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Samba Reddy D.: Recent Advances in Hormonal Contraceptives for Women
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Recent Advances in Hormonal Contraceptives for Women
D. Samba Reddy, Ph.D., R.Ph.
Associate Professor, Department of Neuroscience and Experimental Therapeutics College of Medicine Texas A&M
University Health Science Center 228 Reynolds Medical Building College Station, TX 77843, USA
ABSTRACT: Currently, Contraceptive agents play a key role in family planning in India. Hormonal
contraception is the marketed most common birth control option in women. An estimated 100 million women
throughout the world use hormonal contraceptives for prevention of pregnancy. This article briefly describes
the recent advances in hormonal contraceptive strategies that may minimize side effects while optimizing
effective contraception. There are four types of hormonal contraceptive agents available for birth control.
They include oral contraceptives pills (combined and mini-pills), contraceptive patches, hormonal implants,
intrauterine devices and hormone injection agents. Oral contraceptives (OCs) are among the most widely
used agents because they are highly effective when used properly. Generally, OCs are designed to simulate
the 28 days of the menstrual cycle by daily intake of steroid hormones consisting of an estrogen and/or a
progesterone. The primary mechanism underlying OC action is inhibition of ovulation. This action is achieved
using a variety of OCs with substantially different components, doses, and side effect profile. Two types of
OC pills are widely available: combination pills; and progesterone only pills. The combined daily OC pill is
composed of low dose of synthetic estrogen and progesterone. They are usually taken for 21 days with a 7
day gap during which menstruation-like bleeding occurs. Recently, there are several new OCs that have been
approved to minimize the frequency and/or extent of breakthrough bleeding while achieving reliable means of
contraception for the avoidance of unplanned pregnancies.
KEYWORDS: Oral contraceptives, estrogen, progesterone, birth control, drug interactions, epilepsy
Introduction
Contraceptive management in women is critical for family
planning and the prevention of unplanned pregnancies.
Oral contraceptives (the “pill”) were introduced more than
40 years ago, and presently they are the most popular
method of preventing unwanted pregnancy. An estimated
15 million women in the United States and 100 million
women throughout the world use hormonal contraceptives
(Hatcher and Nelson, 2004). In India, contraceptives have
proven to be most important method for family planning
and also as dominant tools in population control by
avoidance of unplanned pregnancies. Despite the
availability of over 50 hormonal contraceptive products,
there are very few guidelines for their effective use for
birth control purposes. Standard guidelines for women
with various backgrounds and health status should be
considered as key points for achieving effective use of
contraception methods. In order to ensure adequate
efficacy and safety of both classes of drugs, health
practitioners prescribing contraceptives must be aware of
various conventional and newer preparations, potential
benefits and risks, potential interactions between hormone
contraceptives and other drugs. The objective of this article
is to describe the clinical pharmacology of hormonal
contraceptives and recent advances in contraceptive
preparations that are designed for effective contraception
while minimizing side effects in women.
Hormonal Contraceptives
There are two distinct categories of birth control options
for women: hormonal and non-hormonal methods
(Crawford, 2003; Oakeley, 2004). Non-hormonal
contraceptive methods include barrier methods such as
diaphragms, cervical caps, and the rhythm method. Most
barrier methods provide protection against HIV infection
and other sexually transmitted diseases. The rhythm
method or other methods that depend on hormonal changes
are not reliable methods of birth control for women.
Hormonal contraceptives are preparations that contain at
least one natural or synthetic steroid hormone. A wide
range of hormonal methods of contraception are available
(Table 1). There are four categories of hormonal
contraceptive agents available in the United States and in
many countries (Table 1). They include oral contraceptives
pills (combined and mini-pills), contraceptive patches,
hormonal implants, intrauterine devices and hormone
injection agents. They provide a convenient, affordable and
consistent means of contraception in women. The efficacy
of hormonal contraceptives is highly dependent on correct
use and individual lifestyles.
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International Journal of Pharmaceutical Sciences and Nanotechnology
Types of Oral Contraceptives
Oral contraceptives (OCs, also known as “birth control
pills”) are among the most widely used agents since these
preparations are highly effective in preventing pregnancy.
