COMBINED HORMONAL CONTRACEPTIVES


See also Hormone Replacement Therapy 

Contain estrogen & progestin; suppress FSH & LH, thus preventing ovulation

I. Estrogen component

  1. Ethinyl estradiol 20-100ug/day
    1. 1.2-1.4 times more potent than mestranol
  2. Mestranol 50mug/day
    1. Converted hepatically to ethinyl estradiol

II. Progestin component

  1. Older generation: norethindrone, norethindrone acetate, ethynodiol diacetate, norgestrel, levonorgestrel, norethynodrel
  2. Newer generation-Desogestrel (Desogen, Orthocept), Norgestimate, Gestodene (Europe only)
    1. May improve lipid profiles (higher HDL and lower LDL)
    2. Lowers free testosterone levels through increase in sex-hormone binding globulin and less binding to androgen receptors; may be good for women with androgenic sx
    3. In features # 1 and 2 may have no advantage over the pills containing 0.4 or 0.5 norethindrone (Ovcon-35, Modicon, Brevicon)
    4. Lower incidence of amenorrhea compared with other progestins
    5. May increased risk of venous thromboembolism (see below)
  1. Drospirenone
    1. A synthetic progestin with anti-mineralocorticoid and anti-androgenic activity; the former is unique (as of 2002) in progestins used in OC's
    2. Can cause potassium retention
    3. Associated with less weight gain than other progestins
    4. May reduce blood pressure
    5. May be associated with higher risk of thrombosis than other progestins
III. Contraindications (some only relative)
  1. Over 35yo and current smoker > 15 cigs/d, though may use after 1y of tobacco abstinence
  2. Migraine with Aura (associated with increased CVA risk)
  3. Current smoker (relative contraindication)
  4. Thromboembolic disease, unless due to trauma or IV catheter
  5. Cerebrovascular disease or CAD
  6. Neoplastic disease:
  1. Breast Ca or suspicious breast mass
  2. Any GYN malignancy
  3. Liver adenoma or Ca
  1. Chronic liver disease (relative contraindication)
  2. Pregnancy (though little data to support risk of teratogenicity or adverse pregnancy outcomes with unintended use of OCPs in pregnancy)
  3. Polycythemia vera (thrombotic risk)
  4. Gallbladder disease (can worsen with OC's)
  5. Recent delivery (< 2 wks, to avoid hypercoagulable state of pregnancy)
  6. Obesity (Relative contraindication; May increase risk of OC failure and pregnancy--Obs. Gyn. 99:820, 2002--JW; Obs. Gyn. 105:46, 2005--abst)
  7. Considerations in women > 40yo
    1. OK until menopause-Use a monophasic OCP with <30 mcg ethinyl estradiol and low-dose norethindrone
    2. Consider other contraindications though (see above) which are more likely to be present in women > 40yo

IV. Choosing among oral contraceptives

  1. Estrogen component
    1. Avoid > 35ug of estrogen if possible; > 20ug if high risk for thrombosis
  2. Progestin component
    1. Consider an OCP with a newer progestin (desogestrel, norgestimate) if pt has androgenic sx (hirsutism, acne); otherwise, avoid them (higher risk of thromboembolism)
    2. Low progestin advisable in diabetics (see below)

V. Guidelines for use

  1. Discuss HIV risk and recommend condoms if appropriate
  2. Discuss backup method if pt decides to discontinue
  3. Discuss availability of emergency contraception if pt. discontinues and has unprotected sex
  4. Can start any day you're sure you're not pregnant, but usually start on Sunday after start of period
  5. Take same time of day, evening helps reduce nausea
  6. For missed pills:
  1. If miss one, take as roon as remember and take next at reg. time. Can use backup for 7d but ovulation unlikely
  2. If miss 2 in a row, take 2 as soon as remember and 2 the next day, then continue for rest of pack but use backup for 7d
  3. If miss 3 in a row, will prob. get period; in any case, thro away pack and start next one on Sunday; use backup for 7d
  4. If any missed pills are from last 7d of 28d cycle, just throw missed pills away and continue on schedule
  1. If have diarrhea or vomiting, use backup method until next period, b/c may not absorb hormones
  2. Advise that periods may become scanty but missed period should prompt preg. test
  3. Advise to report "ACHES" warning signs: abd. pain, chest pain, HA, eye problems (vision, for CVA), leg pain (for DVT)
  4. Advise pt to report any new medications started, particularly antibiotics, anticonvulsants, antifungals
  5. Advise as to interaction with vit. C (see below)
  6. Advise to stop smoking if a smoker
  7. Discontinue OC's 1mo before any surgery to reduce risk of DVT (ok to use a progestin-only contraceptive during that time)

