• Estrogen component inhibits release of FHS from anterior pituitary, preventing selection of dominant follicle
• Estrogen provides stability to endometrium, decreases rate of breakthrough bleeding, thins cervical mucus
• Estrogen increases concentration of progestin receptors, thus allowing for decreased dosage
• Progestin component inhibits release of LH from anterior pituitary, preventing ovulation
• Progestin dominates in effect on the endometrium leading to decidualized lining, atrophied glands, not receptive to implantation
• Progestin increases viscosity of cervical mucus, making sperm penetration more difficult
• Efficacy of oral contraceptives expected to be about 99.9% effective, but with typical use, efficacy approximates 97% for combination OCs ¹

A. Epidemiologic classification ¹:

*Norgestimate is a newer progestin, developed at the same time as desogestrel, but in epidemiologic studies is classified as a 2^nd generation, because thought to derive most action directly from levonorgesterel. ¹

B. Biologic classification: 2 main families of progestins ²

b. "newer" :desogestrel, gestodene, norgestimate

Yasmin, a new OC containing 3mg drosperinone and 30 mcg EE

• Drosperinone is analogue of spironolactone, biologic action more similar to progesterone
• Has both anti-mineralocorticoid activity and anti-androgenic activity
• In open label study found to have acceptable efficacy, safety, and cycle control (similar to other low-dose OCs, 1% breakthrough bleeding, 9.3% spotting, 3.2% amenorrhea) ³
• Patients reported decreased subjective symptoms of water retention and negative affect
• Also mean decrease in weight, no significant change in lipid profiles after 13 cycles

• Mechanism related more to effect on cervical mucus & endometrium, only inhibits ovulation about 40% of time
• Efficacy slightly less than combination OCs- typical failure rate 5% for 1^st year of use
• Effect on cervical mucus lasts only about 22 hrs, must take pill at same time each day (>3 hr delay = missed pill, use back up for 7 days)
• Used commonly by breast feeding women, due to some evidence that combined OCs lead to decreased breast milk production. There is also theoretical concern that exposure to steroids in breast milk in 1^st 6 weeks postpartum can lead to growth restriction in neonates, thus the WHO suggests avoiding progesterone-only OCs during 1^st 6 wks post-partum.^4,5
• However, limited data show no adverse health effects on infants of women who use progesterone-only OCs during breast feeding; in fact some studies have documented an increase in nutritional quality of milk ⁶
• One study documents increase in diabetes in obese lactating patients with recent gestational diabetes who use progesterone only OCs ⁷

Table 2. Current formulations Progestin Only Pills.

A. Estrogen related side effects

• Can be decreased by use of 20 mcg EE pills ⁸ , which still have good contraceptive efficacy

B. Progestin related side effects

• These side effects tend to decrease with continued use

C. Androgenicity

D. Cycle Control

• Factors which may lead to increased breakthrough bleeding: Chlamydia infection ¹⁴, smoking ¹⁵ , noncompliance ¹⁶
• Breakthrough bleeding has been shown to decrease with continued use, is generally highest in first cycle ¹⁷, and is more frequent with first-time pill users, rather than those switching brands ⁸, so encourage patients to keep taking OCs.
• Most studies have shown levonogestrel containing OCs to have better bleeding pattern than norethindrone preparations ¹⁷
• Although 20 mcg EE pills thought to sacrifice cycle control, at least one study found similar cycle control between Mircette, Alesse, and Tri-cyclen by the 6^th cycle ⁸.
• Lo-Estrin has higher rate of breakthrough bleeding than other preparations ^{18, 19}

Table 3. Comparison of estrogenicity and androgenicity of various OC preparations.