When used properly, OCs are more than 99% successful.
(Drey and Darney, 2002; Kaunitz, 2005). Designed to
simulate the 28 days of the natural menstrual cycle, most
OCs consist of an estrogenic and/or a progestogenic agent.
A variety of OCs with substantially different components,
doses, and side effects are available (Table 2). The primary
mechanism underlying OC action is the inhibition of
ovulation. They prevent the release of eggs from the ovary
and thereby prevent the pregnancy. Although they
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essentially act by suppression of gonadotropins by
feedback actions of estrogenic and/or progestogenic
components, other alterations include changes in cervical
mucus (which increase the difficulty of sperm entry into
the uterus), and the endometrium (which reduce the
likelihood of implantation) (Oakeley, 2004; O’Brien and
Guillebaud, 2006). Two major types of OC pills are widely
available: combination pills (these pills contain both
progestin and estrogen); and Mini-pills (these pills contain
only the hormone progesterone) (Table 2). Unlike barrier
methods, the use of OCs do not protect women from
sexually transmitted diseases such as HIV, herpes and
gonorrhea.
Table 1. Categories of hormonal contraceptive preparations.
Category 1: Oral contraceptives
Combination pills; Progesterone-only pills
Category 2: Non-surgical agents
Contraceptive patch (Ortho-Evra); Contraceptive vaginal ring (NuvaRing)
Category 3: Surgical device agents
Progesterone implants; Progesterone intruterine devices
Category 4: Injection preparations
Progestogen injection (Depo-Provera)
Table 2. List of oral contraceptive drug substances.
Product Name
Progesterone (mg)
Estrogen (mg)
(A) Combination pills:
Monophasic
Alesse
Cryselle
Demulen
Desogen
Loestrin
Nordette
Ortho-Novum
Norinyl−1/50
Ortho-Cyclen
Ovcan-35
Ovral
Yasmin
Yaz
Levonorgestrel (0.1)
Norgestrel (0.3)
Ethynodiol diacetate (1)
Desogestrel (0.15)
Norethindrone acetate (1)
Levonorgestrel (0.15)
Norethindrone (1)
Norethindrone (1)
Norgestimate (0.25)
Norethindrone (0.4)
Norgestrel (0.5)
Drospirenone (3)
Drospirenone (3)
Ethinyl estradiol (0.02)
Ethinyl estradiol (0.03)
Ethinyl estradiol (0.035)
Ethinyl estradiol (0.03)
Ethinyl estradiol (0.02)
Ethinyl estradiol (0.03)
Ethinyl estradiol (0.035)
Mestranol (0.05)
Ethinyl estradiol (0.035)
Ethinyl estradiol (0.035)
Ethinyl estradiol (0.05)
Ethinyl estradiol (0.03)
Ethinyl estradiol (0.02)
Desogestrel (0.15)
Levonorgestrol (0.15)
Ethinyl estradiol (0.02/0.01)
Ethinyl estradiol (0.05/0.01)
Norgestimate (0.18/0.215/0.25)
Norethindrone (0.5/0.75/1)
Ethinyl estradiol (0.035/0.035/0.035)
Ethinyl estradiol (0.035/0.035/0.035)
Levonorgestrel (0.05/.075/0.125)
Norethindrone (0.5/1/0.5)
Ethinyl estradiol (0.03/0.04/0.03)
Ethinyl estradiol (0.035/0.035/0.035)
Norethindrone (0.35)
Norgestrel (0.075)
−
−
Biphasic
Mircette
Seasonale
Triphasic
Ortho Tri-Cyclen
Ortho-Novum−7/7/7
Tri-Levlen
Tri-Norinyl
(B) Progesterone only pills:
Micronor
Ovrette
Samba Reddy D.: Recent Advances in Hormonal Contraceptives for Women
Combination Oral Contraceptives
The combined daily OC pill is composed of low dose of
synthetic estrogen and progestogen. They are usually taken
for 21 days with a 7 day gap (usually filled with either
sugar or iron pills) during which withdrawal bleeding
occurs. The two major synthetic estrogens used in OCs are
ethinyl estradiol and mestranol. Mestranol is a prodrug,
and hence is inactive until it is converted to ethinyl
estradiol in the body. The main synthetic progestogens
include norethindrone, levonorgestrel, norgestimate,
norgestrel, desogestrel and drospirenone (Drey and
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Darney, 2002; Wilbur and Ensom, 2000; Teal and Ginosar,
2007). Pharmacological studies have shown that these
synthetic progestogerone analogs have high progestational
activity with minimal intrinsic androgenicity. Chemical
structures of estrogens and progesterone analogs used in
OCs are shown in Fig.1. Currently, the combined OCs
available in the market can be divided into three types:
monophasic (only one dose of estrogen and progestogen
during the 21 days); biphasic (varying doses of estrogen
and progestogen); and triphasic (varying doses of estrogen
and progestogen) (Table 2).