VI. Beneficial effects: improves or reduces risk of:

  1. Dysmenorrhea (in at least one randomized trial: Obs. Gyn. 106:97, 2005--JW)
  2. Mittelschmerz
  3. Functional ovarian cysts (less with triphasic and very low-dose OC's)
  4. Acne-Proven benefit with the following progestins:
    1. Norgestimate (Obs. Gyn. 89:615, 1997; J. Am. Acad. Dermat. 37:746, 1997)
    2. Levonorgestrel (Fertil. Steril. 76:461, 2001--JW)
    3. Norethindrone acetate (Contrac. 60:255, 1999)
  5. Premenstrual Syndrome
    1. Monophasic pills prob. best for this.
    2. No benefit of 3rd-generation progestin (desogestrel) over levonorgestrel in one randomized 9mo study in 34 women w/acne (Am. J. Obs. Gyn 188:1158, 2003--JW)
    3. In some women symptoms may worsen with OCPs
  6. Pelvic inflammatory disease (perhaps due to less menstrual bleeding or changes in cervical mucus)
  7. Endometriosis
  8. Ovarian cancer (RR 0.7 for any use; 0.4 for 5-11 yrs; 0.2 for 12 or more yrs; Obs. Gyn 80:708, 1992, cited in AFP; also BMJ 318:96, 1999)
  9. Endometrial cancer (RR 0.6 for 2-4yrs; 0.4 for >4yrs)
  10. Osteoporosis-Ever-use of OCP's was ass'd with RR of 0.75 (sig.) for hip fx after adjusting for confounding factors in one case-control study (Lancet 353:1481, 1999--JW)
  11. Benign breast disease
  12. Decrease menstrual flow & thus may decrease risk of anemia
  13. Gives woman control over menstrual period (can delay menses if wish for vacations, etc.)
  14. Can be used to correct menstrual irregularity and unopposed estrogen effect in Chronic Anovulation or Amenorrhea due to hypothalamic dysfunction