A. Estrogenic Effect of Progestins

B. Anti-Estrogenic Effect of Progestins

C. Androgenic Effect of Progestins

A. Venous Thromboembolism (VTE)

• Risk of VTE 3-4 X greater for users of all oral contraceptives compared to non-users
• This is primarily an estrogen dose related phenomenon
• Epidemiologic data initially suggested that risk is higher for users of third generation progestins (desogestrel, gestodene), but many potential biases in these studies ^{20, 21}
• More careful analyses and accounting for confounders such as age and duration of use have found no significant difference in risk between second and third generation users. ²²
• A more recent case control study found that the relative risk of VTE is increased 1.3 X with desogestrel containing OC’s (still absolute risk is very small) ²³
• Risk is also highest in first year of use, with higher dose estrogen products, and with smoking, obesity, family history of VTE and coagulation disorders. ²³
• VTE is the most common cardiovascular event among users of oral contraceptives, however the associated mortality is relatively low compared with that associated with arterial diseases. Long-term disability from non-fatal venous thromboembolic disease is also low.

• Risk of MI not increased with newer generation OC’s, in fact gradient of decreasing risk from 1^st generation to 3^rd generation pills demonstrated in Transnational study ²⁴
• WHO multi-center study concluded that risk of MI among women who are current users of OC’s is increased only in smokers; no increased risk for past users ²⁵
• Risk of MI with 3^rd generation pills may even be lower than for 2^nd generation pills ( see Table 4 below)²⁶
• No relationship between duration of use and risk of MI demonstrated in Nurses Health Study ( OCs do not promote coronary artery disease) ²⁷
• Greater risk of MI for smokers who use second generation OCs rather than third generation OCs ²⁴
• Early data demonstrated that smoking is greater risk factor for MI than OCs ²⁸

C. Stroke

1. Ischemic Stroke

• Risk of ischemic stroke increased 1.5- 2.5X among users of oral contraceptives, directly related to estrogen dose ^{29, 30, 31}
• Hypertension, smoking ³¹ and migraines plus OC use substantially increase risk of stroke ²⁶
• Women >35 who reported having a BP check prior to starting OCs were at significantly decreased risk of ischemic stroke compared to those who did not report a BP check ³¹
• Recent case control study from Denmark found 61% higher risk association for cerebral thromboembolic event with second generation progestins than with third generation progestins ²⁹

• WHO study found a slightly increased risk of hemorrhagic stroke in older women (>35), probably only those with risk factors such as hypertension or smoking ³²

*Incidence per 100,000 annually

Based on International Federation of Fertility Societies: Consensus conference of combination oral contraceptives and cardiovascular disease. Fertil Steril 1999; 71(3):15-65.

D. Summary of Cardiovascular Risks

• OCs increase risk of ischemic stroke by 1.5-2.5 X baseline; VTE 3-4 X baseline
• Risk of VTE may be slightly greater for users of 3^rd generation pills (desogestrel )
• Risk of ischemic stroke may be less with 3^rd generation pills
• Risk of MI may also be less with 3^rd generation pills
• Risks are significantly increased in women who are older, who smoke or have hypertension
• WHO Scientific Group Meeting on Cardiovascular Disease and Steroid Hormone Contraception. (Geneva, 1997) concluded that that the incidence and mortality rates of all cardiovascular diseases (stroke, MI, and VTE) in women of reproductive age are very low. Any additional cardiovascular disease incidence or mortality attributable to oral contraceptives is very small if the users do not smoke and do not have other cardiovascular risk factors.

• Large meta-analysis from 1996 found relative risk of breast cancer of current users compared to never users to be 1.24 ³³
• Increased risk disappeared after about 10 years
• No effect of OC use by dosage, formulation, duration, age at time of use, age at time of diagnosis or family history
• Users also more likely to have localized disease at diagnosis (?promotional effect of OC’s leading to earlier diagnosis?) ²⁶

• Since 1990, new studies have continued to show an increased risk of carcinoma in situ and invasive carcinoma (both squamous carcinoma and the less common adenocarcinoma) of the cervix among long-term users of combined oral contraceptives.
• Long-term use of combined oral contraceptives by women with persistent HPV infection is a contributing factor in the development of cervical cancer. This increased risk is currently thought to be two to four fold after long-term use (five years or more), and the effect persists for up to 15 years. ³⁵

