Contraceptives

Dr. Ali Alyahawi

Ass. Professor of Clinical Pharmacy & Therapeutics
Introduction:
 Historically, the 1950s was an important time in the control of human fertility.

 It was during that decade that the first combination oral contraceptives
(COCs) were developed.

 Shortly after the discovery that the exogenous administration of hormones

such as progesterone successfully blocked ovulation, the use of hormonal
steroids quickly became the most popular method of contraception
worldwide.

 Since the introduction of oral contraceptives, many additional

contraceptive forms have been developed and are available for use in the
United States, including transdermal systems, transvaginal systems, and
intrauterine devices (IUDs).

 These additional forms of contraception offer women effective and potentially more
convenient alternatives to oral contraceptives.
  PHYSIOLOGY
 The female menstrual cycle is divided into four functional phases:

 Follicular
 Ovulatory
 Luteal
 menstrual.
 The follicular phase begins the cycle, and ovulation generally occurs
around day 14.

 The luteal phase then begins and continues until menstruation occurs.

 The menstrual cycle is regulated by a negative-feedback hormone loop

between the hypothalamus, anterior pituitary gland, and ovaries.
 Initially, the hypothalamus releases gonadotropin-releasing hormone
(GnRH), which stimulates the anterior pituitary to produce follicle-
stimulating hormone (FSH) and luteinizing hormone (LH).

 The levels of FSH and LH released vary depending on the phase of the
menstrual cycle.

 Just prior to ovulation, FSH and LH both are at their peak levels.
 The FSH helps to promote growth of the follicle in preparation for
ovulation by causing granulosa cells lining the follicle to grow and
produce estrogen.

 LH promotes androgen production by theca cells in the follicle, promotes

ovulation and oocyte maturation, and converts granulosa cells to cells
that secrete progesterone after ovulation.
 Conception is most likely to occur when viable sperm are

present in the upper region of the reproductive tract at the time

of ovulation.

 Fertilization occurs when a spermatozoan penetrates an ovum.

 Approximately 6 to 8 days after ovulation, attachment of the

early embryo to the lining of the uterine cavity—implantation—

occurs.
 Choice of Contraceptives: Important Considerations
 When helping a patient with contraceptive selection, the most important
goal is finding an option the patient is comfortable with and the clinician
feels is beneficial for the patient.

 It is imperative to explain the side effects, safety concerns, and

noncontraceptive benefits of each alternative to the patient so that she
may make an informed decision.

 Fertility goals vary for each patient.

 It must be determined whether the goal is to postpone conception, space out

the next pregnancy, or avoid further pregnancy altogether.

 Also, a clinician must understand the patient’s desire to have or not have a
regular bleeding pattern, because many contraceptives will affect menses
 Patients must be evaluated by a health care professional to rule out medical
contraindications to certain contraceptives.

 The physical examination also allows health care professionals to identify other
medical concerns, such as hypertension or liver disease, that need to be
considered when selecting an appropriate contraceptive agent.

 Clinicians also should review family history for potential risks with certain
forms of birth control.

 Sexual behavior of the female must be determined to understand the risk for
STIs.

 Women not in a monogamous relationship must consider their risk of STIs

as a factor in their contraceptive decision.

 Some barrier methods protect against STIs, but hormonal contraceptives

do not prevent STIs if used alone.
 Personal preference plays a large role when determining the best
contraceptive option.

 For instance, if a woman is not interested in using a method that

interrupts sexual activity, then a diaphragm would be an
inappropriate choice.

 Preference of the sexual partner may also be important. Certain agents

such as male condoms require the male partner to play an active role in
contraception.

 Cost may also be an issue for patients.

 Insurance may not cover all forms of contraception, and patients

may have to bear the entire cost for certain options.
  Oral Contraceptives (Combination)
 COCs contain a synthetic estrogen and one of several steroids with
progestational activity.

 Most oral contraceptives contain one of three types of estrogen:

 ethinyl estradiol (EE), which is pharmacologically active;

 mestranol, which is converted by the liver to EE;
 estradiol valerate, which is metabolized to estradiol and valeric acid.
 Many different progestins are found in the various oral contraceptives.

 These include norethindrone, norethindrone acetate, ethynodiol

diacetate, norgestrel, levonorgestrel, desogestrel, norgestimate,
drospirenone, and dienogest.
 The primary mechanism by which COCs prevent pregnancy is through inhibition of
ovulation.

 FSH and LH regulate the production of estrogen and progesterone by the ovaries.

