factors, it appears there is no significant increase in myocardial infarction or stroke. However, there is a demonstrated increase in venous thromboembolism, and this risk is increased further if the patient is a smoker. The risk of a thromboembolic event does not persist after discontinuation of the oral contraceptive.
Over the last three decades, new progestins have been incorporated into oral contraceptive regimens. The most recently developed "third generation" progestins, gestodene, norgestimate, and desogestrel, received attention in the last several years due to an increase in venous thrombosis observed with their use.
Although cardiovascular events are the culprit for more deaths in women, the primary concern voiced by the majority of women is fear of breast cancer. Many are concerned that the risk of breast cancer is increased with use of oral contraceptives. The risk of breast cancer in women of child-bearing age who use oral contraceptives is low. There is a small increase in relative risk of breast cancer in these women of approximately 1.1 to 1.2. Ten years after use, there appears to be no difference in the development of breast cancer in past users and never users. There is no significant difference in cumulative risk for breast cancer in past users and never users.
Nontraditional Uses: Oral contraceptives offer many short- and long-term health benefits and are often used for reasons other than contraception alone. The evidence suggesting protection against ovarian and endometrial cancer is well-documented, and there is a growing belief that the risk of colorectal cancer may also be reduced with oral contraceptive use. Oral contraceptives significantly reduce the risk of uterine leiomyomata , or fibroid tumors. Additionally, results from clinical studies suggest that long-term use of oral contraceptives may interfere with the progression of rheumatoid arthritis , and it has been shown that oral contraceptives demonstrate a positive effect on preservation of bone mineral density. Other conditions in which oral contraceptive use is believed to have beneficial effects include benign breast disease, or fibrocystic breast disease, pelvic inflammatory disease, asthma, and porphyria. Clinical trials in these areas are ongoing.
Recently the FDA approved two formulations for postcoital contraception, or "emergency contraception," Plan B® and Preven®. Plan B® contains 75 mcg of the progestin levonorgestrel, while Preven® is a formulation of both levonorgestrel at a lower dose of 25 mcg plus an estrogen component, 5 mcg ethinyl estradiol. The first dose must be administered within 72 hours of intercourse and followed by a second dose 12 hours later. If taken appropriately, the risk of pregnancy is decreased by 75%.
Women who use oral contraceptives many times enjoy amelioration of menstrual symptoms. Young women, in particular, experience pain and discomfort with menses, which may be alleviated with the addition of an oral contraceptive. Likewise, heavy and prolonged menstrual flow is reduced by providing a synchronous delivery of hormones to the endometrium, allowing an increase in serum ferritin concentrations and regularity of the cycle. Dermatological symptoms associated with hormone fluctuations are observed less in oral contraceptive users. Also of interest, certain migraneurs experience a decrease in the number of migraine headaches with oral contraceptive use.
Dysmenorrhea
Greater than 50% of menstruating females suffer from
dysmenorrhea, the pain and discomfort associated with
menses.
This accounts for
60-90% of
adolescents.
One of the most
apparent benefits of oral contraceptive usage to females is
the relief of
dysmenorrhea.
The beneficial
effect allows for improvement in quality of life by minimizing
the disruptions of normal daily
activities.
This relief of
discomfort and pain are thought to result from the decrease in
endometrial tissue growth and, therefore, the inhibition of
prostaglandin production.
Cycle
control
One common use of
oral contraceptives for menstruating females is the control of
the menstrual
cycle.
Recent studies
compared the cycle-controlling effects of the different
strengths of ethinyl estradiol (EE), 20, 30, and 35 mcg, and
compared the effects of various progestin components of oral
contraceptives, norgestimate (NGM), norethindrone acetate
(NETA), levonorgestrel (LNG), and desogestrel
(DSG).
In new oral
contraceptive users, 35 mcg EE / triphasic NGM (Ortho
Tri-Cyclen®) and 20 mcg EE / DSG (Mircette®) resulted in
better cycle control than 20 mcg EE / LNG
(Alesse®).