• Smoking greater than age 35
• History of CVA or MI or multiple risk factors for coronary artery disease (older, smoker, hypertension, DM)
• Moderate or severe hypertension ( baseline BP > 160/100), should also avoid in patients who have more adequately controlled hypertension as risks usually outweigh benefits
• Diabetes with significant vascular complications
• Complicated valvular heart disease
• Thrombophilia or Thromboembolic disorder (history of DVT/PE)
• Major surgery with prolonged hospitalization
• Known or suspected pregnancy
• Undiagnosed vaginal bleeding
• Known or suspected breast cancer (or history of breast cancer)
• Markedly abnormal liver function, active viral hepatitis, malignant liver tumor
• Avoid in patients with symptomatic gall bladder disease current or treated
• Migraine with focal neurologic symptoms (flashing lights, loss of vision, weakness, slurred speech, dizziness, cranial nerve abnormalities)

For other conditions or more info see link below.

• Reduction in endometrial cancer by 50% (when used for at least 12 mo, greatest benefit with >3 yrs use) ³⁷
• Reduction in ovarian cancer by 40%, most notable after 3 yrs. use, but present after as little as 3-6 months of use³⁸
• Reduction in benign breast disease
• Reduction in blood loss, anemia, and dysmenorrhea
• Protection against pelvic inflammatory disease
• Decreased risk of ectopic pregnancy
• Possible reduction in risk of colon cancer
• Possible decrease in uterine leiomyomata
• Reduction in acne
• Possible protection against rheumatoid arthritis
• Protection against osteoporosis

** first-day start-- women always start new pill pack on first day of menses, never use more than 3-5 days of placebo before starting a new pack ³¹

• Starting OCs
• Women with regular menstrual cycles can start OCs within 5 days of starting their period and need no backup
• Women who start the pill at a time other than their period should be reasonably sure they are not pregnant first, and use back-up for 7 days.
• Women who are amennorheic can start OCs at any time if they are reasonably sure they are not pregnant, and should use back-up for 7 days.
• Missing pills ^{1, 36}
• Miss 1 pill: take missed pill as soon as remembered and continue regular schedule
• If pack is started late ( > 7 day hormone free interval) should use back-up for 7 days, consider emergency contraception (EC).
• Missed 2 pills: during week 1- take 2 pills daily for 2 days then finish pack. Use back up for 7 days, offer EC.
• Missed 2 pills during week 2- take pills daily for 2 days then finish the pack. No back-up needed.
• Missed 2 pills during week 3- take missed pill as soon as remembered, then continue regular schedule (even if you need to take 2 pills at same time). Skip placebo pills and start a new pack. Use back up for 7 days - OR - start a new pack right away and use back up for 7 days.
• Missed 3 or more pills- start a new pack and use back up for 7 days. Offer EC.

1. Yuzpe method: high dose combination OCs
2. High dose progestin only pills
3. Copper IUD insertion

A. Mechanism

• primarily acts as contraceptive, disrupts normal follicular growth, blocks LH surge, inhibits ovulation if taken prior to ovulation. May create deficient luteal phase, have some effect on endometrium. May inhibit tubal transport of sperm/ova. NOT AN ABORTIFACIENT.

B. Effectiveness

• Combination OCs (Yuzpe method) lead to 60-75% reduction in pregnancies
• POPs lead to 85% reduction in pregnancies

C. Prescribing Information

• Must use EC pills within 72 hours of unprotected intercourse
• If using combination OCs, prescribe anti-emetic medication to take 1 hour before 1^st dose
• Take one dose then repeat identical dose 12 hours later
• If no menses within 21 days should have pregnancy test

Table 7. Approved Pills for EC

Compiled by Jessica J. Lalley MD. Updated July 2002.

Thanks to Hope K. Hafner MD and Rudi M. Ansbacher, MD MS for editorial assistance.

Also thanks to Organon pharmaceuticals for educational grant assistance.