Gynecology_Novak

Gynecology_Novak. Condoms In the 1700s, condoms made of animal intestine were used by the aristocracy of Europe, but condoms were not widely available until the vulcanization of rubber in the 1840s (1). Modern condoms usually are made of latex rubber, although condoms made from animal intestine are still sold and are preferred by some who feel they afford better sensation. New condoms made from nonlatex materials—such as polyurethane or synthetic elastomers that are thin, odorless, transparent, and transmit body heat—are available. Although the nonlatex condoms may break more easily than the latex varieties, substantial numbers of study participants preferred them and would recommend them to others (25). The risk of condom breakage is about 3% and is related to friction (26). Use of water-based lubricants may reduce the risk of breakage. Petroleum-based products such as mineral oil must be avoided because even brief exposure to them markedly reduces the strength of condoms (27).


Gynecology_Novak

Gynecology_Novak. Gonorrhea, ureaplasma, and pelvic inﬂammatory disease (PID) and its sequel (tubal infertility) are reduced with consistent use of barrier methods (28–30). Tested in vitro, Chlamydia trachomatis, herpes virus type 2, HIV, and hepatitis B did not penetrate latex condoms but did cross through condoms made from animal intestine (31). Follow-up of sexual partners of HIV-infected individuals showed that condom use provides considerable protection (32). Consistent condom use provides more protection than inconsistent use (33). In one study, couples who use condoms 0% to 50% of the time had an HIV seroconversion rate of 20.8 per 100 couple years, whereas those who used condoms 100% of the time had a conversion rate of only 2.3 per 100 couple years (34). Nonoxynol-9 should not be used with condoms for HIV protection because it is associated with genital lesions. Nonoxynol-9 does not add to the protection afforded by condoms alone (35).


Gynecology_Novak

Gynecology_Novak. Condoms offer protection from cervical neoplasia (36). The relative risk for invasive cervical cancer was 0.4 when those who used condoms or diaphragms were compared with those who never used them (37). The presumed mechanism of protection is reduced transmission of human papillomavirus (HPV). Latex allergy could lead to life-threatening anaphylaxis in either partner from latex condoms. Nonlatex condoms of polyurethane and Tactylon should be offered to couples who have a history suggestive of latex allergy.


Gynecology_Novak

Gynecology_Novak. Female Condom The original female condom introduced in 1992 was a polyurethane vaginal pouch attached to a rim that partly covered the vulva. The recently FDA approved FC2 female condom is an improved version made from softer synthetic latex that does not require hand assembly during manufacture and is therefore less expensive (38). It is recommended for prevention of pregnancy and STDs, including HIV. Breakage may occur less often with the female condom than the male condom; slippage appears to be more common, especially for those new to its use (39). Exposure to seminal ﬂuid is slightly higher than with the male condom (40). Initial US trials showed a pregnancy rate of 15% in 6 months. Subsequent analysis found that with perfect use, the pregnancy rate may be only 2.6%. This rate is comparable to perfect use of the diaphragm and cervical cap, the other female barrier methods (41). As with the male condom, failure rates fall with increasing experience. Colposcopic studies of women


Gynecology_Novak

Gynecology_Novak. to perfect use of the diaphragm and cervical cap, the other female barrier methods (41). As with the male condom, failure rates fall with increasing experience. Colposcopic studies of women using the female condom demonstrate no signs of trauma or change in the bacterial ﬂora (42).


Gynecology_Novak

Gynecology_Novak. Vaginal Spermicides Currently available vaginal spermicides combine a spermicidal chemical, either nonoxynol-9 (N9)or octoxynol, with a base of cream, jelly, aerosol foam, foaming tablet, film, suppository, or a polyurethane sponge. Nonoxynol-9 is a nonionic surface-active detergent that immobilizes sperm. Nonoxynol-9 spermicides alone appear considerably less effective in preventing pregnancy than condoms or diaphragms. Women using nonoxynol-9 spermicides frequently have higher rates of genital lesions than women not using spermicides. These lesions may increase their risk for STDs and HIV (43). In the same studies of serodiscordant couples in which condoms were proven effective in preventing transmission of HIV, nonoxynol-9 spermicides alone were not effective (34).


Gynecology_Novak

Gynecology_Novak. Concerns were raised about possible teratogenicity of spermicides. Nonoxynol-9 is not absorbed from the human vagina (44). Several large studies found no greater risk of miscarriage, birth defects, or low birth weight in spermicide users than in other women (45,46). Nonoxynol-9 is toxic to the lactobacilli that normally colonize the vagina. Women who use spermicides regularly have increased vaginal colonization with the bacterium Escherichia coli and may be predisposed to E. coli bacteriuria after intercourse (47).


Gynecology_Novak

Gynecology_Novak. Vaginal Barriers At the beginning of the 20th century, four types of vaginal barriers were used in Europe: vaginal diaphragm, cervical cap, vault cap, and Vimule. Vaginal diaphragms, new varieties of cervical caps and the synthetic sponge are used in the United States. When used consistently, vaginal barriers can be reasonably effective. They are safe, and, as with condoms, they have the non-contraceptive benefit of relative protection from STDs, tubal infertility, and cervical neoplasia. A recent search for alternatives to condoms for HIV prevention in high-prevalence areas has rekindled interest in the other vaginal barriers (48).


Gynecology_Novak

Gynecology_Novak. Diaphragm The diaphragm consists of a circular spring covered with fine latex rubber (Fig. 10.3). There are several types of diaphragms, as determined by the spring rim: coil, ﬂat, or arcing. Coil-spring and ﬂat-spring diaphragms become a ﬂat oval when compressed for insertion. Arcing diaphragms form an arc or half moon when compressed; they are easiest to insert correctly. The practitioner must fit the diaphragm for the patient, and instruct her in its insertion and verify by examination that she can insert it correctly to cover the cervix and upper vagina. Spermicide is always prescribed for use with the diaphragm; whether this practice is necessary is not well studied. Fitting a diaphragm should be performed as follows: 1.


Gynecology_Novak

Gynecology_Novak. Fitting a diaphragm should be performed as follows: 1. A vaginal examination should be performed. With the first and second fingers in the posterior fornix, the thumb of the examining hand is placed against the first finger to mark where the first finger touches the pubic bone. The distance from the tip of the middle finger to the tip of the thumb is the diameter of the first diaphragm that should be tried. 2. A set of test diaphragms of various sizes is used, and the test diaphragm is inserted and checked by palpation. The diaphragm should open easily in the vagina and fill the fornices without pressure. The largest diaphragm that fits comfortably should be selected. A size 65, 70, or 75 diaphragm will fit most women. 3.


Gynecology_Novak

Gynecology_Novak. 3. The patient should practice insertion and should be reexamined to confirm proper position of the device. About 1 teaspoon of water-soluble spermicidal jelly or cream is placed in the cavity of the dome. The diaphragm is inserted with the dome downward so that the cervix will sit in a pool of the spermicide. 4. The diaphragm can be inserted several hours before intercourse. If intercourse is repeated, additional spermicidal jelly should be inserted into the vagina without removing the diaphragm. The diaphragm should be left in place at least 6 hours after intercourse to allow for immobilization of sperm. When removed, it is washed with soap and water, allowed to dry, and stored away from heat. It should not be dusted with talc because genital exposure to talc may increase the risk of ovarian cancer. Figure 10.3 Wide-seal diaphragm. A: Outer caudal side. B: Inner cephalad side.


Gynecology_Novak

Gynecology_Novak. Figure 10.3 Wide-seal diaphragm. A: Outer caudal side. B: Inner cephalad side. Diaphragm use, especially prolonged use during multiple acts of intercourse, appears to increase the risk of bladder infections. The risk of cystitis increases with the numbers of days the diaphragm is used in a week (49). A smaller-sized, wide-seal diaphragm or a cervical cap can be used if recurrent cystitis is a problem, although the problem may relate not only to mechanical obstruction but also to alterations in vaginal ﬂora produced by the spermicide. An epidemiologic study comparing cases of toxic shock with controls found no increased risk from diaphragm use (50). Other Barriers The Prentif cervical cap made of latex rubber is no longer available in the United States. It was in continuous use for most of the 20th century, but competition from other methods made its continued production impractical. The FemCap


Gynecology_Novak

Gynecology_Novak. The FemCap This new version of the cervical cap made of silicone rubber was approved by the FDA in 2003. It looks like a sailor’s hat with the dome covering the cervix and the brim fitting into the vaginal fornices (51). It is made in three sizes—22-, 26-, and 30-mm diameter—and is expected to be reusable for 2 years. It is used with spermicide and should be left in place for at least 6 hours after intercourse, but it may be left in place as long as 48 hours at a time. Additional acts of intercourse require insertion of more spermicide. Femcap requires a clinician’s fitting and prescription for use. The only available efficacy study compared the FemCap to the vaginal diaphragm. The 6-month pregnancy rate for the FemCap was 13.5%, substantially higher than the 7.9% rate for the diaphragm. Both groups used N-9 spermicide with the devices (52).


Gynecology_Novak

Gynecology_Novak. Lea’s Shield, approved by the FDA in 2002, is another vaginal barrier device made of silicone rubber. It is intended for use with a spermicide. It is shaped like an elliptical bowl with a central air valve approximately the size of a diaphragm, featuring an anterior loop to assist its removal. The posterior end is thicker and therefore less likely to rotate when in place. It comes in one size; proper fitting requires only that it cover the cervix, sit behind the symphysis, and be comfortable. The shield needs to be inserted prior to each act of intercourse and should not be left in the vagina for longer than 48 hours (53). A prescription is required. Approximately 87% of those responding to a question about their use of the shield stated that they would recommend its use to a friend (51). Of 59 women who used the device with N-9 spermicide, the 6-month pregnancy rate was 15% (54).


Gynecology_Novak

Gynecology_Novak. The Sponge The Today sponge is a polyurethane dome-shaped device containing nonoxynol-9. It is moistened with water and then inserted high in the vagina to cover the cervix. It combines the advantages of a disposable barrier with spermicide and provides protection for 24 hours. The contraceptive efficacy appears to differ with parity. Nulliparous women are reported to have a perfect use pregnancy rate of 9% per year, whereas parous women have a pregnancy rate of 20% (Table 10.2). Rates with typical use are estimated as 16 per year in nullipara and 32% in multipara (55). A trial comparing the sponge with a vaginal spermicide preparation used alone without barrier showed the sponge had a slightly lower pregnancy rate (56). Figure 10.4 Copper T380A (ParaGard) intrauterine device.