 Secretion of estrogen and progesterone by the ovaries occurs in a cyclic manner,

which determines the regular hormonal changes that occur in the uterus, vagina,
and cervix associated with the menstrual cycle.

 Cyclic changes in the levels of estrogen and progesterone in the blood, together with
FSH and LH, modulate the development of ova and the occurrence of ovulation.

 The estrogen component of COCs is most active in inhibiting FSH release. However,
at sufficiently high doses, estrogens also may cause suppression inhibition of LH
release. In low-dose COCs, the progestin component causes of LH.

 Ovulation is prevented by this suppression of the midcycle surge of both FSH and
LH and mimics the physiologic changes that occur during pregnancy.
 Although suppression of FSH and LH is the primary mechanism by
which COCs prevent ovulation, there are other mechanisms by which
these hormones work to prevent pregnancy.

 Other mechanisms include reduced penetration of the egg by sperm,

reduced implantation of fertilized eggs, thickening of cervical mucus
to prevent sperm penetration into the upper genital tract, and slowed
tubal motility, which may delay transport of sperm.

 Thus, in addition to inhibiting ovulation, COCs induce

changes in the cervical mucus and endometrium that make
sperm transport and implantation of the embryo unlikely.
 Since the mid-1960s, EE has been the primary estrogen used in most COCs.

 However, the amount of EE used in COCs has decreased progressively since

that time, and most now contain 35 mcg or less of EE.

 In addition, to reduce side effects and improve tolerability associated with oral
contraceptive use, new progestins and different routes of administration have
been explored.

 In an attempt to minimize the undesirable androgenic side effects associated

with the progestins of COCs, the original synthetic progestins were
modified to create “third generation” progestins (eg, desogestrel and
norgestimate), and newer progestins with antiandrogenic properties (eg,
drospirenone) have been discovered.

 Overall, the synthetic progestins found in today’s COCs are extremely

potent in their ability to inhibit ovulation and prevent pregnancy.
 COCs are available in monophasic, biphasic, triphasic, and quadriphasic preparations.

 Monophasic preparations contain fixed doses of estrogen and progestin in each active
pill.

 Although all four preparations contain both estrogens and progestins, biphasic, triphasic,
and quadriphasic preparations contain varying proportions of one or both hormones
during the pill cycle.

 These preparations were introduced to reduce a patient’s cumulative exposure to

progestins, as well as to mimic more closely the hormonal changes of the menstrual cycle.

 Most traditional COCs are packaged as 21/7 cycles (ie, 21 days of active pills and 7 days of
placebo).

 However, newer regimens offer either fewer hormone-free days per traditional, 28-day
pill cycle or extended (or in some cases continuous) cycles, which may allow for fewer
withdrawal bleeds per year and fewer menstrual-related side effects (eg, menstrual pain,
bloating, headaches) for some women.
 Noncontraceptive Benefits of Combination Oral Contraceptives

 In addition to preventing pregnancy, there are several

noncontraceptive benefits associated with the use of COCs.

 Reduction in the Risk of Endometrial Cancer

 The risk of endometrial cancer among women who have used oral
contraceptives for at least 1 year is approximately 40% less and for at
least 10 years is approximately 80% less than the risk in women who
have never used oral contraceptives.

 There is additional evidence to suggest this benefit is detectable within

1 year of use, and the reduced risk may persist for up to 20 years
following discontinuation of oral contraceptives.
 Reduction in the Risk of Ovarian Cancer
 When compared with women who have never used oral contraceptives,
women who have used oral contraceptives for up to 4 years are 30% less
likely to develop ovarian cancer.

 There is also additional evidence to suggest that the longer the duration of
oral contraceptive use, the greater the reduction in the risk of ovarian cancer.

 Women who have taken oral contraceptives for 5 to 11 years are 60% less
likely to develop ovarian cancer, and women who have taken oral
contraceptives for more than 12 years are 80% less likely to develop ovarian
cancer than those who have never used oral contraceptives.

 As with the reduced risk of endometrial cancer, there is evidence to suggest

the reduced risk of ovarian cancer may persist for years following
discontinuation of oral contraceptives.
 Improved Regulation of Menstruation and Reduction in the Risk of Anemia

 Women who take oral contraceptives typically experience more regular

menstrual cycles.

 In general, oral contraceptive use is associated with less cramping and

dysmenorrhea.

 Also, women who take oral contraceptives have a smaller volume of menstruum
and experience fewer days of menstruation each month and consequently
experience less blood loss with each menstrual period.