Ethinyl estradiol
Levonorgestrel
Mestranol
Desogestrel
Norethindrone
Norgestimate
Fig 1. Chemical structures of synthetic estrogens (ethinyl estradiol and mestranol) and progesterones
(levonorgestrel, desogestre, norethindrone, and norgestimate) that are components of oral contraceptive pills.
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International Journal of Pharmaceutical Sciences and Nanotechnology
Monophasic OCs: In monophasic combinations, the
progestogen and estrogen are present in fixed amounts and
hence the blood levels of hormones rise and fall together.
Consequently, fixed amounts of the estrogen and
progesterone are present in each monophasic pill, which is
taken daily for 21 days, followed by a 7-days with placebo
(sugar) pills or iron preparations. The most frequently used
monophasic OCs are listed in Table 2.
Biphasic OCs: Biphasic combinations are developed to
mimic nearly physiological levels of steroid hormone
fluctuations. In the biphasic regimen, the progestogen dose
is increased during the last 11 days of the cycle. The
biphasic preparations contains 21 pills of fixed amounts of
estrogen (0.02 mg ethinyl estradiol) and progesterone (0.15
mg desogestrel) and 2 placebo pills (rather than the regular
7 placebo pills), and 5 pills of low dose estrogen (0.01 mg
ethinyl estradiol). The FDA approved biphasic OCs are
listed in Table 2.
Triphasic OCs: The triphasic regimen consists of
progestogen/estrogen regimen that is changed 3 times.
Triphasic combinations are developed to closely mimic
physiological levels of steroid hormone fluctuations. The
triphasic OCs provide 3 different pills containing varying
amounts of estrogen and progesterone (7 days each
regimen), to be taken at different times during the 21-day
cycle. The FDA approved triphasic OCs are listed in
Table 2.
There are several key points about use of OCs. Women
should follow complete instructions on the patient
prescription labeling. Many physicians instruct women to
start taking their OC pills on the first Sunday after their
cycle. Some women start taking their pills on the first or
fifth day of their cycle or as directed by their physician.
However, women who use OCs should take the pill at the
same time every day to maintain hormone levels. If they
miss a dose, they should take a pill as soon as they
remember, but the next pill should be taken at regular time.
Progesterone-Only Oral Contraceptives
The progesterone-only pill, also referred as “mini-pill”
contains a progestogen without estrogen and is taken
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continuously without gaps. Currently there are two
progesterone-only OCs: Micronor and Ovrette (Table 2).
The mechanism of action of progesterone-only pills is
inhibition of ovulation and progesterone actions in the
cervix. Contraceptive efficacy appears to rely mainly on
their progestogenic effect of thickening the cervical mucus
and thereby reducing sperm viability and penetration
(Glasier, 2006). Since the contraception is based on
progesterone alone, these agents are slightly less effective
than combination OCs. However, due to lack of the
oestrogen of combined pills, mini-pills are not associated
with increased risks of cardiovascular diseases.
Newer Oral Contraceptives
OCs that were approved in 1970s are referred as “firstgeneration” because they often contain high dose estrogen.