Gynecology_Novak

Gynecology_Novak. Figure 10.4 Copper T380A (ParaGard) intrauterine device. Worldwide over 15% of married women use intrauterine contraception (57). In the United States, usage is increasing, but the estimates are that only 3.4% of women and only 5.0% of married women use intrauterine contraception (4). Candidacy includes nulliparous women, adolescents, and immunocompromised women. Immediate use postpartum or after a first or second trimester abortion broadened usage. Two IUDs are in use in the United States: the copper T380A (ParaGard) and the levonorgestrel-releasing T (Mirena). The copper T380A has bands of copper on the cross arms of the T in addition to copper wire around the stem, providing a total surface area of 380 mm of copper, almost double the surface area of copper in earlier copper devices (Fig. 10.4). It is approved for up to 10 years of continuous use. The levonorgestrel T (Fig.


Gynecology_Novak

Gynecology_Novak. 10.5) is approved in the United States for 5 years of use, although studies through 7 years of use show no loss of efficacy (58). Both provide safe, long-term contraception with effectiveness equivalent to tubal sterilization. Mechanism of Action


Gynecology_Novak

Gynecology_Novak. Mechanism of Action Intrauterine devices cause the formation of “biologic foam” within the uterine cavity that contains strands of fibrin, phagocytic cells, and proteolytic enzymes. All IUDs stimulate the formation of prostaglandins within the uterus, consistent with both smooth muscle contraction and inﬂammation. Copper IUDs continuously release a small amount of the metal, producing an even greater inﬂammatory response. Scanning electron microscopy studies of the endometrium of women wearing nonmedicated IUDs show alterations in the surface morphology of cells, especially of the microvilli of ciliated cells (59). There are major alterations in the composition of proteins within the uterine cavity and new proteins and proteinase inhibitors are found in washings from the uterus (60). The altered intrauterine environment interferes with sperm passage through the uterus, preventing fertilization. Figure 10.5 Levonorgestrel T (Mirena™) intrauterine device.


Gynecology_Novak

Gynecology_Novak. Figure 10.5 Levonorgestrel T (Mirena™) intrauterine device. The levonorgestrel in the T device is much more potent than natural progesterone and has a strong effect on the endometrium. The hormone is released at an initial rate of 20 μg daily, which declines to half this rate by 5 years. Blood hormone levels are significantly lower than with other progesterone-only contraception and remain stable at approximately 150 to 200 pg/mL (61). About 85% of cycles are ovulatory. The contraceptive effect of the levonorgestrel intrauterine device is a result of thickened and scant cervical mucus, endometrial atrophy, and an intrauterine inﬂammatory response (62).


Gynecology_Novak

Gynecology_Novak. The IUD is not an abortifacient. The contraceptive effectiveness does not depend on interference with implantation, although this phenomenon occurs and is the basis for using copper IUDs for emergency contraception. Sperm can be obtained by laparoscopy in washings from the fallopian tubes of control women at midcycle; fewer sperm are present in the tubal washings from women wearing IUDs (63). Ova ﬂushed from the tubes at tubal sterilization showed no evidence of fertilization in women wearing IUDs (64). Studies of serum β-human chorionic gonadotropin (β-HCG) levels in women wearing IUDs do not indicate pregnancy (65).


Gynecology_Novak

Gynecology_Novak. The copper T380A and the levonorgestrel T have remarkably low pregnancy rates, less than 0.2 per 100 woman-years. Total pregnancies over a 7-year period were only 1.1 per 100 for the levonorgestrel T and 1.4 for the copper T380A (58). Twelve-year data on the copper T380A showed a cumulative pregnancy rate of only 1.9 per 100 women and no pregnancies at all after year 8 (66).


Gynecology_Novak

Gynecology_Novak. Modern IUDs provide excellent contraception without continued effort by the user. Both the copper T380A and the levonorgestrel T protect against ectopic pregnancy. The levonorgestrel T, by releasing levonorgestrel, reduces menstrual bleeding and cramping. It is used extensively to treat heavy menstrual bleeding and is used in Europe and the United Kingdom as an alternative to hysterectomy for menorrhagia (67). The levonorgestrel T also has a beneficial effect on menorrhagia from uterine fibroids; the benefit may be diminished with distorting submucosal fibroids (68,69). The levonorgestrel T is an effective way to deliver the necessary progestin therapy in postmenopausal women on estrogen therapy (70). Additional noncontraceptive benefits include a reduced risk of endometrial cancer and improvement in symptoms of endometriosis and adenomyosis (71–74).


Gynecology_Novak

Gynecology_Novak. Infection The Women’s Health Study found the Dalkon Shield device (now withdrawn from the market) to increase the risk of PID eightfold when women hospitalized for PID were compared with control women hospitalized for other illnesses (75). In contrast, risk from the other IUDs was markedly less. Increased risk was detectable only within 4 months of insertion of the IUD. A prospective World Health Organization study revealed that PID increased only during the first 20 days after insertion. Thereafter, the rate of diagnosis of PID was about 1.6 cases per 1,000 women per year, the same as in the general population (76).


Gynecology_Novak

Gynecology_Novak. Exposure to sexually transmitted pathogens is the more important determinant of PID risk than is wearing an IUD. In the Women’s Health Study, women who were married or cohabiting and who said they had only one sexual partner in the past 6 months had no increase in PID (75). In contrast, previously married or single women had marginal increase in risk, even though they had only one partner in the previous 6 months (77). The only pelvic infection that was unequivocally related to IUD use is actinomycosis (78). It appears that PID with actinomycosis was reported only in women wearing an IUD. Rates of colonization with actinomycosis increase with duration of use for plastic devices but appear to be much less for copper-releasing IUDs. Actinomyces may be found in cervical cytology of up to 7% of women with an IUD. Because of the low positive predictive value and a lack of sensitivity and specificity of cervical cytology to diagnose this organism, antibiotic treatment and IUD removal should


Gynecology_Novak

Gynecology_Novak. women with an IUD. Because of the low positive predictive value and a lack of sensitivity and specificity of cervical cytology to diagnose this organism, antibiotic treatment and IUD removal should be reserved for symptomatic women (79).


Gynecology_Novak

Gynecology_Novak. When PID is suspected in a woman wearing an IUD, appropriate cultures should be obtained, and antibiotic therapy should be administered. Removal of the IUD is not necessary unless symptoms do not improve after 72 hours of treatment (80). Pelvic abscess, if suspected, should be ruled out by ultrasound examination.


Gynecology_Novak

Gynecology_Novak. Ectopic Pregnancy All contraceptive methods protect against ectopic pregnancy by preventing pregnancy. But when the method fails and pregnancy occurs, risk of ectopic is affected by the method of contraception. IUDs and tubal sterilization increase the probability of the pregnancy being ectopic when pregnancy occurs, but the rate of any pregnancy is so low that women using either of these methods have much lower rates of ectopic pregnancy than women not using contraception (81). Risk of any pregnancy with a levonorgestrel IUD is between 0.1 and 0.2 per 100 woman-years. The rate of an ectopic in wearers of this device is reported as 0.02 per 100 woman-years (82). In a large study of the copper T380A, the first-year pregnancy rate was 0.5 per 100 woman-years, and the rate of ectopic was 0.1 per 100 woman-years (83). Ectopic is a very rare event with either IUD, but should a woman wearing one present with pelvic pain and a positive β-HCG, an ectopic must be ruled out. Increased risk of


Gynecology_Novak

Gynecology_Novak. per 100 woman-years (83). Ectopic is a very rare event with either IUD, but should a woman wearing one present with pelvic pain and a positive β-HCG, an ectopic must be ruled out. Increased risk of ectopic among past users of older IUDs was reported. The copper T380A and the levonorgestrel T were not included (81).


Gynecology_Novak

Gynecology_Novak. Fertility Tubal factor infertility is not increased among nulligravid women who used copper IUDs, but exposure to sexually transmitted pathogens such as C. trachomatis does increase risk (84). The Oxford study found that women gave birth just as promptly after IUD removal as they did after discontinuing use of the diaphragm (85). Expulsion and Perforation The rate of expulsion with the copper T380A is reported to be 2.5 per 100 woman-years in the first year, and cumulates to 8 per 100 woman-years after 8 years (83). Expulsion rates with the levonorgestrel T were reported at 4.2% in years 1 and 2, 1.3% in years 3 through 5, and 0% in years 6 and 7 (86). The risk of uterine perforation associated with insertion is dependent on the inserter. The risk in experienced hands is on the order of 1 per 1,000 insertions or less (87). There are no studies specifically addressing perforation in nulliparous as compared to parous women (88).


Gynecology_Novak

Gynecology_Novak. Clinical Management Contraindications to IUD use listed by the World Health Organization include pregnancy, puerperal sepsis, PID, or STDs current or within the past 3 months, endometrial or cervical cancer, undiagnosed genital bleeding, uterine anomalies, and fibroid tumors that distort the endometrial cavity (87). Infection with HIV is not considered a contraindication for IUD use. No increase in pelvic infection, female-to-male transmission, or viral shedding was found among HIV-1 infected women (89,90). Copper allergy and Wilson’s disease are contraindications to the use of copper IUDs.


Gynecology_Novak

Gynecology_Novak. IUDs are appropriate for long-term contraception in most women given their ease of use, high efficacy, and favorable side effect profile. Nulliparous women, adolescents, women undergoing a first or second trimester surgical abortion, women with a recent medical abortion, and women immediately postpartum should all be considered candidates for IUDs (91). There is renewed interest in postpartum and postabortal insertion of IUDs. In both circumstances, the woman is clearly no longer pregnant, she may be highly motivated to accept contraception, and the setting is convenient for both the woman and the provider (92,93). Postpartum and postabortal insertions are safe. Complications are not increased by comparison to interval insertion. The only disadvantage is that the expulsion rate is higher. In comparing postpartum to interval insertion, all the women requesting postpartum IUD received the device, but many women scheduled for interval insertion did not return. When surveyed at 6 months


Gynecology_Novak

Gynecology_Novak. In comparing postpartum to interval insertion, all the women requesting postpartum IUD received the device, but many women scheduled for interval insertion did not return. When surveyed at 6 months postpartum, more women who had postpartum insertion were wearing IUDs than were those who had scheduled for interval insertion (94). Goodman and colleagues found many fewer repeat abortions among women followed after postabortal IUD insertion compared to a cohort of women choosing non-IUD methods of contraception after an induced abortion (94).


Gynecology_Novak

Gynecology_Novak. At the contraceptive visit, the patient’s history is obtained and a physical examination, screening for Neisseria gonorrhoeae and chlamydia in high-risk women, and detailed counseling regarding risks and alternatives are provided. The IUD usually is inserted during menses to be sure the patient is not pregnant, but it can be inserted at any time in the cycle if pregnancy can be excluded (95). The copper-T380A IUD can be inserted within 5 days of unprotected intercourse for 100% effective emergency contraception. There are limited data on effective treatment of pain during IUD insertion. One randomized nonblinded study suggested a benefit with 2% lidocaine gel applied to the cervical canal 5 minutes before insertion. Other techniques such as paracervical block were not evaluated. Premedication with oral prostaglandin inhibitors such as ibuprofen is strongly advised, although evidence of its benefit with modern IUDs is limited (96).