For women
switching from an oral contraceptive to one of these
alternative oral contraceptives, there was no significant
difference in cycle
control.
However, a second
study comparing 20 mcg EE / DSG (Mircette®) with 30 mcg EE /
DSG (OrthoCept®, Desogen®), mid-cycle breakthrough spotting
and bleeding were more common with the formulation containing
the lower daily estrogen
dose.
This was true for
both oral contraceptive naive patients and those switching
from an alternative
agent.
When comparing 35
mcg EE / NGM (Ortho Tri-Cyclen®) to 20 mcg EE / NETA
(Lo-Estrin 1/20 Fe®) researchers found more cycle control,
less breakthrough spotting and bleeding, with 35 mcg EE / NGM
than with 20 mcg EE /
NETA.
Finally, a study
of two oral contraceptives, both containing equal amounts of
the same estrogen but different progestins, was undertaken to
identify the possible correlation between the progestin
component and cycle
control.
Fewer subjects
experienced breakthrough bleeding and amenorrhea with LNG
(Alesse®) than with NETA (Lo-Estrin 1/20
Fe®).
Therefore, from
the results of this trial, it is believed that the progestin
has an effect on cycle
control.
Oral
contraceptives contribute to menstrual regularity by providing
a rhythmic delivery of estrogen and progestins to the
body.
Before using oral
contraceptives as a source of cycle control, pathologic causes
of menstrual irregularity, such as anorexia nervosa, premature
ovarian failure, gonadal dysgenesis, exercise-induced
amenorrhea, and hyperprolactinemia should be considered and
treated if present.
Dysfunctional Uterine Bleeding
and Iron
Deficiency
Anemia
A number of women
experience a prolonged duration of menses with or without an
excessive volume of menstrual
flow.
This lengthened
bleeding time often leads to iron deficiency
anemia.
With oral
contraceptive therapy, these symptoms may be
ameliorated.
A number of
studies demonstrate a decrease in duration and amount of
menstrual flow, as well as an increase in iron stores, with
combination oral contraceptive
regimens.
One recent trial
provided evidence that women using a triphasic oral
contraceptive containing 35 mcg EE / NGM (Ortho Tri-Cyclen®)
experienced significant improvement in dysfunctional uterine
bleeding.
The mechanism by
which the oral contraceptive alters the length and amount of
menstrual flow is through decreasing endometrial tissue
proliferation.
Acne
Acne is the most common dermatological problem in the United
States, affecting about 27% of menstruating
females.
Although acne was
once considered a possible adverse effect of oral
contraceptives, it is now recognized by many as a viable
treatment option for
acne.
Studies
demonstrate fewer acne lesions with use of oral contraceptive
products containing the progestins norgestimate, desogestrel,
levonorgestrel, and
norgestrel.
Two randomized,
placebo-controlled trials evaluated the effect of oral
contraceptives containing 35 mcg EE and triphasic NGM, a
progestin with low androgenic
activity.
Statistically
significant reductions in the total number of acne lesions and
inflamed acne lesions were
seen.
This formulation,
marketed at Ortho Tri-Cyclen®, Ortho Tri-Cyclen Lo® (25 mcg EE
/ NGM), and Estrostep® (triphasic EE / NETA) are the only oral
contraceptives currently approved by the FDA for the treatment
of moderate
acne.
One
placebo-controlled clinical trial comparing a lower daily
estrogen dose, 20 mcg EE, combined with the progestin
levonorgestrel confirmed that this lower dose is also
efficacious in the treatment of acne
vulgaris.
The mechanism by
which oral contraceptives reduce the number of lesions
involves decreasing ovarian-produced androgens by the
suppression of gonadotropins, decreasing the adrenal-produced
androgens,
increasing sex
hormone-binding globulin, and decreasing the androgen
dihydrotestosterone by the inhibition of 5-alpha
reductase.
This represents
an overall suppression of ovarian, adrenal, and peripheral
androgen metabolism.