These original OC agents were associated with significant
side effects and complications. In 1988, the FDA
recommended the withdrawal of all OCs with mestranol
0.05 mg. Advancements in the dosage optimization of
estrogen is made based on the rationale that “low-dose”
estrogen containing OCs are associated with minimal side
effects. Today, most oral contraceptives contain a mixture
of low-dose estrogen and/or progestin. The estrogen
content of OCs ranges from 0.02 to 0.05 mg. OCs
containing 0.035 mg or less of an estrogen are generally
referred to as low-dose or “second-generation” OC pills
(see Table 2).
Recently, the FDA has approved nonconventional
formulations of OCs that change the hormone-free-interval
by reducing the number of hormone-free days for each
cycle, increasing the time period between hormone-freeintervals, supplementing the hormone-free-intervals with
low-dose estrogen, or a combination of these strategies
(Anderson et al., 2006) (Table 3). These new OCs, which
change the hormone-free-interval, may decrease the
incidence of hormone fluctuations experienced by women
using OCs, reduce withdrawal bleeding, and maximize
ovarian follicular suppression (Terrie, 2008). Overall, the
new OCs appears to cause fewer and/or shorter hormone
withdrawal periods.
Table 3. Overview of newer oral contraceptive preparations.
Product name
Seasonique
Active ingredients (mg)
Levonorgestrel (0.15)+ ethinyl estradiol
(0.03) x 84 days, followed by 7 days of
low-dose ethinyl estradiol (0.01) pills
Hormone-free interval (bleeding)
4 cycles per year, median 3 days per
cycle
Seasonale
Levonorgestrel (0.15) + ethinyl estradiol
(0.03) x 84 days, followed by 7 days of
placebo.
Levonorgestrel (0.09) + ethinyl estradiol
(0.02)
4 cycles per year, median 4 days per
cycle
Lybrel
No scheduled withdrawal
Median of 4-5 days per
regimen
period;
28-day
Samba Reddy D.: Recent Advances in Hormonal Contraceptives for Women
In women taking OCs, the menstrual bleeding is due to
withdrawal of hormones during the hormone-free-interval
and is not a natural menstrual period. During each natural
cycle, a woman’s body is preparing for a potential
pregnancy—ovulation occurs and the uterine lining builds
up. When pregnancy does not occur, hormone levels drop
and the lining of the uterus sheds. During use of OC pills,
ovulation is prevented and build-up of the uterine lining is
minimized. Just as in a natural cycle when hormones are
withdrawn, the uterine lining sheds (Terrie, 2008). A
number of OC products that extend the cycle or alter the
hormone-free-interval are available (Table 3). The first
approved extended regimen, Seasonale, uses a 91-day
regimen (84 days of active pills followed by 7 days of
placebo). Seasonale consist of 84 tablets containing
levonorgestrel and ethinyl estradiol, followed by 7 days of
placebo pills. Seasonique also uses a 91-day regimen, with
the addition of 7 days of low-dose estrogen during the
hormone-free-interval. The only continuous use product
currently available is Lybrel, which is a continuous-use,
low-dose OC containing levonorgestrel 90 mcg and ethinyl
estradiol 20 mcg in a 28-day pack with all active tablets.
In several developed countries, there is emerging
interest in menstrual suppression in many women. More
than 50% of women reportedly disliked having a menstrual
cycle and would consider using an OC that would
temporarily halt menstruation (Andrist et al., 2004).
Although the extended-regimen OCs are developed to meet
the growing interest in menstrual suppression, there is no
clear evidence on the long-term consequence of menstrual
suppression on reproductive function (Anderson et al.,
2006). Extended-regimen OCs may result in unscheduled
bleeding and/or spotting during the early stages of therapy,
which tend to decrease as therapy continues. The
continuous use of OCs without any break has been shown
to incrementally induce amenorrhea in about 60% of
women taking a continuous regimen for 1 year.