Gynecology_Novak

Gynecology_Novak. Antibiotic prophylaxis is not beneficial, probably because the risk of pelvic infection with IUD insertion is so low. A large randomized trial of 1,985 patients receiving either oral azithromycin or placebo found no difference in rates of IUD removal during the first 90 days after insertion and no difference in rates of salpingitis (97). These women were screened for STDs only by self-history. Screening for gonorrhea and chlamydia at the time of insertion is recommended for adolescents, but it is not necessary to wait for the results before insertion because patients with positive results have no adverse effects if treated promptly (98). PID, puerperal sepsis, or postabortion sepsis within the past 3 months are considered contraindications and patients with purulent cervicitis should be tested and treated before insertion. The technique of insertion is as follows: 1.


Gynecology_Novak

Gynecology_Novak. The technique of insertion is as follows: 1. The cervix is exposed with a speculum. The vaginal vault and cervix are cleansed with a bacteriocidal solution, such as an iodine-containing solution. 2. The uterine cavity should be measured with a uterine sound. The depth of the cavity should measure at least 6 cm from the external os. A smaller uterus is not likely to tolerate currently available IUDs. 3. Use of a tenaculum for insertion is mandatory to prevent perforation. The cervix is grasped with a tenaculum and gently pulled downward to straighten the angle between the cervical canal and the uterine cavity. The IUD, previously loaded into its inserter, is then gently introduced through the cervical canal. 4.


Gynecology_Novak

Gynecology_Novak. 4. With the copper T380A, the outer sheath of the inserter is withdrawn a short distance to release the arms of the T and is gently pushed inward again to elevate the now-opened T against the fundus. The outer sheath and the inner stylet of the inserter are withdrawn, and the strings are cut to project about 2 cm from the external cervical os. 5. The levonorgestrel T IUD is inserted somewhat differently from the copper T380A. The inserter tube is introduced into the uterus until the preset sliding ﬂange on the inserter is 1.5 to 2 cm from the external os of the cervix. The arms of the T device are released upward into the uterine cavity, and the inserter is pushed up under them to elevate the IUD up against the uterine fundus. In nulliparous women, insertion may be more difficult because of a narrower cervical canal than in parous women. Mechanical dilation may be necessary. Pretreatment with misoprostol may be beneficial in difficult IUD insertions (99).


Gynecology_Novak

Gynecology_Novak. If an intrauterine pregnancy is diagnosed and the IUD strings are visible, the IUD should be removed as soon as possible to prevent later septic abortion, premature rupture of the membranes, and premature birth (100). When the strings of the IUD are not visible, an ultrasound examination should be performed to localize the IUD and determine whether expulsion has occurred. If the IUD is present, there are three options for management: 1. 2. Ultrasound-guided intrauterine removal of the IUD 3. Continuation of the pregnancy with the device left in place


Gynecology_Novak

Gynecology_Novak. 2. Ultrasound-guided intrauterine removal of the IUD 3. Continuation of the pregnancy with the device left in place If the patient wishes to continue the pregnancy, ultrasound evaluation of the location of the IUD should be considered (101). If the IUD is not in a fundal location, ultrasound-guided removal using small alligator forceps may be successful. If the location is fundal, the IUD should be left in place. When pregnancy continues with an IUD in place, the patient must be warned of the symptoms of intrauterine infection and should be cautioned to seek care promptly for fever or ﬂulike symptoms, abdominal cramping, or bleeding. At the earliest sign of infection, high-dose intravenous antibiotic therapy should be given and the pregnancy evacuated promptly. Duration of Use


Gynecology_Novak

Gynecology_Novak. Duration of Use Annual rates of pregnancy, expulsions, and medical removals decrease with each year of use (102,103). Therefore, a woman who has no problem by year 5, for example, is very unlikely to experience problems in the subsequent years. The copper T380A is FDA approved for 10 years and the levonorgestrel T for 5 years, though as previously noted, good data support use of the copper T380A through 12 years and of the levonorgestrel T through 7 years (66,86). Choice of Devices Both of the IUDs available in the United States, the copper T380A and the levonorgestrel T, provide protection for many years, have remarkably low pregnancy rates, and substantially reduce the risk of ectopic pregnancy. The levonorgestrel T reduces the amount of menstrual bleeding and dysmenorrhea. The copper T380A initially can be expected to increase menstrual bleeding. It is the most effective means for emergency contraception. Management of Bleeding and Cramping with Intrauterine Devises


Gynecology_Novak

Gynecology_Novak. The most important medical reason that women give for requesting removal of an IUD is bleeding and pelvic pain. These symptoms are common in the first few months, but diminish. Nonsteroidal anti-inﬂammatory drugs are usually helpful. When pain and bleeding occur later, the patient should be examined for signs of PID, partial expulsion of the device, or an intracavitary fibroid. Two ultrasonographic studies comparing women with these symptoms after 6 months to women with no bleeding complaints show downward displacement of the IUDs into the cervical canal in many of the symptomatic women and in some cases, intracavitary fibroids (104,105). When the patient wishes to continue with an IUD, removal of the displaced device and insertion of a new one is advisable. In situations where IUDs are inexpensive and ultrasound is expensive or not available, the best course is to offer immediate removal and replacement of the IUD without ultrasound proof of displacement.


Gynecology_Novak

Gynecology_Novak. Hormonal contraceptives are female sex steroids, synthetic estrogen and synthetic progesterone (progestin), or progestin-only without estrogen. They can be administered in the form of OCs, patches, implants, and injectables. The most widely used hormonal contraceptive is the combination OC containing both estrogen and progestin. Combination OCs can be monophasic, with the same dose of estrogen and progestin administered each day, or multiphasic, in which varying doses of steroids are given through a 21-day or 24-day cycle. Combination OCs are packaged with 21 active tablets and 7 placebos, or 24 active tablets and 4 placebo tablets. The inclusion of placebos allows the user to take one pill every day without having to count. The medication-free interval while the user takes the placebo tablets allows withdrawal bleeding that mimics a 28-day menstrual cycle. To begin OC use, the user takes the first pill any time from the first day of menses through the Sunday after menstruation begins


Gynecology_Novak

Gynecology_Novak. allows withdrawal bleeding that mimics a 28-day menstrual cycle. To begin OC use, the user takes the first pill any time from the first day of menses through the Sunday after menstruation begins and thereafter starts a new pack as soon as the first pack is completed. The 7-day medication-free interval was standard for years, but studies showed that a shorter medication-free interval is adequate to trigger cyclic withdrawal bleeding and maintains better suppression of ovulation. Ovarian follicles mature more during the 7-day medication-free interval than during the 4-day interval. Hence the new 24/4 combination theoretically could be more effective in preventing pregnancy than the 21/7 combination, but this has not been demonstrated. Other variations of OC administration are the extended cycle and the continuous cycle methods. Users take active pills containing an estrogen–progestin combination for 3 months at a time (extended cycle) or indefinitely for a year or more (continuous


Gynecology_Novak

Gynecology_Novak. cycle and the continuous cycle methods. Users take active pills containing an estrogen–progestin combination for 3 months at a time (extended cycle) or indefinitely for a year or more (continuous cycle). Users on these regimens have more unscheduled days of spotting or bleeding than those on 28-day cycles in the beginning, but become amenorrheic. As a result they experience fewer cycle triggered symptoms such as headache and menstrual pain. Continuous-combined regimens are preferred for women with chronic pelvic pain or when dysmenorrhea is not relieved by OCs taken in 28-day cycles (106).


Gynecology_Novak

Gynecology_Novak. Progestin-only OCs are taken every day without interruption. Other forms of hormonal contraception include transdermal administration with the patch, injectable progestins, injectable estrogen–progestin combinations, subdermal implants that release progestin, and vaginal rings that release either estrogen–progestin or progestin alone (107). Steroid Hormone Action Sex steroids are characterized by their affinity for specific estrogen, progesterone, or androgen receptors, and by their biologic effects in different systems (108). Steroids are rapidly absorbed in the gut but go directly into the liver through the portal circulation, where they are rapidly metabolized and inactivated. Therefore, large doses of steroids are required when they are administered orally. The addition of the ethinyl group to carbon-17 of the steroid molecule hinders degradation by the liver enzyme 17-hydroxysteroid dehydrogenase and allows potent biological activity after oral doses of only micrograms.


Gynecology_Novak

Gynecology_Novak. Progestins Progestins are synthetic compounds that mimic the effect of natural progesterone but differ from it structurally. The progestins differ from one another in their affinities for estrogen, androgen, and progesterone receptors; their ability to inhibit ovulation; and their ability to substitute for progesterone and to antagonize estrogen. Some are directly bound to the receptor (levonorgestrel, norethindrone), whereas others require bioactivation as, for example, desogestrel, which is converted in the body to its active metabolite, etonogestrel. The 17-acetoxy progestins (e.g., medroxyprogesterone acetate) are bound by the progesterone receptor. Norgestrel exists as two stereoisomers, identified as dextronorgestrel and levonorgestrel. Only levonorgestrel is biologically active. Three newer progestins (norgestimate, desogestrel, and gestodene) are viewed as more “selective” than the other 19-nor progestins, in that they have little or no androgenic effect at doses that inhibit


Gynecology_Novak

Gynecology_Novak. newer progestins (norgestimate, desogestrel, and gestodene) are viewed as more “selective” than the other 19-nor progestins, in that they have little or no androgenic effect at doses that inhibit ovulation (109). The FDA approved norgestimate-and desogestrelcontaining OCs, and gestodene is available in Europe. Gestodene is a derivative of levonorgestrel that is more potent than the other preparations (i.e., very little of it is required for antifertility effects). Similarly, norelgestromin is an active metabolite of norgestimate and more potent than the parent compound. It is used in the transdermal patch. Drospirenone, a progestin introduced in the United States, is a derivative of the diuretic spironolactone. It has high affinity for progesterone receptors, mineralocorticoid receptors, and androgen receptors. It acts as a progesterone agonist but is a mineralocorticoid antagonist and androgen antagonist (110). Comparative studies suggest a small decrease in body weight and in blood


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Gynecology_Novak. and androgen receptors. It acts as a progesterone agonist but is a mineralocorticoid antagonist and androgen antagonist (110). Comparative studies suggest a small decrease in body weight and in blood pressure, with equivalent cycle control and contraceptive efficacy, in women taking an OC containing 3 mg of drospirenone/30 μg ethinyl estradiol versus women taking a 150 μg levonorgestrel/30 μg ethinyl estradiol (EE) preparation (111). Pilot studies of women with polycystic ovary syndrome showed good cycle control and reduction in androgen levels with no change in weight, blood pressure, or glucose metabolism (112). The FDA approved the 20 μg EE/3 mg drospirenone OC for premenstrual dysphoric disorder (PMDD) in women who choose OCs for contraception. When compared to an OC with 30 μg EE/150 μg levonorgestrel, women taking the drospirenone OC had better relief of menstrual symptoms, better improvement in acne, reduction in negative affect during the menstrual phase, and a greater feeling


Gynecology_Novak

Gynecology_Novak. μg levonorgestrel, women taking the drospirenone OC had better relief of menstrual symptoms, better improvement in acne, reduction in negative affect during the menstrual phase, and a greater feeling of well-being (113). Dienogest, another progestin introduced in the United States, is combined with estradiol valerate, not ethinyl estradiol. Whether it offers any advantage over already marketed OC combinations is not yet evident. The dienogest/estradiol valerate combination is as effective as levonorgestrel/ethinyl estradiol as a contraceptive, and in treating abnormal uterine bleeding (114).


