Oral Contraceptives Combination

Combination oral contraceptives contain a combination of a synthetic estrogen and one of several steroids with progestational activity. Most oral contraceptives contain one of two types of estrogen: ethinyl estradiol, which is pharmacologically active, or mestranol, which is converted by the liver to ethinyl estradiol. Many different progestins are found in the various oral contraceptives. These include norethindrone, norethindrone acetate, ethynodiol diacetate, norgestrel, levonorgestrel, desogestrel, norgestimate, and drospirenone.

The primary mechanism by which combination oral contraceptives 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, in turn, 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 combination oral contraceptives is most active in inhibiting FSH release.1 However, at sufficiently high doses, estrogens also may cause inhibition of LH release. In low-dose combination oral contraceptives, the progestin component causes suppression of LH.1 Ovulation is prevented by suppression of the midcycle surge of both FSH and LH,1 and this suppression, which is induced by combination oral contraceptives, mimics the physiologic changes that occur during pregnancy.

Table 48-1 Unintended Pregnancy Rates

Percentage of Women Experiencing Unintended Pregnancy Within First Year of Use

Method

Typical Use"

Perfect

Use*

Percentage of Women Continuing Use at 1 Yea I*

No method 85

Spermicides 29

Withdrawal 27

Fertility awareness- 25

based methods Standard days method Two-day method Sponge

Parous women 32

Nulliparous women 16

Diaphragm 16 Condom

Female (reality) 21

Male 15

Combination pill 8

and mini-pill

Ortho Evra patch 8

NuvaRing 8

Depo-Pro vera 3 IUD

ParaGard (copper T) 0.8

Mirena (LNG-IUS) 0.2

Implanon 0.05

Female sterilization 0.5

Male sterilization 0.15

85 18 4

43 51

46 57 57

49 53 68

68 68 56

78 80

100 100

*Among typical coupfes who initiate use of a method (not necessity for the first time), the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason, Estimates of the probability of pregnancy during the first year bf typical use for spermicides, withdrawal, periodic abstinence, the diaphragm, the male condom, the pill and Depo-Provera are taken from the 1995 National Survey of Family bAmong couples who initiate use of a method (not necessarily for the first time) and who use it perfectly (both consistently and correctly}, the percentage who experience an accidental pregnancy during the first year if they do not stop use for any other reason.

fAmong couples attempting to avoid pregnancy, the percentage

Although suppression of FSH and LH is the primary mechanism by which combination oral contraceptives 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.1 Thus, in addition to inhibition of ovulation, combination oral contraceptives induce changes in the cervical mucus and endometrium that make sperm transport and implantation of the embryo unlikely.1

Table 48-2 contains a partial listing of the many oral contraceptives available in the United States today.8 Although the efficacy of combination oral contraceptives was quickly demonstrated following their introduction into the market, it took longer to determine their safety and acceptability for patients. Since the mid-1960s, ethinyl estradiol has been the primary estrogen used in most combination oral contraceptives. However, the amount of ethinyl estradiol used in combination oral contraceptives has decreased progressively since that time, and most pills now contain 35 mcg or less of ethinyl estradiol. 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 combination oral contraceptives, the synthetic progestins were modified to create "third generation" progestins (e.g., desogestrel and norgestimate). These synthetic progestins are extremely potent in their ability to inhibit ovulation and prevent pregnancy.

Combination oral contraceptives are available in monophasic, biphasic, and triphasic preparations. Monophasic preparations contain fixed doses of estrogen and progestin in each active pill. Although all three preparations contain both estrogens and progestins, biphasic and triphasic preparations differ from monophasic preparations in that they 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. However, there is no evidence to suggest that biphasic and triphasic preparations offer any clinical advantage over monophasic pills.8

Noncontraceptive Benefits of Combination Oral Contraceptives

In addition to preventing pregnancy, there are several noncontraceptive benefits associated with the use of combination oral contraceptive pills. Some of the potential non-contraceptive benefits are highlighted below.

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 than the risk in women who have never used oral contraceptives.9 There is additional evidence to suggest that the benefit of reduced risk for endometrial cancer is detectable within 1 year of use10-12 and that the benefit may persist for years following discontinuation of oral contraceptives.9

Reduction in the Risk of Ovarian Cancer

When compared with women who have never used oral contraceptives, women who have used oral contraceptives for 4 years or less 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 contra ceptives. As with the reduced risk of endometrial cancer, there is evidence to suggest that the reduced risk of ovarian cancer may persist for years following discontinuation of oral contraceptives.10-12

Table 48-2 Some Available Oral Contraceptives

Estrogen

Progestin

Brand Name

(mcg/Tablet)

(mg/Tablet)

Monophasic Preparations

Loestrin 21 1/20

EE (20)

Norethindrone (1)

Loestrin Fe 1/20

EE (20)

Norethindrone (1)