Emergency Oral Contraceptives
Emergency contraception involves preventing pregnancy
after unprotected sexual intercourse. Combined and
progesterone-only pills are taken in high doses for
emergency contraception −referred as the "morning-after
pill" or “postcoital pills”. There are two preparations for
postcoital contraception: Plan-B (levonorgestrel) and
Preven (levonorgestrel+ethinyl estradiol). They are
effective (~75%) if taken within 72 hours after coitus.
Plan-B is proven to have a better safety profile than the
Preven regimen.
The FDA has recently approved Plan-B as behind-thecounter drug that is available from pharmacies without a
prescription for women 18 and older. A prescription is
needed only for women under 17 and younger. Plan-B is
composed of two (levonorgestrel, 0.75 mg) progestin-only
tablets. It reduces the chance of pregnancy by up to 89%
when taken as directed within 72 hours after unprotected
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intercourse, contraceptive failure, or sexual assault.
However, Plan-B is more effective the sooner it's taken,
especially within the first 24 hours.1 The first tablet should
be taken within 72 hours of unprotected intercourse, and
the second tablet 12 hours later. Plan-B is believed to exert
its therapeutic action by preventing ovulation or
fertilization. In addition, it may inhibit implantation;
however, it is not effective once the process of
implantation has begun. Thus, levonorgestrel is indicated
for use as an emergency contraceptive to prevent
pregnancy following unprotected intercourse or a known or
suspected contraceptive failure. Plan B does not protect
against sexually transmitted diseases and it won't terminate
an existing pregnancy.
Non-oral Hormonal Contraceptives
Non-oral hormonal contraceptive preparations include
transdermal patches (“Ortho Evra”), vaginal rings
(“NuvaRiing”), sub-cutaneous implants and intra-uterine
devices containing progesterone, and progestogen
injections administered every three months (“DepoProvera”). The Ortho Evra patch provides monophasic
combination of norelgestromin (6 mg) and ethinyl estradiol
(0.75 mg) delivered via a transdermal system (once patch
per week for 3 weeks and then no patch for one week).
Ortho-Evra is the first transdermal system approved for
birth control in the United States. Once-weekly application
may improve overall compliance and provide longer-acting
birth control.
Norplant is a contraceptive system consisting of
levonorgestrel (progesterone) formulated within small,
silastic-covered rods. These rods are placed under the skin
of the inside of the lower arm. The progesterone is slowly
released and the system protects against pregnancy for up
to 3 years. Other hormonal contraception methods, such as
medroxyprogesterone acetate (Depo-Provera) depot
injection and implantable hormonal contraceptive
(Norplant) or hormone releasing intrauterine system, offer
potential benefits such as greater compliance and minimal
drug interactions (Wilbur and Ensom, 2000). The non-oral
hormonal contraceptives may provide alternative options
for some women for better compliance.
Side Effects and Drug Interactions
Currently available OCs are considered generally safe in
most healthy women. The use of combination OCs is
associated with untoward effects involving several major
systems. Some side effects observed are adverse
cardiovascular effects such as hypertension, myocardial
infarction, hemorrhagic or ischemic stroke, venous
thrombosis and embolism. Consequently, OCs are
contraindicated for women with certain conditions such as
history of thromboembolic disease, coronary artery
disease, suspected carcinoma of the breast or other
reproductive tract organs.
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International Journal of Pharmaceutical Sciences and Nanotechnology
OCs may cause a number of endocrine and metabolic
effects as well as carcinoma of the reproductive organs,
breast, and liver. Women who take oral contraceptives and
smoke cigarettes increase their risk of developing heart
attacks, blood clots, and strokes. Based on the FDA
pregnancy drug use categories, hormonal contraceptives
are category X drugs (contraindicated during pregnancy).
However, there are some non-contraceptive health benefits
with the use of OCs. There is clear evidence that OCs may
lower the risk of cancer of the ovaries or uterus, as well as
pelvic inflammatory disease.