Gynecology_Novak

Gynecology_Novak. Estrogens In the United States, most OCs contain either of two estrogens: mestranol or ethinyl estradiol (EE). Mestranol is EE with an extra methyl group. It requires bioactivation in the liver, where the methyl group is cleaved, releasing the active agent, EE. Oral contraceptives with 35 μgof EE provide the same blood levels of hormone as do OCs containing 50 μgof mestranol. (115). Estradiol cypionate and estradiol valerate are esters of natural 17 β-estradiol also in use for contraception.


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Gynecology_Novak. Ovulation can be inhibited by estrogen or by progestin alone. Pharmacologic synergism is exhibited when the two hormones are combined and ovulation is suppressed at a much lower dose of each agent. Combination OCs, patches, and the NuvaRing suppress basal follicle-stimulating hormone (FSH) and LH. They diminish the ability of the pituitary gland to synthesize gonadotropins when it is stimulated by hypothalamic GnRH (116). Ovarian follicles do not mature, little estradiol is produced, and there is no midcycle LH surge. Ovulation does not occur, the corpus luteum does not form, and progesterone is not produced. This blockade of ovulation is dose related. Newer low-dose OCs do not provide as dense a block and allow somewhat higher baseline FSH and LH levels than higher dose formulations (117). This makes ovulation somewhat more likely to occur if pills are missed or if the patient takes another medication that reduces blood levels of the contraceptive steroids.


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Gynecology_Novak. Highly effective contraception can be provided by progestin alone, thus avoiding the risks of estrogen. The mode of action of progestin-only contraceptives is highly dependent on the dose of the compound (118). With low levels of progestin in the blood, ovulation will occur part of the time. At moderate levels of progestin in the blood, normal basal levels of FSH and LH are present, and some follicle maturation may occur. At higher blood levels as seen with DepoProvera, the basal FSH is reduced, and there is less follicular activity, less estradiol production, and no LH surge. Transdermal Hormonal The patch (OrthoEvra), which adheres to the user’s skin, and the vaginal NuvaRing both contain Contraception combinations of EE and a potent progestin. Both provide sustained release of the steroids and result in relatively constant serum levels that are less than the peak levels seen with OCs but sufficient to prevent ovulation.


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Gynecology_Novak. Hormonal Implants With the levonorgestrel subdermal implants there is some follicular maturation and estrogen production, but LH peak levels are low and ovulation is often inhibited. In the first year of use, ovulation is believed to occur in about 20% of cycles. The proportion of ovulatory cycles increases with time, probably as a result of the decline in hormone release. By the fourth year of use, 41% of cycles are ovulatory. The more potent progestin released by the etonogestrel implant is even more effective at preventing ovulation (119). The mechanisms of action of low-dose progestins include effects on the cervical mucus, endometrium, and tubal motility. The scant, dry cervical mucus that occurs in women using implants inhibits sperm migration into the upper tract. Progestins decrease nuclear estrogen receptor levels, decrease progesterone receptors, and induce activity of the enzyme 17-hydroxysteroid dehydrogenase, which metabolizes natural 17 β-estradiol (118).


Gynecology_Novak

Gynecology_Novak. The sustained release offered by contraceptive implants allows for highly effective contraception at relatively low steroid blood levels. Figure 10.6 depicts expected steroid blood levels with implants, injectables, and oral contraceptives. An additional mechanism for contraception was discovered with the antiprogesterone mifepristone (RU486). In the normal cycle, there is a small amount of progesterone production from the follicle just before ovulation. This progesterone appears essential to ovulation, because if mifepristone is given before ovulation this can be delayed for several days (120,121). Efficacy of Hormonal Contraception


Gynecology_Novak

Gynecology_Novak. When used consistently, combination OCs have pregnancy rates as low as 2 to 3 per 100 women per year. Progestin-only OCs are less effective than combination estrogen–progestin preparations, with best results of 3 to 4 pregnancies per 100 woman-years. All methods have the potential for user error; therefore, there may be a 10-fold difference between the best results and results in typical users of OCs. Injectable progestins and implants are much less subject to user error than are OCs. The difference between the best results and results in typical users is small and is comparable to pregnancy rates after tubal sterilization (Table 10.2). Pregnancy rates with the OrthoEvra patch and the NuvaRing were equivalent to those of OCs; however, because it is easier to use these methods consistently, larger studies may well demonstrate better typical user results than with OCs (122,123). Typical use pregnancy rates with DMPA are lower. The subdermal implants have the lowest rates of any hormonal


Gynecology_Novak

Gynecology_Novak. larger studies may well demonstrate better typical user results than with OCs (122,123). Typical use pregnancy rates with DMPA are lower. The subdermal implants have the lowest rates of any hormonal contraceptive method.


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Gynecology_Novak. The present rate of obesity in Europe and the United States is 30% and is increasing. Most studies of contraceptive efficacy intentionally excluded obese women, so the available information is limited. Obese women are no less likely than other women to become pregnant, but they do have an increased risk of pregnancy complications (124). A systematic review of hormonal contraception for overweight and obese women found only seven relevant studies (125). Overweight and obese women appear to be at a similar or slightly higher risk of pregnancy with oral contraceptives. The attributable risk is minimal (124). The efficacy of DMPA does not appear to be reduced in heavier women. A possible increase in pregnancies was reported for users of the contraceptive patch who weight more than 90 kg. Heavier women using the vaginal ring


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Gynecology_Novak. Figure 10.6 Schematic representation of the expected pharmacokinetic profiles of progestogens administered in different formulations. (From Landgren BM. Mechanism of action of gestagens. Int J Gynaecol Obstet 1990;32:95–110, with permission.) had no increase in pregnancies. Few heavy women were studied with the etonogestrel implant because the studies excluded women of body weight greater than 130% of ideal body weight. Pregnancy rate does appear to increase with weight in women using the levonorgestrel implants at weight 70 kg or more but it is still low. There were no pregnancies in any weight group during the first 3 years of use in a large study (125,126).


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Gynecology_Novak. Venous Thrombosis Women who use estrogen containing hormonal contraceptives are at increased risk for venous thrombosis and thromboembolism. Normally the coagulation system maintains a dynamic balance of procoagulant and anticoagulant systems. Estrogens affect both systems in a dose-related fashion. For most women, fibrinolysis (anticoagulation) is increased as much as coagulation, maintaining the dynamic balance at increased levels of production and destruction of fibrinogen (127,128) (Fig. 10.7). Older studies included women with what are now considered contraindications to use of estrogen-containing hormonal contraceptives: previous thrombosis, preexisting vascular disease, coronary artery disease, cancers, and serious trauma (127,128). Current low-dose OCs have a less measurable effect on the coagulation system, and fibrinolytic factors increase at the same rate as procoagulant factors. Lower estrogen dose (30–35 μg EE) OCs reduce the risk of a thromboembolic event when compared


Gynecology_Novak

Gynecology_Novak. on the coagulation system, and fibrinolytic factors increase at the same rate as procoagulant factors. Lower estrogen dose (30–35 μg EE) OCs reduce the risk of a thromboembolic event when compared with higher dose (50 μg estrogen) OCs (129) (Table 10.5). A very large Danish study showed for the first time that combination OCs with 20 μgof ethinyl estradiol have an 18% further reduction in thrombosis risk compared with 30 to 40 μg OCs after adjustment for duration of use (130). The progesterone-only OCs and the levonorgestrel-releasing intrauterine device were not associated with venous thrombosis.


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Gynecology_Novak. Figure 10.7 Dynamic balance of hemostasis. (From Winkler UH, Buhler K, Schlinder AE. The dynamic balance of hemostasis: implications for the risk of oral contraceptive use. In: Runnebaum B, Rabe T, Kissel L, eds. Female contraception and male fertility regulation. In Advances in Gynecological and Obstetric Research Series. Confort, England: Parthenon Publishing Group, 1991:85–92, with permission.)


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Gynecology_Novak. The absolute risk of deep vein thrombosis was strongly inﬂuenced by age, increasing from 1.84 per 10,000 women aged 15 to 19 years to 6.59 per 10,000 for women aged 45 to 49 years with current users, former users, and never users combined. With all types of OCs combined, the overall absolute rate of deep vein thrombosis was 6.29 per 10,000 woman-years for current OC users compared to 3.01 among nonusers, giving an adjusted rate ratio of 2.83 (95% confidence interval [CI], 2.65–3.01) (Table 10.6). This is a higher absolute risk than the 3 per 10,000 woman-years previously estimated and may reﬂect, among other things, the use of better means for diagnosis of deep vein thrombosis (131). This population-based study includes all Danish women aged 15 to 49, excluding only women with a diagnosis of cancer or of cardiovascular disease diagnosed before the study interval. Thrombosis risk was highest during the first year of use and decreased thereafter (Table 10.6).


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Gynecology_Novak. Thrombophilia Changes in the coagulation system are detectable in all women, including those taking lower-dose OCs; some women are genetically predisposed to thrombosis when challenged by pregnancy or administration of exogenous estrogen. Women with inherited deficiencies of antithrombin III, protein C, or protein S are at very high risk for thrombosis with pregnancy or estrogen therapy, but they make up a very small proportion of potential OC users. A much more common variation, factor V Leiden exists in 3% to 5% of the Table 10.5 Oral Contraceptive Estrogen Dose and Risk for Deep Vein Thrombosis aBaseline risk used to calculate risk for higher doses. From Gerstman BB, Piper JM, Tomita DK, et al. Oral contraceptive dose and the risk of deep venous thrombosis. Am J Epidemiol 1991;133:32–37, with permission. Table 10.6 Crude Incidence Rates and Adjusted Rate Ratios of Venous Thrombosis in Women Using Different Types of Hormonal Contraception


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Gynecology_Novak. Table 10.6 Crude Incidence Rates and Adjusted Rate Ratios of Venous Thrombosis in Women Using Different Types of Hormonal Contraception OC, oral contraceptive; IUD, intrauterine device. aAdjusted for current use of oral contraceptives, calendar year, and educational level. bAdjusted for age, calendar year, and educational level. From Lidegaard O, Lokkegaard E, Svendsen AL, et al. Hormonal contraception and risk of venous thromboembolism: national follow up study. BMJ 2009;339:b2890 [Table I on page 3], with permission.