Benefits
in Cancer
Ovarian Cancer
The American
Cancer Society (ACS) estimates that in the year 2003,
approximately 25,400 American women will be diagnosed with
ovarian cancer, and the ovarian cancer-related deaths will
reach 14,000, representing the second most fatal gynecologic
malignancy.
The prognosis
often is poor because of its late diagnosis; only 75% of the
tumors are localized at
diagnosis.
Those at risk for
ovarian cancer include females who are nulliparous, have a
positive family history for ovarian cancer, and carry the
BRCA-1 and BRCA-2 mutations, which specifically increase the
risk by as much as 25-45%.
It has been hypothesized that oral contraceptives provide strong protection from ovarian cancer. The Cancer and Steroid Hormone (CASH) Study, a case controlled trial, demonstrated a 40% reduction in the risk of developing ovarian cancer after short-term exposure (3 to 6 months) to oral contraceptives and an increased degree of protection with longer duration of oral contraceptive use. This trial evaluated 50 mcg estrogen, a dose higher than the usual recommended regimen of 20 to 35 mcg. Long-term use, defined as greater than 10 years, may confer as much as 0.8 risk reduction. This suggests a biologic gradient such that increased duration of oral contraceptives enhances the protective effect. On average, one year of oral contraceptive use confers a 10-12% increase in protection from ovarian cancer; 5 years, 50%; and 10 years, 80%.
Upon discontinuation of the oral contraceptive, protection does not cease; however, it may last 10 to 30 years. Since most cases of ovarian cancer are diagnosed during a female’s perimenopausal and postmenopausal years, and because females are prescribed oral contraceptives principally during their second and third decades, the persistence of the protective effect is vital.
Those at an increased risk from a positive family history and the BRCA-1 and BRCA-2 genetic mutations also benefit from oral contraceptives’ protective effect. In studies of this population, continuous oral contraceptive use for 10 years reduced the ovarian cancer risk to a level equal to or less than that of a female without a family history. For those who have the genetic mutation, use of high dose oral contraceptives decreased the risk by 50%.
The mechanism by which protection from ovarian cancer is conveyed is not totally understood. It is believed to result from ovulation suppression, which decreases injury and subsequent repair of the ovary.
Endometrial
Cancer
Endometrial
cancer is currently the fourth leading cause of cancer
morbidity in
females.
It is more common
but less fatal than ovarian
cancer.
The ACS predicts
that 40,100 new cases of endometrial cancer will be diagnosed
in 2003 and over 6,500 women will die from this gynecologic
malignancy.
A larger
percentage of women with endometrial cancer versus ovarian
cancer will survive due to early
detection.
Presence of
symptoms, such as vaginal bleeding and spotting, in
postmenopausal females allows for timely recognition and
diagnosis of endometrial
cancer.
Studies evaluating the effects of oral contraceptives on the risk of endometrial cancer show that one year of oral contraceptive use reduces the risk of endometrial cancer by 20%. As with the protection versus ovarian cancer, a longer duration of contraceptive use endows more protection. With 2 years duration, there is approximately a 40% risk reduction; with 4 years, a 56% increase in protection; and with 12 or more years, a 72% increase in protection.
The persistence of protection is of utmost importance. At 5 years post-oral contraceptive use, the female continues to hold a 67% protection; and 20 years post-oral contraceptive use, a 49% protection from endometrial cancer. As with the studies for oral contraceptives and ovarian cancer, most trials included doses of EE which are rarely used today; however, oral contraceptives with 30 to 35 mcg estrogen continue to exhibit the protective effects.
Colorectal
Cancer
Colorectal cancer
is the third leading cause of cancer morbidity and mortality
in both males and
females.
Approximately
75,000 new diagnoses will be made in females in 2003, and
about 29,000 deaths in females will result from colorectal
cancer.