Oral contraceptives interact with a variety of drugs with
a devastating impact on the clinical outcome of drug
therapy when given concurrently. Estrogens and
progesterone are both susceptible to drug interactions
because of common drug metabolizing enzymes
(Guengerich, 1990; Lin et al, 2002). Cytochrome P450
(CYP) is a group of enzymes that metabolize many drugs
to a more water-soluble form, rendering them available for
renal excretion. Steroid hormones such as estrogens and
progesterone are metabolized by the hepatic cytochrome
P450 isoenzymes, especially CYP3A4 enzyme system
(Fig. 2). Therefore, pharmacokinetic type drug interactions
are expected as many drugs that are eliminated via
CYP3A4 enzyme system. A number of drugs – such as
antibiotics (rifampin, griseofulvin), St. John’s Wort and
antiepileptic
drugs
(barbiturates,
phenytoin,
carbamazepine, felbamate, oxcarbazepine, topiramate) –
could reduce the efficacy of OC due to pharmacokinetic
interaction (Sabers et al, 2003; Sarlis and Gourgiotis,
2005). Some drugs increase activity of CYP3A4. Induction
of the 3A4 system increases the metabolism of both the
estrogenic and progesterone components of OCs and
Volume 1 • Issue 3 • October - December 2008
reduces their circulating levels. This could lead to reduced
efficacy of OCs and thereby could lead to pregnancy or
menstrual irregularities. Therefore, enzyme-inducing drugs
can decrease serum levels of the OC steroids leading to
increased risk of contraception failure.
Antiepileptic drugs (AEDs) are the mainstay for the
treatment of seizure disorders in women with epilepsy
(Reddy, 2007) However, many AEDs can influence the
performance of hormonal contraceptives which poses a
serious risk because of potential AED-induced
teratogenicity (Back et al., 1980; Fattore et al, 1999;
Harden and Leppik, 2006). Studies indicate that OCs
failures are the cause of one in four unplanned pregnancies
in women with epilepsy (Fairgrieve et al., 2000). The
failure rate for OCs in women with epilepsy was 3.1 per
100 woman-years compared with 0.7 per 100 woman-years
in the general population (Kaneko, 1998). AEDs such as
phenobarbital, carbamazepine, phenytoin, felbamate,
topiramate, promidone, and oxcarbazepine are mainly
metabolized by the CYP3A4 enzyme system (Crawford,
2002), which is also the primary enzyme metabolizing
estrogens and progesterone. These AEDs can increase
activity of CYP3A4. Induction of the 3A4 system increases
the metabolism of both the estrogenic and progestogenic
components of OCs and reduces their circulating levels by
as much as 50% (Back et al., 1980, Crawford et al., 1990).
This could lead to reduced efficacy of all hormonal
contraceptives such as the low-dose daily intake pills and
low releasing subdermal progestogen implants. Therefore,
enzyme-inducing AEDs can decrease serum levels of the
OC steroids leading to increased risk of contraception
failure.
Fig 2. Drug interactions between steroid hormone components of oral contraceptives (OCs) and other drugs
by common metabolic pathway via cytochrome P-450 enzyme system.
Samba Reddy D.: Recent Advances in Hormonal Contraceptives for Women
Conclusions
There are several options for birth control including
hormonal
and non-hormonal
agents.
Hormonal
manipulation is an effective method of preventing
pregnancy. Hormonal contraception is the most common
birth control option in women throughout the world.
Contraceptive management in women is critical to promote
effective contraception and to reduce drug interactions.
Oral contraceptives are highly effective for pregnancy
prevention. Two types of OC pills are widely available:
combination pills; and progesterone only pills. Newer
contraceptive agents may be more suitable who experience
severe breakthrough bleeding with the conventional 28-day
regimen. Several drugs can interact with OCs and thereby
reduce the efficacy of hormonal contraception. This is
thought to result from the induction of CYP34A
metabolism of estrogen/progestogens and also from
increased synthesis of sex hormone-binding globulins. This
reduced efficacy is evident with all forms of hormonal
contraceptives. Women on OCs and enzyme-inducing
drugs such as some antiepileptic drugs concurrently should
report breakthrough bleeding to their physician. New
extended-forms of OCs may provide suitable method of
contraception for women who prefer to limit menstrual
frequency. Non-hormonal methods of contraception such
as intrauterine contraceptive device or barrier methods can
be considered as alternate or additional methods.
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