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Gynecology_Novak. Caucasian population. It codes for a one amino acid mutation in the factor V protein, inhibiting cleavage of the protein by activated protein C, which is an essential step in maintaining the balance between coagulation and fibrinolysis (109,132). Risk for a first thromboembolic episode among women using OCs was 2.2 per 10,000 woman-years for women without the factor V mutation and 27.7 per 10,000 woman-years for women with the mutation (133). Cigarette smoking did not affect this risk. There are pronounced ethnic differences in the presence of this mutation. The Leiden allele is found in 3% to 5% of whites but is rare in Africans, Asians, Amerindians, Eskimos, and Polynesians (134). A similar mutation is found in the prothrombin gene at position 20210 and is described as prothrombin G20210A. This mutation occurs in 3% of the European population and is strongly associated with venous thrombosis in women taking OCs (135). Many more genetic conditions predisposing to thrombosis were


Gynecology_Novak

Gynecology_Novak. This mutation occurs in 3% of the European population and is strongly associated with venous thrombosis in women taking OCs (135). Many more genetic conditions predisposing to thrombosis were described. Pregnancy is an even greater challenge for women with inherited defects of anticoagulation (136). A woman who sustains a venous event while using OCs should be evaluated thoroughly after she has recovered. Assessment should include at minimum the measurement of antithrombin III, protein C, and protein S levels, resistance to activated protein C, serum homocysteine, factor V Leiden mutation, the prothrombin G20210A mutation and testing for antiphospholipid syndrome. It should not be assumed that hormonal contraception was the unique cause of the thrombotic episode.


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Gynecology_Novak. Routine screening for all women before prescribing hormonal contraception is not justified because effective contraception would be denied to 5% of Caucasian women, and only a small number of fatal pulmonary emboli would be prevented (137,138). Screening women with a personal or family history of deep vein thrombosis before starting estrogen-containing hormonal contraception or pregnancy is strongly recommended. Women already diagnosed as having factor V Leiden should not receive estrogen-containing contraceptives, i.e., the pill, patch or ring.


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Gynecology_Novak. Thrombosis and the New Progestins Several studies found increased risk of venous thrombosis when users of OCs containing the newer progestins desogestrel or gestodene combined with 20 to 30 μgof EE were compared with users of levonorgestrel combined with the same doses of estrogen (115). A controversy resulted. It is likely that the biases “attrition of susceptibles,” “adverse selection,” and “healthy user bias” explain the apparent increase in thrombosis. Most cases of venous thrombosis attributable to OCs occur during the initial months of use (116). Comparing new users to women already taking OCs for some time without incident will demonstrate an apparent increase with the new product that is artificial. Physicians may presume that newer drugs are safer and prescribe them selectively for women with risk factors. Additional studies have not resolved this controversy. Heinemann and colleagues found no difference in thrombosis risk in users of OCs containing desogestrel or gestodene


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Gynecology_Novak. for women with risk factors. Additional studies have not resolved this controversy. Heinemann and colleagues found no difference in thrombosis risk in users of OCs containing desogestrel or gestodene compared to users of OCs with other progestins in a large study of cases occurring between 2002 and 2006 in Austria (139). In contrast, both Lidegaard’s group in Sweden and van Hylckama Vlieg’s group in the Netherlands reported increased risk with the newer progestins (130,140).


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Gynecology_Novak. Ischemic Heart Disease Ischemic heart disease and stroke were the major causes of death attributed to OC use in the past. It is known that the principal determinants of risk are advancing age and cigarette smoking (141). With the higher-dose OCs used in the 1980s, smoking had a profound effect on risk. Women smoking 25 or more cigarettes per day had a 30-fold increased risk for myocardial infarction if they used OCs, compared with nonsmokers not using OCs (142). Use of OCs is became safer because most women are taking low-dose pills and because physicians prescribe selectively, excluding women with major cardiovascular risk factors. A very large study in the United States confirmed the safety of OCs as currently prescribed. A total of 187 women aged 15 to 44 years with confirmed myocardial infarction were identified during 3.6 million woman-years of observation in the Kaiser Permanente Medical Care Program in California from 1991 to 1994. This is a rate of 3.2 per 100,000 woman-years


Gynecology_Novak

Gynecology_Novak. infarction were identified during 3.6 million woman-years of observation in the Kaiser Permanente Medical Care Program in California from 1991 to 1994. This is a rate of 3.2 per 100,000 woman-years (143). Nearly all of the users took OCs with less than 50 μgof EE. After adjusting for age, illness, smoking, ethnicity, and body mass index, risk for myocardial infarction was not increased by OC use (odds ratio [OR], 1.14; 95% CI, 0.27–4.72). Of heart attack victims, 61% smoked; only 7.7% were current users of OCs. In a later study, the same investigators pooled results from the California study with a similar study from Washington State. The results were the same. Current users of low-dose OCs had no increased risk for myocardial infarction after adjustment for major risk factors and sociodemographic factors (144). Past use of OCs does not increase risk for subsequent myocardial infarction (145). These observations are supported by another population-based prospective study. OC use and


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Gynecology_Novak. factors (144). Past use of OCs does not increase risk for subsequent myocardial infarction (145). These observations are supported by another population-based prospective study. OC use and myocardial infarction were studied prospectively among 48,321 randomly selected women aged 30 to 49 in the Uppsala Health Care Region of Sweden (146). There was no association between current or past OC use and myocardial infarction. Most current users were taking low-dose estrogen pills (defined as less than 50 μg of ethinyl estradiol or less than 75 μgof mestranol) with second or third generation progestins, more than half were aged 35 or older, and 26% were current cigarette smokers.


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Gynecology_Novak. Oral Contraceptives and Stroke In the 1970s, OC use appeared to be linked to risk of both hemorrhagic and thrombotic stroke, but these studies failed to take into consideration preexisting risk factors (147). A rare form of cerebrovascular insufficiency, moyamoya disease, is linked to OC use, especially among cigarette smokers (148). The present evidence shows no risk of stroke among women who are otherwise healthy and who use low-dose pills. One study identified all Kaiser Permanente Medical Care Program patients aged 15 to 44 years who sustained fatal or nonfatal stroke in California from 1991 to 1994 (149). Hypertension, diabetes, obesity, current cigarette smoking, and black ethnicity were strongly associated with stroke risk, but neither current nor past OC use was associated with stroke. A World Health Organization study of cases from 1989 to 1993 from 17 countries in Europe and the developing world included women taking higher-dose OCs and low-dose OCs. European women using


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Gynecology_Novak. stroke. A World Health Organization study of cases from 1989 to 1993 from 17 countries in Europe and the developing world included women taking higher-dose OCs and low-dose OCs. European women using low-dose OCs had no increased risk for either type of stroke, thrombotic or hemorrhagic. Those taking higher-dose OCs did have measurable risk (150,151). Women in developing countries had an apparent modest increase in risk, but this finding was attributed to undetected existing risk factors. Another study from Europe found less stroke risk from low-dose pills than from older, higher-dose pills, and that risk was less if the patient’s blood pressure was checked before starting OCs.


Gynecology_Novak

Gynecology_Novak. Women who smoke and those who have hypertension and diabetes are at increased risk for cardiovascular disease regardless of whether they use oral contraceptives. The important question is whether risk is further increased if they use low-dose OCs, and if so, by how much. The World Health Organization study described previously provides some insight: smokers taking OCs had seven times the risk of ischemic (thrombotic) stroke when compared with smokers who did not use OCs, and hypertensive women had 10-fold increased risk if they took OCs, but a fivefold risk if they did not (150). Similarly, a study from Denmark found that women with diabetes had a fivefold increase risk for stroke, which increased to 10-fold if they took OCs (152). These data were not limited to low-estrogen OCs. The data suggest that although risk is primarily determined by the predisposing condition—hypertension, diabetes, or cigarette smoking—the risk can be magnified by OC use, even when the OCs are low dose.


Gynecology_Novak

Gynecology_Novak. data suggest that although risk is primarily determined by the predisposing condition—hypertension, diabetes, or cigarette smoking—the risk can be magnified by OC use, even when the OCs are low dose. These observations were confirmed in a recent systematic review (153). Hypertensive women using combination estrogen–progestin oral contraceptives (COCs) had higher risk for ischemic stroke and acute myocardial infarction than hypertensive women not using COCs. The current US practice of limiting hormonal contraceptives containing estrogen by women older than 35 years of age to nonsmokers without other vascular disease risk factors is prudent (7).


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Gynecology_Novak. Blood Pressure Oral contraceptives have a dose-related effect on blood pressure. With the older high-dose pills, as many as 5% of patients could be expected to have blood pressure levels greater than 140/90 mm Hg. The mechanism is believed to be an estrogen-induced increase in renin substrate in susceptible individuals. Low-dose pills have minimal blood pressure effects, but surveillance of blood pressure is advised to detect the occasional idiosyncratic response. Glucose Metabolism Oral estrogen alone has no adverse effect on glucose metabolism, but progestins exhibit insulin antagonism (154). Older OC formulations with higher doses of progestins produced abnormal glucose tolerance tests with elevated insulin levels in the average patient. The effect on glucose metabolism, similar to the effect on lipids, is related to androgenic potency of the progestin and to its dose.


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Gynecology_Novak. Lipid Metabolism Androgens and estrogens have competing effects on hepatic lipase, a liver enzyme critical to lipid metabolism. Estrogens depress low-density lipoproteins (LDL) and elevate high-density lipoproteins (HDL), changes that can be expected to reduce the risk of atherosclerosis (155). Androgens and androgenic progestins can antagonize these beneficial changes, reducing HDL and elevating LDL levels. Estrogens elevate triglyceride levels. Low-dose formulations have minimal adverse effect on lipids, and the newer formulations (with desogestrel and norgestimate as the progestin) produce potentially beneficial changes by elevating HDL and lowering LDL (156,157). Although average values of a large group show only small lipid changes with the use of current OCs, an occasional patient may have exaggerated effects. Women whose lipid values are higher than the mean before treatment are more likely to experience abnormalities during treatment (156).


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Gynecology_Novak. Other Metabolic Effects Oral contraceptives can produce changes in a broad variety of proteins synthesized by the liver. The estrogen in OCs increases circulating thyroid-binding globulin, thereby affecting tests of thyroid function that are based on binding, increasing total thyroxine (T4) levels, and decreasing triiodothyronine (T3) resin uptake. The results of actual thyroid function tests, as measured by free T4 and radioiodine tests, are normal (158).