Loestrin 24 Fe

EE (20)

Norethindrone (1)

iVlicrogestin Fe 1/20

EE (20)

Norethindrone (1)

Messe

EE (20)

Levonorgestrel (0.1)

Lybrel

EE (20)

Levonorgestrel (0.09)

Yaz

EE (20)

Drospirenone (3)

Desogen

EE (30)

Desogestrel (0.15)

Ortho-Cept

EE (30)

Desogestrel (0.15)

Levlen

EE (30)

Levonorgestrel (0.15)

Nordette

EE (30)

Levonorgestrel (0.15)

Seasonale

EE (30)

Levonorgestrel (0.15)

Yasmin

EE (30)

Drospirenone (3)

Lo/Ovral

EE (30)

Norgestrel (0.3)

Loestrin 21 1.5/30

EE (30)

Norethindrone (1.5)

Loestrin Fe 1.5/30

EE (30)

Norethindrone (1.5)

Microgestin Fe 1.5/30

EE (30)

Norethindrone (1.5)

Ortho Cyclcn

EE (35)

Norgcstimotc (0.25)

Ovcon-35

EE (35)

Norethindrone (0.4)

Brevicon

EE (35)

Norethindrone (0.5)

Necon 0.5/35

EE (35)

Norethindrone (0.5)

Necon 1/35

EE (35)

Norethindrone (1)

Ortho-Novum 1/35

EE (35)

Norethindrone (1)

Demulen 1/35

EE (35)

Ethynodiol diacetate (1)

Zovia 1/35E

EE (35)

tthynodiol diacetate (1)

Ovral

EE (50)

Norgestrel (0.5)

0vcon-50

EE (50)

Norethindrone (1)

Demulen 1/50

EE (50)

Ethynodiol diacetate (1)

Zovia 1/50E

EE (50)

tthynodiol diacetate (1)

Mornn 1/^H

Mactranr\l fVft

MrirothinHrrmo in

Biphasic Preparations

Mircette EE (20,0,10)

Triphasic Preparations

Estrostep Fe fVi-Levlen

Irlphasil

Ortho I r ¡-Cycle n Tri-Norinyl Oftho-Novum 7/7/7 Ortho Trif Cycle n Lo EE (25) Veil viet Cyclessa

Desogestrel (0,15) Desogest re I (0.15) ISI&rethirrirone {0.5,1} Norethindrone (05,1)

EE .(20, 30r35)

Norethindrone (1)

hE (30,40, 30)

Levonorgestrel

(0.05, 0,075,0,125)

bt (30,40,30)

Levonorgestrel

(0,05,0,075,0,125)

EE (35}

Noreaesttmate

(0,1 a 0.215,0,25)

EE (35}

Norethindrone

(0,5,10,5)

EE (35)

Norethindrone

(0,5,0,75,1)

EE (25)

Norgestimate

(0.13r 0.215,0.25}

EE (25)

Desogestrel

(01,0.125,015)

EE (25)

Desogestrel

(0.1,0.125,0.15)

EE, ethinyl estradiol. From Reft. 8r 19,

Improved Regulation of Menstruation

Women who take oral contraceptives typically experience more regular menstrual cycles. In general, oral contraceptive use is associated with less cramping and dysmenorrhea.1'8 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, which may be particularly beneficial in women who are anemic.1

Relief of Benign Breast Disease

Women who use oral contraceptives are less likely to develop benign breast cysts or fibroadenomas.1,8

Prevention of Ovarian Cysts

Because oral contraceptives suppress ovarian stimulation, women who take them are less likely to develop ovarian cysts.8

Reduction in the Risk of Symptomatic Pelvic Inflammatory Disease

The risk of hospitalization owing to symptomatic pelvic inflammatory disease caused by gonorrheal infection is reduced in oral contraceptive users.14 While the exact protective mechanism is unknown, it is believed that thickening of the cervical mucus and/or reduction in the ability of pathogens to enter the fallopian tubes may contribute to the lower incidence of pelvic inflammatory disease experienced by oral contraceptive users.1

Improvement in Acne Control

All combination oral contraceptives can improve acne by increasing the quantity of sex hormone-binding globulin and thereby decreasing free testosterone concentra-tions.8 Third generation progestins, such as desogestrel and norgestimate, are believed to have less androgenic activity.8 However, it is not clear that combination oral contraceptives containing these progestins confer any advantage over other combination oral contraceptives with respect to their ability to improve acne control. Only Ortho Tri-Cyclen (ethinyl estradiol and norgestimate) and Estrostep Fe (ethinyl estradiol and norethindrone acetate) are approved by the FDA for the treatment of acne.1,8

Potential Risks of Combination Oral Contraceptives

While there are many noncontraceptive benefits associated with the use of combination oral contraceptives, their use is not without risk or potential for adverse effects.