VII. Detrimental effects

  1. Symptoms due to estrogen:
  1. Nausea and vomiting (most common in first cycle or two)
  2. Fluid retention with cyclic weight gain (may cause breast tenderness)
  3. Leukorrhea
  4. Menstrual disruption (breakthrough bleeding, amenorrhea)
  1. Breakthrough bleeding
  1. Can result from insufficient estrogen (more common with 20ug than with 30-35ug estrogen preparations) or inadequate progestin
  2. Tends to decrease after first few cycles
  3. First rule out pregnancy; consider infection, anatomic lesion
  4. Confirm that didn't miss any pills
  5. Can be managed by switching to a 50ug pill, but most clinicians would first increase progestin component instead; another tactic is to give NSAIDs for 2-3mos
  1. Amenorrhea-tend to get less endometrial buildup through the month on the pill than naturally; get scantier menses and sometimes none at all; if amenorrhea occurs and not pregnant, consider switch to higher progestin pill to produce greater endometrial buildup
  1. Reduced milk production in lactating women (slight); some recommend waiting until milk production has kicked in (sev. weeks) before starting OC's; consider progestin-only hormonal contraception; see below
  1. Symptoms due to progestin:
  1. Depression and fatigue
  2. Weight gain-May actually be no more than placebo (ACOG Ed. Bulletin #256, 12/99)
  3. Breakthrough bleeding (see above)
  4. Decreased libido and decreased orgasm
  5. Acne (if has androgenic properties)
  1. Symptoms due to both estrogen and progestin:
  1. Increased breast size and breast tenderness (treat by decreasing estrogen or progestin componen; reduced caffeine, vint. E 400UI BID)
  2. May worsen headaches
  3. Chloasma ("mask of pregnancy")
  1. Thrombotic complications (DVT, PE, CVA, etc.)
  1. Aggravating risk factors: smoker, >35yo, sedentary, overweight, h/o DM or HTN
  2. Probably mostly due to estrogen component
  3. Venous thromboembolism risk
    1. In a case-control study of 196 women with VTE and 746 controls, current use of oral contraceptives was ass'd with sig. higher VTE risk (OR 4.07); past use was not ass'd with sig. increased risk for VTE (Contraception 70:3, 2004--JW)
  4. Involvement of progestin component--"3rd-Generation" progestins may confer higher risk
  1. Case-control study of 471 women with thromboembolism and 1772 age-and location-matched controls. RR for thromboembolism was about 4 with current use of any OC's; about 3.0 for those taking second-generation pill c/w taking no pills; about 5.0 for those on 3rd-generation pills (so higher than overall). Estimated risk of thromboembolism was 20 per million users/yr for 3rd-generation pills, 14 for second-generation pills, and 5 for nonusers (BMJ 312:83, 1996-JW)
  2. In a meta-analysis of 3 cohort & 9 case-controlled studies, OR for venous thromboembolism was 1.7 for 3rd- vs. 2nd-generation progestins in OC's (sig.) (BMJ 323:119, 2001--JW)
  1. CVA risk
  1. NEJM 335:8, 1996
  1. Unlike most previous studies, looked at low-dose estrogen OC's (30-35 ug)
  2. Case-control with 295 women (15-44yo) who had CVA and 774 controls
  3. No sig. increase in risk for ischemic or hemorrhagic CVA with current OC use after adjustment for risk factors
  4. Did find sig. interaction between smoking and current OC use for hemorrhagic stroke
  1. Lancet 348:505, 1996-JW
  1. Int'l case-control study in women aged 20-44 with CVA (697 ischemic; 1068 hemorrhagic)
  2. OC's ass'd with OR 3.0 for ischemic CVA; OR 7.2 for OC users who smoked; higher risk with 50ug than 30ug estrogen
  1. BMJ 315:1502, 1997--JW
    1. Case-control study of 220 women 16-44yo w/ischemic CVA c/w 775 controls
    2. RR for ischemic CVA after adjustment for HTN, smoking, and parity was:
      1. 4.4 for women on high-dose OC's
      2. 3.4 for women on low-dose OC's
      3. 3.9 for women on low-dose OC's with "3rd gen." progestins (gestodene or desogestrel)
  1. JAMA 284:72, 2000
    1. Meta-analysis of 16 studies
    2. Current OC use ass'd with RR 2.75 for ischemic CVA (sig.); 1.93 for low-estrogen OC's (sig. less than higher-estrogen OC's)
  2. In a case-control study of 234 women 15-55yo with CVA and age- and 234 neighborhood-matched controls, current use of OCP's (with 50ug/d estrogen or less) was ass'd with nonsig. increased risk of CVA (95% CI for RR 0.86-3.61) (Stroke 34:1575, 2003--abst)
  1. MI--Little if any increased risk; data from nonrandomized trials only
    1. Case-control of 153 women with MI and 498 matched controls; only second-generation pills (vs. no OC's) carried sig. risk for MI (OR 3.2) (BMJ 312:88, 1996-JW)
    2. Meta-analysis of 13 studies concluded no incr. risk of CAD among past users of OC's (Am.J. Obs. Gyn. 163:285, 1990; cited in NEJM 332:1758, 1995)
    3. RR 4-8 for MI in women who smoke > 25cigs/d c/w smokers who don't use OCP's; no increased risk w/OCP use in nonsmokers < 40yo (Ann. Int. Med 128:467, 1998--AFP)
    4. Meta-analysis of 2 case-control studies in 271 women 18-44yo with MI (summary didn't say how many control pts) found no increase in MI risk among current OC users in multivariate analysis. Past OC users had a nonsig. reduced risk of MI (OR 0.54) (Circ. 98:1058, 1998--JW)
    5. 2nd-generation (levonorgestrel-contraining) OC's were ass'd with OR 2.4 (sig.) for MI after adjustment for age and other risk factors with in a case-control study of 248 women 24-49 with MI and 925 controls; 3rd-generation (desogestrel- or gestodene-containing) OC's NOT ass'd with sig. increased risk (NEJM 345:1787, 2001--JW)
    6. In a prospective study in > 48,000 women 30-49yo enrolled in the Women's Lifestyle and Health Study, followed for mean 11y, risk for MI was not sig. diff. in women with h/o current OR in women with h/o prior use of oral contraceptives (Fertil. Steril. 88:310, 2007--JW)
  1. Cervical cancer:
    1. Duration of combined OC use for > 5y is associated with increased risk fo cervical cancer and returns to the level of a "never user" after 10y post-cessation
    2. Unclear if a causal relationship; may be confounded by # of partners and frequency of pap smears
  2. Breast cancer: may increase risk on some subgroups of women but for women on the whole don't appear to increase risk.
  1. Lancet 347:1713, 1996
  1. Meta-analysis of 54 studies on 53,000 women with breast Ca and 100,000 without
  2. RR of 1.24 for breast Ca with current use of combined OC's
  3. After cessation of use, RR decreased to 1 in 10y
  4. Ca's dx'd in women who had ever used combined OC's were less advanced than if never used
  5. For a given duration of combined OC use, RR was not affected by age when started; however, RR was greater if started OC's before age 20 than for all women regardless of age when started
  1. In a cohort study of 3,396 relatives of women with breast Ca and 2,754 controls followed for mean 36y, ever-use of OCP's ass'd with RR of 3.3 for breast Ca in sisters or daughters of women with breast Ca--in families with greater #'s of women with breast Ca, RR was higher--Most of these were women who had used OCP's before 1975, when estrogen doses were higher(JAMA 284:1791, 2000--FP News, JW)
  2. In a case-control study of 4575 women 35-64yo with breast Ca and 4682 controls, use of OC's was not ass'd with risk of breast Ca; no association was found either in various subgroups (NEJM 346:2025, 2002--JW)
  3. In a meta-analysis of 34 case-control studies of oral contraceptive use in premenopausal women < 50yo, OC use was associated with sig. increase risk of breast Ca (OR 1.19). Risk for women who used OCs before first full-term pregnancy was sig. greater than those who started after (1.44 vs. 1.15) (Mayo Clin. Proc. 81:1290, 2006--JW)
  4. Risk with Progestin-only contraception
    1. Case-control study comparing 891 with newly-dx'd breast Ca with 1864 controls showed RR of breast Ca in all users of medroxyprogesterone acetate was 1.0; in women 25-34yo, was 2.0 (suggests that may accelerate growth of breast Ca in young women; Brit. Med. J. 299:759, 1989)\
    2. WHO Collaborative Study showed no inc. risk for breast (or cervical Ca) among women using Depo in a case-control study of 427 women with breast Ca and 5951 controls (Lancet 338:833, 1991)
    3. In a case-control study of 4,575 women 35-64yo with invasive breast Ca and 4,682 location-, age-, and race-matched controls, use of progestin-only contraception was not associated with risk for breast cancer (Contraception 69:353, 2004--JW)
  1. Increases risk for hepatocellular adenomas (still very low risk for low-dose OC's), and perhaps for hepatocellular carcinoma as well.
  2. Very minor tendency toward hypertension
  3. Serum lipids: unclear effect (estrogens and progestins move them in opposite directions)
  4. May impair glucose tolerance (progestin effect)
  5. Increased risk for chlamydial cervicitis; no clear increased risk of chlamydial PID, though