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Gynecology_Novak. Endometrial Cancer and Ovarian Cancer Combination OCs reduce the risk of subsequent endometrial cancer and ovarian cancer (159,160). Two-year use of OCs reduces the risk of endometrial cancer by 40%, and 4 or more years of use reduces the risk by 60%. The evidence for this benefit continues to accumulate (161). A 50% reduction in ovarian cancer risk for women who took OCs for 3 to 4 years and an 80% reduction with 10 or more years of use was reported (162). There was some benefit from as little as 3 to 11 months of use. A review of all available studies in the world published in English through 2008 concluded that ovarian cancer risk decreased by 20% for each 4 years of use and was seen for carriers of the BRCA1 and 2 mutations as well. The benefit persisted for at least 30 years after last use (163). A similar reduction of risk of ovarian epithelial cancer was found in a prospective study from Norway and Sweden, with borderline tumor risk equally reduced. Combination OCs with less


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Gynecology_Novak. last use (163). A similar reduction of risk of ovarian epithelial cancer was found in a prospective study from Norway and Sweden, with borderline tumor risk equally reduced. Combination OCs with less than 50 μgof EE, or less than 100 μg of mestranol and reduced doses of progestin, provided as much protection as higher dose pills (164). Today’s lower-dose 20 μg EE pills were not separately studied. Whether or not they provide the same benefit remains unproven; however, progestinonly contraceptives are reported to provide risk reduction equivalent to that of combined OCs (165).


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Gynecology_Novak. Cervical Cancer There may be a weak association between OC use and cancer of the cervix. A systematic review of 28 epidemiologic studies of cervical cancer in OC users compared with those who never used OCs reported summary relative risks of 1.1 (95% CI, 1.1–1.2) at less than 5 years of pill use, 1.6 (1.4–1.7) at 5 to 9 years, and 2.2 (1.9–2.4) at 10 or more years (166). A 2007 update by these same authors reported a pooled relative risk for all studies of 1.9 (95% CI, 1.69–2.13) for invasive cervical cancer or CIN3/carcinoma in situ (CIS) with 5 or more years of OC use. Risk declined after use ceased and by 10 years returned to that of never users. Too few had used progestin-only pills to provide a conclusion as to their effect. For injectable progestins, the relative risk was very slightly increased to 1.22 (95% CI, 1.01– 1.46), which was just statistically significant (167). Critics of these studies argued that causation is not proven because few adequately control for the key


Gynecology_Novak

Gynecology_Novak. increased to 1.22 (95% CI, 1.01– 1.46), which was just statistically significant (167). Critics of these studies argued that causation is not proven because few adequately control for the key behavioral factors of partners, use of barrier contraception, and adequacy of cervical cancer screening (168). Important risk factors for cervical cancer are early sexual intercourse and exposure to HPV. Women who used OCs typically started sexual relations at younger ages than women who have not used OCs and, in some studies, report having had more partners. These factors increase one’s chance of acquiring HPV, the most important risk factor for cervical cancer. Because barrier contraceptives reduce the risk of cervical cancer, use of alternative choices for contraception compounds the difficulty in establishing an association with OC use alone (169). The presence of HPV types 16 or 18 is associated with a 50-fold increase in risk for preneoplastic lesions of the cervix (170). Adenocarcinomas of


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Gynecology_Novak. establishing an association with OC use alone (169). The presence of HPV types 16 or 18 is associated with a 50-fold increase in risk for preneoplastic lesions of the cervix (170). Adenocarcinomas of the cervix are rare, they are not as easily detected as other lesions by screening cervical cytology, and the incidence appears to be increasing. One study found a doubling of risk for adenocarcinoma with OC use that increased with duration of use, reaching a relative risk of 4.4 if total use of OCs exceeded 12 years (171). The results of this study were adjusted for history of genital warts, number of sexual partners, and age at first intercourse. Another summary of case-control studies that includes testing for HPV. HPV types 16 or 18 were present in 82% of the patients, yielding a relative risk of 81.3 (95% CI, 42.0–157.1) for the disease. Cofactors identified with adenocarcinoma included longer-term use of hormonal contraception. Intrauterine device use was associated with reduced


Gynecology_Novak

Gynecology_Novak. risk of 81.3 (95% CI, 42.0–157.1) for the disease. Cofactors identified with adenocarcinoma included longer-term use of hormonal contraception. Intrauterine device use was associated with reduced relative risk of 0.41 (95% CI, 0.18–0.93) (172). Use of hormonal contraception by women from aged 20 to 30 years is estimated to increase the incidence of cervix cancer (any cervix cancer, or CIN3/CIS) diagnosed by age 50 from 7.3 to 8.3 per 1,000 women in lesser-developed countries and from 3.8 to 4.5 in developed countries (172). Use of OCs is, at most, a minor factor in causation of cervical cancer; these findings emphasize the need to immunize against HPV and to provide cervical cancer screening worldwide. To reduce risk, women who are not in mutually monogamous relationships should be advised to use barrier methods in addition to hormonal contraception.


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Gynecology_Novak. Breast Cancer There is a large volume of conﬂicting literature on the relationship between OC use and breast cancer (173). No increase in overall risk is found from OC use, but some studies found that risk may increase in women who used OCs before their first term pregnancy, used OCs for many years, are nulligravid, are young at the time of diagnosis, or continue using OCs in their 40s. A meta-analysis of 54 studies of breast cancer and hormonal contraceptive use reanalyzed data on 53,297 women with breast cancer and 100,239 controls from 25 countries, representing about 90% of the epidemiologic data available worldwide at that time (174). Current use of OCs was associated with a very small, but statistically stable 24% increased relative risk (1.24; 95% CI, 1.15–1.33). The risk fell rapidly after discontinuation, to 16% 1 to 4 years after stopping and to 7% 5 to 9 years after stopping. Risk disappeared 10 years after cessation (relative risk, 1.01; 95% CI, 0.96–1.05). Results did not


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Gynecology_Novak. after discontinuation, to 16% 1 to 4 years after stopping and to 7% 5 to 9 years after stopping. Risk disappeared 10 years after cessation (relative risk, 1.01; 95% CI, 0.96–1.05). Results did not differ in any important way by ethnic group, reproductive history, or family history. Since the meta-analysis was published, subsequent studies found no increased risk. A case-control study of 4,575 women with breast cancer and 4,682 controls aged 35 to 64 years living in five cities in the United States concluded that breast cancer risk was not increased for current or past users of OCs and did not increase with prolonged or with higher-estrogen OC use (175). Neither family history of breast cancer nor beginning use at a young age was associated with increased risk. A similar study in Sweden compared 3,016 women aged 50 to 74 years who had invasive breast cancer with 3,263 controls of the same


Gynecology_Novak

Gynecology_Novak. Health Benefits of Oral Contraceptives age. No relation was found between past use of OCs and breast cancer (176). Effect of hormone dose was explored in a 2008 US study of 1,469 women with breast cancer who were matched by race, age, and neighborhood to community controls. The investigators then administered questionnaires and performed BRCA1 and 2 testing. Subjects who began OC use during or after 1975 were considered to have used low-dose pills. “Low-dose” was not further defined. Neither OC use overall or “low-dose” OC use was associated with breast cancer risk, among the total group, or within any subset. Women with BRCA1 or 2 did not have higher rates of cancer whether they were OC users or were nonusers (177). The controversy over the association between breast cancer and OC use is likely to continue. The best information available is that there is little or no connection.


Gynecology_Novak

Gynecology_Novak. Liver Tumors Oral contraceptives were implicated as a cause of benign adenomas of the liver. These hormonally responsive tumors can cause fatal hemorrhage. They usually regress when OC use is discontinued; risk is related to prolonged use (178). The tumors are rare; about 30 cases per 1 million users per year were predicted with older formulations. Presumably, newer low-dose products pose less risk. A link to hepatic carcinoma was proposed. This cancer is closely associated with chronic hepatitis B and C infections and is usually seen in cirrhotic livers. There are case reports of hepatocellular carcinoma in young women with no risk factors other than long-term OC use (179). A large study from six countries in Europe found no association between use of OCs and subsequent liver cancer (180). A systematic review looked for evidence of harm associated with hormonal contraceptive use among women already at risk because of liver disease (181). The authors concluded from the limited data


Gynecology_Novak

Gynecology_Novak. A systematic review looked for evidence of harm associated with hormonal contraceptive use among women already at risk because of liver disease (181). The authors concluded from the limited data available that OCs do not affect the course of acute hepatitis or chronic hepatitis, and do not affect the rate of progression or severity of cirrhotic fibrosis, the risk of hepatocellular carcinoma in women with chronic hepatitis, or the risk of liver dysfunction in hepatitis B virus carriers.


Gynecology_Novak

Gynecology_Novak. Oral Contraceptives and Sexually Transmitted Infections Chlamydial colonization of the cervix appears more likely in OC users than in nonusers but, despite this finding, several case-control studies found a reduced risk of acute PID among OC users (182,183). In contrast, a subsequent study found no protection with OC use (184). Whether hormonal contraceptives inﬂuence acquisition of HIV remains uncertain. The largest study concluded that overall risk was not increased by oral combination OCs or injected DMPA (185). Oral contraceptives have important health benefits (Table 10.7). These include contraceptive and noncontraceptive benefits 182).


Gynecology_Novak

Gynecology_Novak. DMPA (185). Oral contraceptives have important health benefits (Table 10.7). These include contraceptive and noncontraceptive benefits 182). Oral contraceptives provide highly effective contraception and prevent unwanted pregnancy, an important public health problem. Where safe abortion services are not available, women seek unsafe services and risk death from septic abortion. Combination OCs block ovulation and offer marked protection from ectopic pregnancy. Risk of ectopic pregnancy in a woman taking combination OCs is estimated to be 1/500 of the risk of women not using contraception; progestin-only OCs appear to increase risk of ectopic pregnancy (186).


Gynecology_Novak

Gynecology_Novak. As noted earlier, OC use produces strong and lasting reduced risk for endometrial and ovarian cancer. In addition, protection was found for women with known hereditary ovarian cancer. Any past use of OCs conferred a 50% reduction in ovarian cancer risk when women with this history who took OCs were compared with their sisters as controls (OR, 0.5; 95% CI, 0.3–0.8). Protection increased with increasing duration of use (187). The mechanism of action of OCs in the prevention of ovarian cancer is unknown but may involve selective induction of apoptosis (programmed cell death). Macaques treated with EE plus levonorgestrel or levonorgestrel alone showed an increase in the proportion of ovarian epithelial cells in apoptosis in comparison with animals fed a diet containing no hormones (188).