 Some studies suggest that oral contraceptive use decreases overall monthly
menstrual flow by 60% or more and conserves hemoglobin and ferritin levels,
which may be particularly beneficial in women who are anemic or at risk for
anemia.

 In addition, some COC formulations contain iron, which may also minimize the risk
for anemia (Unique Oral Contraceptives)
Reduction in the Risk of Fetal Neural Tube Defects
 While COCs are not 100% effective at preventing pregnancy, it is
possible that a woman may conceive while taking a COC.

 In addition, many women may become pregnant very soon

after discontinuing a COC.

 In order to decrease the risk of neural tube defects in the fetuses

associated with such pregnancies, COC formulations that contain
a source of folate in every pill are also available.
 Relief from Symptoms Associated with Premenstrual

 Premenstrual dysphoric disorder (PMDD)

 COCs have been widely used for the treatment of premenstrual
dysphoric disorder (PMDD).

 Current evidence suggests that these agents are most effective at

targeting the physical symptoms associated with the disorder and less
effective in treating mood-related symptoms.

 Although multiphasic COCs have been used effectively in the treatment

of PMDD, monophasic preparations may yield fewer mood swings and
are generally easier to manage.

 Yaz, which contains the progestin, drospirenone, carries an FDA-

approved indication for PMDD.
 Relief of Benign Breast Disease
 Women who use oral contraceptives are less likely to develop benign breast
cysts or fibroadenomas and are less likely to experience progression of such
conditions.

 Prevention of Ovarian Cysts

 Because oral contraceptives suppress ovarian stimulation, women who take
them are less likely to develop ovarian cysts.

 Decrease in Symptoms Related to Endometriosis

 COC use has been linked to a decreased incidence of symptomatic
endometriosis.

 In women who suffer from endometriosis, the extended-cycle COCs may

provide the most effective relief from menstrual pain by reducing the total
number of painful episodes per year.
 Improvement in Acne Control
 All COCs can improve acne by increasing the quantity of sex hormone–
binding globulin and thereby decreasing free testosterone concentrations.

 Third generation progestins, such as desogestrel and norgestimate, are

believed to have less androgenic activity compared with older progestins,
and drospirenone is considered to be antiandrogenic.

 However, it is not clear that COCs containing any of these progestins confer
any advantage over other COCs with respect to their ability to improve acne
control.

 Ortho Tri-Cyclen (EE and norgestimate), Estrostep Fe (EE and

norethindrone acetate), Yaz, and Beyaz (EE and drospirenone) each carry
an FDA-approved indication for the treatment of acne
Potential Risks of Combination Oral Contraceptives

 Although there are many noncontraceptive benefits associated

with the use of COCs, their use is not without risk or potential for
adverse effects

 Sexually Transmitted Infections

 Cardiovascular Events and Hypertension

 Venous Thromboembolism

 Gallbladder Disease

 Hepatic Tumors

 Cervical Cancer
 Adverse Effects of Oral Contraceptives and Their Management

 As with all medications, there are potential adverse effects with COCs.

 Many side effects can be minimized or avoided by adjusting the

estrogen and/or progestin content of the oral contraceptive.

 It is also important to individualize the selection of oral

contraceptives, because some women are at increased risk for
potentially serious side effects.
  Progestin-Only Pills
 For women unable to take estrogen-containing oral contraceptives, there is an alternative:
oral contraceptives containing only the progestin, norethindrone.

 These agents are slightly less effective than COCs but have other advantages over
COCs.

 Progestin-only products have not shown the same thromboembolic risk as estrogen-
containing products.

 Therefore, women at increased risk for or with a history of thromboembolism may be

good candidates for progestin-only oral contraceptives.

 Also, these products can minimize menses, and many women have amenorrhea after
six to nine cycles.

 These products have also been found safe to use in women who are nursing, so they are
a viable option for women who breast-feed and desire hormonal contraception.

 These products should be taken at the same time every day, and there is no pill free or
hormone-free period.
  Unique Oral Contraceptives
 Along with varying doses of estrogen and different progestins, there are
also formulation modifications that may benefit various patient
situations.

 In the United States, these formulations include products such as Lo-

Loestrin Fe; Amethia, Camrese, Daysee, Introvale, and Seasonale;
Amethia Lo and Camrese Lo; Seasonique and Lo Seasonique; Yasmin,
Yaz, and Beyaz; Ortho Tri-Cyclen and Estrostep Fe; Kariva, Mircette,
Pimtrea, and Viorele; Ovcon; Lybrel; Natazia; and Quartette.