Oral contraceptive use and its effect on colorectal cancer is an area of emerging interest. Studies demonstrate the use of oral contraceptives reduced the risk of colon cancer by 37%; the development of colorectal adenomatous polyps is also decreased. Several studies documented an increase in protection with prolonged use. One study in particular showed that 8 years or more of oral contraceptive use conferred a 40% colorectal cancer risk reduction. This study, however, lacked the use of contemporary dosed oral contraceptives. Various studies have concluded that ever-use of oral contraceptives confers a relative risk reduction for colorectal cancer of 0.81 to 0.84. Currently, conflicting results exist regarding the duration of use and its relation to protection against colorectal cancer.
One mechanism by which oral contraceptives protect against this type cancer has been proven. Oral contraceptives stimulate the estrogen receptors in the colon’s epithelium, thereby, inhibiting epithelial cell proliferation. It has also been theorized that estrogen induces favorable changes in bile synthesis and excretion.
Uterine Leiomyomata
Uterine
leiomyomata, also referred to as uterine fibroids, are
currently the most common pelvic tumors in
females.
In one study,
current oral contraceptive users demonstrated a 70% risk
reduction for developing uterine
fibroids.
Additionally,
past-users of oral contraceptives exhibited increasing
protection with escalating exposure; seven or more years of
continuous oral contraceptive use reduced the risk of having
uterine leiomyomata by approximately 50%.
Other Potential
Benefits
Rheumatoid
Arthritis
Controversy
exists regarding the correlation between oral contraceptive
use and rheumatoid
arthritis.
A recent
meta-analysis was unable to identify a true correlation due to
diverse results in the individual
studies.
However, evidence
points toward a decrease in progression to more severe disease
with current, but not previous, use of oral
contraceptives.
No risk reduction
in the development of rheumatoid arthritis has been
demonstrated, only an alteration in the clinical course of
disease.
Bone Mineral
Density
The
National Osteoporosis Foundation
estimates that 34
million American females have low bone mass and that 10
million females have
osteoporosis.
Bone mineral
density peaks between the ages of 20 and 40 years old, with a
reduction during the perimenopausal and postmenopausal
years.
Several studies demonstrated that oral contraceptive use during the menstruating years of a woman’s life provides protection against deterioration of bone mass, with the duration of oral contraceptive use and the estrogen dose being primary factors in determining the amount of protection conferred. Oral contraceptives with 20 mcg ethinyl estradiol provide protection, but higher doses of 25 to 35 mcg ethinyl estradiol appear to result in greater bone mass preservation. Any previous use, termed “ever-use,” of oral contraceptives provides some degree of protection. Research shows, however, that longer duration of use confers an increase in protection, especially continued use into the fourth decade. Therefore, for women at moderate to high risk for low bone density and osteoporosis, oral contraceptive use may provide protection against fractures of the hip, lumbar spine, the distal radius, and the ulna. The exact mechanism by which estrogen and progestin protect against lowering bone mass is not fully understood.
Migraines
Migraine
headaches are common in menstruating
women.
Oral
contraceptives may improve, worsen, or have no apparent effect
on
migraines.
Menstrual
migraines, those occurring closely to the onset of menses and
at no other time during the menstrual cycle, may be caused by
the drastic decrease in estrogen levels, and therefore may be
relieved with continuous oral contraceptive use or the
addition of estrogen to the inactive pill
interval.
Women who
experience migraines independent of their menstrual cycle may
experience adverse effects from oral
contraceptives.
Evidence
demonstrates that migraines with aura increases the risk of
ischemic
stroke.
The addition of
an oral contraceptive regimen may further raise this
risk.
Migraines without
aura may not be as closely associated with ischemic
stroke.
However, caution
should still be used when considering oral
contraceptives.
Conclusion: A growing body of evidence exists to support the use of oral contraceptives in arenas above and beyond the prevention of pregnancy. Pharmacists should become familiar with these noncontraceptive benefits and anticipate increased use of these agents as supporting literature becomes available. As utilization increases, pharmacists will be called upon to provide counseling for patients not only with regard to benefits, but also the potential adverse effects associated with estrogen and progestin products.
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