Gynecology_Novak

Gynecology_Novak. Other documented benefits of OC use include reduction of benign breast disease (189). Use of OCs helps relieve dysmenorrhea (166). Oral contraceptives offer effective therapy for women with menorrhagia and dysfunctional uterine bleeding (163). Table 10.7 Established and Emerging Noncontraceptive Benefits of Oral Contraceptives Reduced symptoms of premenstrual dysphoric disordera Inhibition of ovulation Treatment of bleeding disorders Treatment of hyperandrogenic anovulation Treatment of endometriosis Treatment of perimenopausal changes aOnly the low-dose EE/droperidol oral contraceptive has U.S. Food and Drug Administration approval for premenstrual dysphoric disorder treatment. From Burkman R, Schlesselman JJ, Zieman M. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol 2004;190(Suppl):S12, with permission.


Gynecology_Novak

Gynecology_Novak. All combination OCs offer some protection from functional ovarian cysts, but this is dose related (190). Although OCs may prevent cyst formation, they are not helpful in treating large functional ovarian cysts and should not be used for this purpose (191). OCs appear to decrease the risk of developing leiomyomata (192). All combination OCs reduce circulating androgen levels and usually improve acne. Three OCs were specifically FDA approved for acne treatment: the norgestimate/EE triphasic (TriCyclen), the norethindrone/EE multiphasic (Estrostep), and the 20 μg EE /3 mg droperidol OC.


Gynecology_Novak

Gynecology_Novak. There is some evidence that OC use is protective against colon cancer. A case-control study in Italy comparing women with colon cancer with controls found a 37% reduction in colon cancer and a 34% reduction in rectal cancer (colon cancer OR, 0.63; 95% CI, 0.45–0.87 and rectal cancer OR, 0.66; 95% CI, 0.43–1.01). Longer use produced more protection against colon cancer (193). Results of the U.S. Nurses Health Study disclosed some degree of protection. Women who used OCs for 96 months or more had a 40% lower risk of colorectal cancer (RR, 0.60; 95% CI, 1.15–2.14) (194). A large case-control study from Wisconsin found most of the benefit limited to women who were less than 14 years since discontinuing OCs (195). The mechanism of protection has not been identified.


Gynecology_Novak

Gynecology_Novak. After discontinuing OCs, return of ovulatory cycles may be delayed for a few months. Women who have amenorrhea more than 6 months after discontinuation of OCs should undergo a full evaluation because of the risk for prolactin-producing pituitary tumors. This risk is not related to OC use but rather to the probability that the slow-growing tumor was already present and produced menstrual irregularity, prompting the patient to take OCs (196).


Gynecology_Novak

Gynecology_Novak. This risk is not related to OC use but rather to the probability that the slow-growing tumor was already present and produced menstrual irregularity, prompting the patient to take OCs (196). Sexuality In a study that recorded all episodes of female-initiated sexual behavior throughout the menstrual cycle, an increase in sexual activity at the time of ovulation was noted. This increase was not present in women who were taking OCs (197). No other study appears to have addressed female initiated sexual activity and OC use. A 2003 study from Spain studied sexual desire in a comparative cohort of women using OCs and a cohort using IUDs. Sexual desire decreased over time, but was not affected by the contraceptive method (198). OCs containing the new progestin drospirenone are reported to improve sexual functioning and feelings of well-being (199,200).


Gynecology_Novak

Gynecology_Novak. Teratogenicity A meta-analysis of 12 prospective studies, including 6,102 women who used OCs and 85,167 women who did not, revealed no increase in overall risk for malformation, congenital heart defects, or limb reduction defects with the use of OCs (201). Progestins were used to prevent miscarriage. A large study compared women showing signs of threatened abortion who were treated with progestins (primarily oral medroxyprogesterone acetate) with women who were not treated. The rate of malformation was the same among the 1,146 exposed infants as among the 1,608 unexposed infants (202). Conversely, estrogens taken in high doses in pregnancy can induce vaginal cancer in female offspring exposed in utero. A recent literature search revealed no recent reports linking teratogenicity to hormonal contraception. Interaction of Oral Contraceptives with Other Drugs


Gynecology_Novak

Gynecology_Novak. Some drugs (e.g., rifampin) reduce the effectiveness of oral contraceptives; conversely, OCs can augment or reduce the effectiveness of other drugs (e.g., benzodiazepines) (203,204). Perhaps of greatest clinical significance are six antiepileptic drugs: phenytoin, phenobarbital, carbamazepine, oxcarbazepine, felbamate, and topiramate (205). These drugs and the antibiotic rifampin all induce synthesis of liver cytochrome P450 enzymes and reduce plasma levels of EE in women taking OCs, increasing the likelihood of contraceptive failure. Some antiseizure agents have no effect on the levels of contraceptive steroids in the blood. These include valproic acid, vigabatrin, lamotrigine, gabapentin, tiagabine, levetiracetam, zonisamide, ethosuximide, and the benzodiazepines (205). St. John’s wort induces cytochrome P450 and is reported to increase clearance of EE and norethindrone (206). The antifungal agents griseofulvin, ketoconazole, and itraconazole induce these hepatic enzymes and may


Gynecology_Novak

Gynecology_Novak. induces cytochrome P450 and is reported to increase clearance of EE and norethindrone (206). The antifungal agents griseofulvin, ketoconazole, and itraconazole induce these hepatic enzymes and may reduce OC efficacy (204). Ampicillin and tetracycline were implicated in numerous case reports of OC failure. They kill gut bacteria (primarily clostridia) that are responsible for hydrolysis of steroid glucuronides in the intestine, which allows reabsorption of the steroid through the enterohepatic circulation. It was not possible to demonstrate reduced plasma levels of EE overall or differences in pregnancy rates (207). Some individuals do experience reduced EE plasma levels when on tetracyclines or penicillins; it is best to advise women taking OCs who will be treated with antibiotics to use condoms as well (208). Certain drugs appear to increase plasma levels of contraceptive steroids. Ascorbic acid (vitamin C) and acetaminophen may elevate plasma EE, as do the antiretrovirals efavirenz


Gynecology_Novak

Gynecology_Novak. condoms as well (208). Certain drugs appear to increase plasma levels of contraceptive steroids. Ascorbic acid (vitamin C) and acetaminophen may elevate plasma EE, as do the antiretrovirals efavirenz and atazanavir/ritonavir (7).


Gynecology_Novak

Gynecology_Novak. An example of OCs affecting the metabolism of other drugs is seen with diazepam and related compounds. Oral contraceptive use reduces the metabolic clearance and increases the half-life of those benzodiazepines that are metabolized primarily by oxidation: chlordiazepoxide, alprazolam, diazepam, and nitrazepam. Caffeine and theophylline are metabolized in the liver by two of the P450 isozymes, and their clearance is reduced in OC users. Cyclosporine is hydroxylated by another of the P450 isozymes, and its plasma concentrations are increased by OCs. Plasma levels of some analgesic drugs are decreased in OC users. Salicylic acid and morphine clearances are enhanced by OC use; therefore, higher doses could be needed for adequate therapeutic effect. Clearance of ethanol may be reduced in OC users.


Gynecology_Novak

Gynecology_Novak. The interactions of antiretroviral drugs with contraceptive steroids are complex. Some of the drugs increase plasma steroid levels and some reduce them. A complete list of interactions is available in the Centers for Disease Control and Prevention’s “U.S. Medical Eligibility for Contraception” (7).


Gynecology_Novak

Gynecology_Novak. Oral contraceptives have the potential to alter a number of clinical laboratory tests as a result of estrogen-induced changes in hepatic synthesis; however, a large study comparing OC users with pregnant and nonpregnant controls found minimal changes (209). Hormone users took a variety of OCs containing 50 to 100 μg of estrogen, higher doses than are used today. Compared with nonpregnant women who were not using OCs, the OC users had an increase in T4 that is explained by increased circulating thyroid-binding protein, no change in creatinine and globulin levels, slight reduction in mean fasting glucose values and serum glutamic oxaloacetic transaminase, and a decrease in total bilirubin and alkaline phosphatase. Choice of Oral Contraceptives


Gynecology_Novak

Gynecology_Novak. Recently introduced OCs include those containing drosperidol, more preparations with only 20 μgof EE, new multiphasic preparations, cyclic OCs with 24 days of active medication and 4 days of either placebo or 10 μgof EE, and extended-cycle and continuous cycle preparations plus branded generic versions of most OCs. A combination OC containing estradiol valerate with a new progestin, dienogest, was approved in 2010. There is new evidence that 20 μg EE pills offer reduced risk for venous thrombosis (130). An approach to OC selection for new patients is to begin with a 20 μg EE combination and then adjust depending on the patient’s symptoms after the first 2 to 3 months. As reported in a large systematic review of 20 μg EE OCs compared to 30 to 35 μg EE pills, women taking the lower dose OCs more often report changes in vaginal bleeding, episodes of irregular bleeding and heavy bleeding, and more amenorrhea (210). If a 20 μg pill is offered, the patient should understand that bleeding


Gynecology_Novak

Gynecology_Novak. more often report changes in vaginal bleeding, episodes of irregular bleeding and heavy bleeding, and more amenorrhea (210). If a 20 μg pill is offered, the patient should understand that bleeding may be a problem and that she should return if this persists and try a different OC rather than stop the pill. The progestin component may become more important in determining cycle control when 20 μg EE is used. A comparison of 20 μg EE OCS, one containing 100 μgof levonorgestrel, the other with 1 mg of norethindrone acetate (NEA) found the NEA to have about twice as many days of unscheduled vaginal bleeding during the first 3 months, a critical time period for new users, which might be expected to lead to discontinuation (211). In a three-way trial, the 35-μg EE/norgestimate triphasic OC (Tri-Cyclen) was compared with two 20-μg EE pills, one containing 100 μgof levonorgestrel (Alesse), the other containing 150 μg desogestrel, followed by 2 hormone-free days and 5 days of 10 μg EE per day


Gynecology_Novak

Gynecology_Novak. was compared with two 20-μg EE pills, one containing 100 μgof levonorgestrel (Alesse), the other containing 150 μg desogestrel, followed by 2 hormone-free days and 5 days of 10 μg EE per day (Mircette) (212). Contraceptive efficacy was not significantly different. In the first two pill cycles more women taking Alesse had breakthrough bleeding and bleeding in the second half of the cycle than those taking the other two OCs in the first two cycles, but thereafter there was little difference. Women taking the higher estrogen Tri-Cyclen consistently experienced more frequent estrogenic side effects—bloating, breast tenderness, and nausea—than did women taking either 20-μg EE OC. These authors concluded that for the specific OCs evaluated, changing to either one of the 20 μg preparations would be beneficial.