 Each of these products may show benefit in certain women

owing to their unique characteristics.
 Lo-Loestrin Fe (norethindrone/EE) contains a low-dose estrogen, a high
amount of progestin, and medium androgenic activity.

 Similar to other low-dose estrogen COCs, Lo-Loestrin Fe may offer a

smaller margin of error when pills are missed but provide the potential
advantage of fewer estrogen-related side effects (eg, nausea and breast
tenderness).

 Unlike the typical 28-pill packs that contain 21 active tablets and
seven placebo tablets, Lo-Loestrin Fe contains 24 combination hormone
tablets, two estrogen-only tablets, and two placebo (iron-only) tablets.

 This product provides a shorter hormone-free interval and may allow for
shorter menstrual periods and fewer menstrual-related symptoms, such
as menstrual related headaches, menorrhagia, and anemia.
 Amethia, Camrese, Daysee, Introvale, Jolessa, and Seasonale,
(levonorgestrel/EE) are each monophasic combinations that are packaged as a
91-day treatment cycles with 84 active tablets that are taken consecutively
followed by seven placebo tablets.

 The extended cycle length of these products allows for one menstrual cycle
per “season,” or four per year.

 This type of formulation may be appealing to women with perimenstrual

side effects or those at higher risk for anemia with menstrual bleeding.

 These products may improve anxiety, headache, fluid retention,

dysmenorrhea, breast tenderness, bloating, and menstrual migraines.

 The risk of intermenstrual bleeding and/or spotting may be higher for patients
taking these extended-cycle combinations than for patients taking typical 28-
day-regimen COCs.
 In 2003, the FDA Advisory Committee for Reproductive Health
Drugs recommended the development of a COC tablet containing
folic acid in order to minimize the risk of neural tube defects in
cases of contraceptive failure.

 Beyaz and Safyral, which were FDA approved in 2010, are

combination tablets containing drospirenone and EE (like Yaz
and Yasmin) and 451 mcg of levomefolate calcium, the primary
metabolite of folic acid.
 Lybrel (levonorgestrel/EE) was the first continuous-cycle COC approved by
the FDA. Active pills are taken every day throughout the year with no pill-
free interval.
 The major advantage of this product is elimination of menstrual periods,
resulting in improvement in or elimination of menstrual-related
symptoms.
 The most bothersome side effect associated with Lybrel is a high incidence
of spotting and breakthrough bleeding during the initial months of use.
 Natazia was approved by the FDA in 2010 and is a quadriphasic COC
containing estradiol valerate and the progestin, dienogest.
 Estradiol valerate is metabolized endogenously to estradiol, and
dienogest is a strong progestin with antiandrogenic activity.
 Natazia provides a unique estrogen step-down/progestin step-up
regimen, and like Mircette, Kariva, Pimtrea, and Viorele, this COC
offers the advantage of a shorter hormone-free interval.
 This results in fewer days of withdrawal bleeding and may help with
menstrual-related headaches.
 Finally, Quartette (levonorgestrel/EE), an extended-cycle,

quadriphasic preparation approved by the FDA in 2013, contains

increasing doses of EE throughout the 91-day pill period.

 The increasing dose of EE is intended to reduce the rate of

breakthrough bleeding or spotting.

 Drug Interactions with Oral Contraceptives
 EE is metabolized in the liver primarily via cytochrome P-450
(CYP450) 3A4.

 When reviewing drug interactions of oral contraceptives, clinicians

should be aware of the many drugs that may potentially interact with
contraceptives—especially those that may reduce the effectiveness of
contraceptives.

 Refer to Table for a list of some of the most common drug interactions
seen with oral contraceptives
  Nonoral Hormonal Contraceptives
 As an alternative to oral contraceptive pills, which must be taken
daily in order to reliably prevent pregnancy, nonoral
contraceptives in the form of transdermal, transvaginal, and
injectable preparations are available and offer patients safe and
effective alternatives to the pills for prevention of pregnancy.

 These formulations also do not require daily administration,

making them more convenient than the pill formulations.
 NuvaRing is a unique transvaginal delivery system that provides 15
mcg of EE and 120 mcg of etonogestrel for the prevention of
ovulation.

 NuvaRing is inserted into the vagina on or before day 5 of the

menstrual cycle and is removed from the vagina 3 weeks later.

 Seven days after the ring is removed, a new ring should be

inserted. In clinical trials, NuvaRing demonstrated comparable
efficacy and cycle control to COCs as well as a similar side-
effect profile.