VIII. Interactions with other drugs

  1. Anticonvulsants: phenobarb, phenytoin, carbamazepine, ethosuximide, primidone; accelerate hepatic breakdown of estrogens; consider 50ug pills for women on these drugs
  2. Antimicrobials: ampicillin, tetracycline (decrease enterohepatic circulation); griseofulvin, rifampin (speed hepatic metabolism)
  3. St. John's Wort may reduce effectiveness of OC's
  4. Vitamin C reduces hepatic steroid metabolism and increases serum level of OC's
  5. OC's increase t-1/2 of benzodiazepines
  6. OC's decrease clearance of theophylline
  7. OC's decrease effect of oral anticoagulants and hypoglycemics

IX. Notes on specific forms of combined OCs

  1. Oral
    1. "Multiphasic" pills vary dose of one or both hormones throughout the cycle. They usually have lower total hormone dose per cycle but no evidence for difference in adverse effects or any other advantage over "monophasic" pills (Med. Letter 42:43, 2000)
    2. Hormone-free and hormone-light intervals
      1. Traditional OCPs have a 21-day active treatment cycle followed by a 7d  hormone-free interval (results in a menses in most women; if subsequent pill cycle is not started on time may have ovulation and risk for pregnancy).
      2. "Mircette" substituted a low-dose estrogen pill (10ug ethinyl estradiol) for 5 of the 7 usual placebo pills; associated with less intermenstrual bleeding than other OCPs
      3. 24 active-dose pills followed by 4d of placebo pills: "Loestrin 24 Fe" and "YAZ" 
      4. 84 active-dose pills followed by 7d of placebo pills: Seasonale (more breakthrough bleeding than traditional 28-day cycles for first few months)
      5. 84 active-dose pills followed by 7d of low-dose estrogen pills: Seasonique
  2. Transdermal
    1. "Ortho Evra" patch approved by FDA 2001; ethinyl estradiol + norelgestromin; change patch Qwk; efficacy may be reduced in women > 90kg body weight (Med. Lett.)
  3. Vaginal contraceptive ring
    1. "NuvaRing" (ethinyl estradiol + etonorgestrel) approved by FDA 2001; used x 3wks with 1wk break then new ring is used