Sexually Transmitted Diseases

Because the use of combination oral contraceptives may decrease the use of selected barrier contraceptive methods that do protect against STDs (e.g., latex condoms), one of the most common risks associated with the use of oral contraceptives is the increased risk of acquiring an STD.8

Cardiovascular Events and Hypertension

A WHO collaborative study found that high-dose (50 mcg or more of ethinyl estradi-ol) oral contraceptive users with uncontrolled hypertension have an increased risk of experiencing a myocardial infarction or stroke.8, 5 In this study, women who had the lowest risk for experiencing a myocardial infarction or stroke were those who did not smoke, took low-dose oral contraceptives, and had their blood pressure checked prior to beginning oral contraceptives.16-18 Hypertension secondary to oral contraceptive use is thought to occur in up to 1% to 3% of women, and this is believed to be attributed to the effect that estrogens and progestins can have on aldosterone activity.1 Given this and the risk for cardiovascular events, women should have their blood pressure checked prior to initiating oral contraceptives, as well as periodically throughout oral contraceptive use. If significant elevations in blood pressure are noted, oral contraceptives should be discontinued. Estrogen-containing contraceptives are not recommended for smokers who are older than 35 years of age, for women with hypertension, or for women who experience migraine headaches (especially those with focal neurologic symptoms).8,19

Venous Thromboembolism

It is believed that the estrogen component of combination oral contraceptives stimulates the liver to produce higher levels of clotting factors. Lower-dose estrogen pills (less than 50 mcg estrogen) have been associated with a threefold to fourfold increase in the risk of venous thromboembolism compared with women who do not use oral contraceptives. Contraceptive users at greatest risk for the development of venous thromboembolism include those who are obese, those who smoke, those who have hypertension, and those with diabetes complicated by end-organ damage. It is important to note, however, that the increase in risk of venous thromboembolism in oral contraceptive users is lower than that of pregnant women. Newer progestins, such as deso-gestrel, were reported initially to be associated with a higher risk of venous throm-boembolism.20, 1 However, prospective studies validating this risk are lacking. In general, progestin-only contraceptives are preferred for women who are at increased risk of cardiovascular or thromboembolic complications, including women with a prior history of thromboembolic disease.8

Glucose Intolerance

Older oral contraceptive formulations containing higher doses of hormones were shown in some cases to induce hyperglycemia.1 Because estrogens may inhibit the release of insulin from islet cells of the pancreas, low-dose estrogen formulations may be preferred in patients with diabetes. Progesterone competes with insulin for binding to its receptor. Although it is thought that progestins may increase insulin resistance, the newer progestins are thought to be less androgenic and have little effect on carbohydrate and lipid metabolism. In general, the use of combination oral contraceptives is relatively contraindicated in patients with diabetes.

Gallbladder Disease

In women with pre-existing gallstones, low-dose estrogen-containing oral contraceptives may enhance the potential for the development of symptomatic gallbladder disease.1 Although this risk has not been demonstrated with the use of higher-dose oral contraceptives, combination oral contraceptives containing estrogen should be used with caution in patients with a history of gallbladder disease.

Hepatic Tumors

Although the use of oral contraceptives is not associated with an increased risk for the development of hepatocellular carcinoma, long-term use of high-dose oral contraceptives has been associated with the development of benign liver tumors.1 Because even benign liver tumors may pose significant risk to the patient, oral contraceptives should be discontinued if liver enlargement is noted on physical examination.

Cervical Cancer

There appears to be an increased risk for the development of cervical cancer among long-term users of oral contraceptives.1 Whether or not this increase in risk can be attributed directly to the use of oral contraceptives is uncertain, however. Data suggest that oral contraceptive users, on average, tend to have more sexual partners and use condoms less frequently, and as a result, this may increase their susceptibility to becoming infected with human papilloma virus (HPV), a known risk factor for cervical cancer.

Breast Cancer

While a history of breast cancer traditionally has been considered an absolute contraindication to the use of oral contraceptives, most recent studies evaluating the relationship between oral contraceptive use and the risk for breast cancer suggest little, if any, association between the two. A recent study illustrated that current or past use of oral contraceptives among women between the ages of 35 and 64 was not associ-

ated with an increased risk for the development of breast cancer. In older studies of patients using combination oral contraceptives containing 50 to 80 mcg ethinyl estradiol per pill, a link between oral contraceptive use and breast cancer was suggested.

The cancers diagnosed in those studies were found to be more localized. Although the relationship between oral contraceptive use and the potential for breast cancer in older patients is becoming better understood, still the question of risk for breast cancer diagnosis in oral eo„,racep,ive nsers nnder age 35 is less elear' Aisolvte and relative contraindications to the use of oral contraceptives are listed in Table 48-3.1

Adverse Effects of Oral Contraceptives and Their Management

As with all medications, there are potential adverse effects with combination oral contraceptives (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.

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