 NuvaRing should not be removed during intercourse.

 Depo-Provera is a progestin-only, injectable contraceptive that contains depot
medroxyprogesterone acetate.
 Depo-Provera is administered intramuscularly as a 150-mg injection once
every 3 months.
 An advantage of Depo-Provera is that it provides an estrogen-free method of
contraception either for women in whom estrogens are contraindicated or for
women who cannot tolerate estrogen-containing preparations. Depo-Provera
is extremely effective in preventing pregnancy. However, the incidence of
menstrual irregularities (including amenorrhea) and weight gain appears to be
much greater than that seen with COCs.
 The use of Depo-Provera also has been demonstrated to result in significant
loss of bone mineral density (BMD).
 Although the effect is known to be reversible following product
discontinuation, a black-box warning within the product labeling cautions
against the risk of potentially irreversible BMD loss associated with long-term
use (eg, greater than 2 years) of the injectable product.
 The return of fertility can be delayed by approximately 10 to 12 months (range
4–31 months)
 Long-Acting Reversible Contraception
 Surveys have shown that LARC has the highest satisfaction rate among
patients using reversible contraceptives, and use within the United States is
on the rise.

 Although the mechanism of action for IUDs is not completely understood,

several theories have been suggested. The original theory is that the
presence of a foreign body in the uterus causes an inflammatory response
that interferes with implantation. It is believed that copper-containing
IUDs may interfere with sperm transport and fertilization and prevent
implantation.

 Progestin containing implantable contraceptives can have direct effects on

the uterus, such as thickening of cervical mucus and alterations to the
endometrial lining.
 IUDs are recommended for women who are in a monogamous relationship, are at low
risk for acquiring STIs, have no history of pelvic inflammatory disease (PID), and no
history or risk of ectopic pregnancy.
 Contraindications to the use of progestin-containing LARC products include (a) known
or suspected pregnancy, (b) hepatic tumors or active liver disease, (c) undiagnosed
abnormal genital bleeding, (d) known or suspected carcinoma of the breast or personal
history of breast cancer, (e) history of thrombosis or thromboembolic disorders, and (f)
hypersensitivity to any components of the products.
 There are also multiple additional contraindications to IUD use. Evaluation of the
patient is essential because IUDs cannot be used in the following situations: (a)
anatomically abnormal or distorted uterine cavity, (b) acute PID or history of PID unless
there has been a subsequent intrauterine pregnancy (c) postpartum endometritis or
infected abortion in the past 3 months, (d) known or suspected uterine or cervical
malignancy, (e) untreated acute cervicitis, (f ) previously inserted IUD still in place, (g)
increased susceptibility to pelvic infections, and (h) Wilson disease (Paragard T 380A
only).
 The most common adverse effects are abdominal/pelvic cramping, abnormal uterine
bleeding, and expulsion of the device.
  Emergency Contraception
 Emergency contraception (EC) is used to prevent pregnancy after known or suspected
unprotected sexual intercourse.

 There are five FDA-approved oral agents available for use as EC, with availability from
over the counter to prescription only access.

 The product known as ella (ulipristal acetate), a progesterone-receptor

agonist/antagonist, can delay follicular rupture if taken just before ovulation and may
cause endometrial changes to interfere with implantation.

 It is important to note that EC is more effective the earlier it is used after unprotected
intercourse.

 If severe abdominal pain occurs, patients should be referred to their health care provider
for evaluation of risk of an ectopic pregnancy. Patients should also contact their health
care provider if their menstrual cycle is more than 1 week late after taking EC.
  Nonpharmacologic Contraceptive Methods
»» Barrier Contraceptives
 Diaphragms and Cervical Caps
 Spermicides
 Condoms
 Sponge
»» Fertility Awareness–Based Methods
 Fertility awareness–based methods depend on the ability of the couple to identify
the woman’s “fertile window,” or the period of time in which pregnancy is most
likely to occur as a result of sexual intercourse.
 During the fertile window, the couple practices abstinence, or avoidance of
intercourse, in order to prevent pregnancy. In some cases, rather than practicing
abstinence during the fertile period, some couples may prefer to employ barrier
methods or spermicides as a means of preventing pregnancy rather than to avoid
intercourse altogether.
 In order to identify the fertile window, a number of different fertility awareness–
based methods may be tried.
 The calendar (rhythm) method involves counting the days in the menstrual cycle
and then using a mathematical equation to determine the fertile window.
Thank You