Gynecology_Novak

Gynecology_Novak. For the average patient, the first choice of preparation for contraceptive purposes is a very low estrogen OC (20 μg EE) unless there are other considerations, for example, previous pregnancy while taking the pill. Patients with persistent break-through spotting or bleeding could be offered a pill with the same low estrogen dose, but a more potent progestin, for example levonorgestrel. Patients with apparent weight gain from ﬂuid retention while taking OCs, or with hirsutism or acne that did not respond to other OCs, may benefit from a change to the drospirenone/EE pill. The lower estrogen drospirenone combination is FDA approved for treatment of PMDD and should be considered for women with these symptoms who want hormonal contraception. Women with acne often benefit from the reduction in circulating testosterone that occurs with all combination OCs. Women who experience continuing pelvic pain, dysmenorrhea, or other menstrual triggered symptoms or who simply prefer fewer


Gynecology_Novak

Gynecology_Novak. reduction in circulating testosterone that occurs with all combination OCs. Women who experience continuing pelvic pain, dysmenorrhea, or other menstrual triggered symptoms or who simply prefer fewer menstruations may be offered an extended-cycle or continuous cycle-OC regimen.


Gynecology_Novak

Gynecology_Novak. The OrthoEvra patch and the NuvaRing both provide combinations of ultrapotent progestins with EE. Both patch and ring provide almost constant low levels of the contraceptive steroids that are less than the peak levels seen with OCs. Both offer greater convenience to the user, which improves compliance. The patch has a surface area of 20 cm2. It delivers a daily dose of 150 μg norelgestromin, the active metabolite of norgestimate, and 20 μgof EE. The patch is worn for 1 week then replaced with a new patch for 7 days, continuing for 3 consecutive weeks followed by a week with no patch. The patch was compared with a multiphasic OC containing levonorgestrel 50 to 125 μg,and 30to40 μg EE (Triphasil) in a randomized trial of 1,417 women (122). The overall and method failure Pearl indices were 1.24 and 0.99 pregnancies per 100 woman-years in the patch group and 2.18 and 1.23 in the OC group, respectively, numerically less in the patch group but not statistically significant. Patch users had


Gynecology_Novak

Gynecology_Novak. and 0.99 pregnancies per 100 woman-years in the patch group and 2.18 and 1.23 in the OC group, respectively, numerically less in the patch group but not statistically significant. Patch users had more breakthrough bleeding or spotting in the first two cycles, but thereafter this did not differ from OC users. Patch users reported more breast discomfort, dysmenorrhea, and abdominal pain than the OC users, but other adverse events were uncommon and did not differ. Perfect compliance was reported for 88.2% of patch users’ cycles versus 77.7% of the pill users’ cycles (p <.001). Pregnancy risk with the patch appears to be higher for women weighing more than 90 kg.


Gynecology_Novak

Gynecology_Novak. The NuvaRing is 54 mm in outer diameter and has a cross section of 4 mm. It delivers daily doses of 120 μgof etonogestrel, the active metabolite of desogestrel, with 15 μgof EE, and thus is the lowest estrogen combination hormonal method available in the United States. The soft, ﬂexible ring is worn in the vagina for 3 weeks, and then removed for 1 week, after which time a new ring is inserted. If inserted on the first day of menstruation, no back up method of contraception is needed. It can be inserted on days 2 to 5 and used with a backup method such as condoms for the first week. In a pharmacokinetic study comparing the ring with a combination OC containing 150 μgof desogestrel and 30 μgof EE, maximum blood levels of EE with the ring were about one-third of those seen with the OC, and the etonogestrel level was about 40% of that produced by the OC. Despite these findings, ovulation was inhibited in all women studied (213). Women wearing the ring are reported to have fewer days of


Gynecology_Novak

Gynecology_Novak. the etonogestrel level was about 40% of that produced by the OC. Despite these findings, ovulation was inhibited in all women studied (213). Women wearing the ring are reported to have fewer days of irregular bleeding or spotting than women taking an OC with 150 μgof levonorgestrel and 30 μgof EE (214). A large study found a total pregnancy rate of 1.18 (95% CI, 0.73–1.80) per 100 woman-years and 0.77 (0.37–1.40) pregnancies per 100 woman-years with perfect use (214). Some women prefer to remove the ring for intercourse, although this is not necessary. It should be reinserted within 3 hours to avoid loss of efficacy.


Gynecology_Novak

Gynecology_Novak. Since both methods provide constant low blood levels of EE, it was hoped that this might reduce risk for thrombosis. The FDA took the unusual step of issuing a “black box warning” for the EE/norelgestromin patch after several thrombosis cases were reported, and a small study of pharmacodynamics was interpreted as showing higher mean EE blood levels for the patch than with the oral route of administration. A small crossover study found increased activated protein C (APC) resistance when women were changed from a 30 μg EE/150 μg desogestrel pill to either the patch or the EE/etonogestrel ring. This was interpreted as prothrombotic (215). In another study, women on a variety of OCs had baseline measurement of APC resistance, and protein S. The patients were then switched either to the patch or to the ring. Those moving to the patch had changes in laboratory parameters that could be interpreted as prothrombotic, while those moved to the ring showed an improvement in the same studies,


Gynecology_Novak

Gynecology_Novak. or to the ring. Those moving to the patch had changes in laboratory parameters that could be interpreted as prothrombotic, while those moved to the ring showed an improvement in the same studies, theoretically reducing the risk of clotting (216).


Gynecology_Novak

Gynecology_Novak. Three databased epidemiologic studies looked at thrombosis in patch users compared to oral contraception. The first found no difference, but two subsequent studies did find risk. One study found an overall doubling of the risk of deep vein thrombosis when patch users were compared to users of an OC containing 30 μg EE/150 μg levonorgestrel, but the risk estimate was of borderline statistical significance and disappeared when the analysis was restricted to women aged 39 or less (217). After publication of this study the FDA issued a new document for consumers suggesting that women concerned about thrombosis and considering the patch discuss the issue with their physicians (218).


Gynecology_Novak

Gynecology_Novak. No similar FDA warnings were issued about the ring. There are two case reports in the world literature of venous thrombosis with the ring. Both were women in their 30s who sustained cerebral venous thrombosis (219,220). The authors of the fist report note that several other thrombosis cases in women using the ring were reported to Health Canada (220). It is best to assume that the ring has the same risk for thrombosis as the other combination hormonal contraceptives and to counsel women about risk in the same way.


Gynecology_Novak

Gynecology_Novak. DMPA, a suspension of microcrystals of a synthetic progestin, was approved for contraception in 1992. A single 150-mg intramuscular dose will suppress ovulation in most women for 14 weeks or longer (221). The regimen of 150 mg every 3 months is highly effective, producing pregnancy rates of about 0.3 per 100 women per year. Probably because of the high blood levels of the progestin, efficacy appears not to be reduced by administration of other drugs and is not dependent on the patient’s weight. Women treated with DMPA experience disruption Figure 10.8 Bleeding pattern and duration of use of depomedroxyprogesterone acetate (DMPA): percentage of women who have bleeding, spotting, or amenorrhea while taking


Gynecology_Novak

Gynecology_Novak. Figure 10.8 Bleeding pattern and duration of use of depomedroxyprogesterone acetate (DMPA): percentage of women who have bleeding, spotting, or amenorrhea while taking DMPA 150 mg every 3 months. (From Schwallie PC, Assenzo JR. Contraceptive use-efficacy study utilizing medroxyprogesterone acetate administered as an intramuscular injection once every 90 days. Fertil Steril 1973;24:331–339, with permission.) of the menstrual cycle and have initial spotting and bleeding at irregular intervals. Eventually, total amenorrhea develops in most women who take DMPA; with continued administration, amenorrhea develops in 50% of women by 1 year and in 80% by 3 years (Fig. 10.8).


Gynecology_Novak

Gynecology_Novak. The most important medical reason women discontinue use of DMPA and other progestinonly methods is persistent irregular vaginal bleeding. A variety of medications are used to stop this bleeding. Many are effective in terminating individual bleeding episodes, but a systematic review concluded that none improved continuation rates long term (222). New approaches include mifepristone and low-dose doxycycline. Mifepristone is of interest because irregular bleeding with DMPA was related to the down-regulation of endometrial estrogen receptors. Treatment with 50 mg of mifepristone every 2 weeks increases endometrial estrogen receptors and reduces breakthrough bleeding in new users of both DMPA and the levonorgestrel progestin implant (223). Another line of investigation concerns endometrial matrix metalloproteinase, which appears to play a regulatory role in the breakdown of the endometrium to produce normal menstruation. Treatment with doxycycline inhibits matrix metalloproteinase


Gynecology_Novak

Gynecology_Novak. matrix metalloproteinase, which appears to play a regulatory role in the breakdown of the endometrium to produce normal menstruation. Treatment with doxycycline inhibits matrix metalloproteinase production in the endometrium in women after insertion of levonorgestrel subdermal implants (224). Five-day courses of either mifepristone 25 mg twice a day for one day, followed by EE 20 μg per day for 4 days, or doxycycline 20 mg twice a day for 5 days, reduced bleeding days by about 50% when compared to placebos during a 6-month randomized trial in women treated for prolonged or frequent bleeding occurring with etonogestrel subdermal implants (225). Capsules of 20 mg doxycycline are sold in the United States for treatment of periodontal disease.


Gynecology_Novak

Gynecology_Novak. DMPA use is commonly associated with weight gain, and that is one of the principal reasons women discontinue use. A large study is representative of the literature. Three cohorts of women who chose their method of contraception were followed for 36 months with measurements of weight and body fat. DMPA users gained an average of 5.1 kg. The cohort using OCs over the same interval gained only 1.47 kg, slightly less than the 2.05 kg gained by the cohort not using any hormonal contraception. Total body fat increased 4.14 kg in the DMPA cohort, while the increase in the OC users was 1.9 kg, only slightly more than the 1.17 kg in the nonhormonal contraceptive cohort. Many women were followed for 2 years after discontinuing DMPA. Those who chose nonhormonal methods after discontinuing DMPA lost a mean of 0.42 kg each 6 months. Those who chose to use oral contraceptives gained a mean of 0.43 kg each 6 months during the follow-up interval (226).


Gynecology_Novak

Gynecology_Novak. Weight gain during the first 6 months and self-reporting of increased appetite are strongly predictive of continued weight gain. Women who gained less than or equal to 5% of body weight in the first 6 months gained a mean of 2.49 kg by 36 months, while those who gained more than 5% by 6 months gained a total mean of 11.08 kg by 36 months (227). Studies are needed of interventions to prevent the weight gain. At minimum, women considering DMPA need to know the possibility of significant weight gain and be advised to avoid calorie-dense foods and weigh themselves regularly. Ideally they should be weighed when they return for subsequent injections so they can be counseled about the need for avoiding further gain. Women who gain 5% of body weight by 6 months should consider other contraceptive options.


Gynecology_Novak

Gynecology_Novak. DMPA persists in the body for several months in women who used it for long-term contraception, and return to fertility may be delayed. It is reassuring that 70% of former users desiring pregnancy conceive within 12 months, and 90% conceive within 24 months after terminating DMPA use (228).