EXHIBIT 1026
`
`EXHIBIT 1026
`
`

`

`Management of
`Common Problems
`in Obstetrics
`and Gynecology
`
`Edited by
`DANIEL R. MISHELL, }R MD
`The Lyle G. McNeile Professor and Chainnan
`
`and
`PAUL F. BRENNER MD
`Professor and Vice Chairman
`
`Department of Obstetrics and Gynecology
`Universihj of Southern California
`School of Medicine, Los Angeles, California
`
`THIRD EDITION
`
`j
`
`•
`
`BOSTON
`
`Blackwell Scientific Publications
`
`OXFORD LONDON EDINBQRGH
`
`MELBOURNE PARIS BERLIN VIENNA
`
`Petitioner Exhibit 1026
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`

`

`© 1994 by
`Blackwell Scientific Publications, Inc.
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`
`First published 1988
`Second edition 1990
`Third edition 1994
`
`Set by Excel Typesetters Co., Hong Kong
`Printed and bound in the United States of
`America by Edwards Brothers, Ann Arbor,
`Michigan
`
`95 96 97 5 4 3 2
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`
`Library of Congress
`Cataloging-in-Publication Data
`Management of common problems in
`ob/gyn:
`edited by Daniel R. MisheU, Jr.,
`Paul F. Brenner. - 3rd ed.
`em.
`p.
`includes bibliographical references
`and index.
`ISBN 0-86542-269-9
`1. Pregnancy-Complications.
`2. Generative organs, Female-Diseases.
`I. Mishell, Daniel R.
`ll. Brenner, Paul F.
`(DNLM: 1. Genital Diseases, Female(cid:173)
`therapy.
`2. Endocrine Diseases-therapy.
`3. Fetal Diseases-therapy.
`4. Pregnancy Complications-therapy.
`WP 140 M266 1994]
`RG571.M23 1994
`618-dc20
`
`Petitioner Exhibit 1026
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`

`

`8
`
`Noncontraceptive effects of
`oral contraceptives: neoplastic,
`reproductive, and metabolic
`
`DANIEL R. MISHELL, JR
`
`Introduction
`
`Oral contraceptives (OCs) have been marketed since 1960 and millions of
`women have used these products during the past 33 years. Much infor(cid:173)
`mation has accumulated regarding the various actions of these steroids in
`addition to their primary effect of inhibition of ovulation. These effects
`· can be arbitrarily divided into three categories: (1) neoplastic; (2) repro(cid:173)
`ductive; and (3) metabolic.
`
`Neoplastic effects
`
`Numerous epidemiologic studies have been performed studying the
`relation of use of OCs with the most common genital neoplasms, breast,
`cerv_ix, endometrium, and ovary, as well as several extragenital tumors,
`namely, hepatic, pituitary, and malignant melanoma. Because as yet
`few elderly women used OCs during their early reproductive years, the
`studies thus far published usuaUy restrict the analysis to women under
`age 60.
`
`Breast cancer
`
`No study has reported a significant increase or decrease in the risk of
`developing breast cancer among the entire population of OC users. The
`combined risk estimate of the 16 case-control studies and four cohort
`studies surnmariz~d by Peterson and Wingo in 1992 was 1.0. In Schles-
`
`805
`
`Petitioner Exhibit 1026
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`

`

`806 Chapter 118
`
`selman's review of 17 different studies in which the risk of developing
`breast cancer in women under 60 years of age was compared with the
`duration of OC use, no overall dose- response was -found to exist and
`long-term use ctid not increase the risk of developing breast cancer.
`The issue of latency, time since first use of OCs, and risk of breast
`cancer has also been studied._ In groups of women using OCs for more
`than 10 years there was found to be no change in risk of breast cancer
`with increasing duration of time since first use. Thus, there is no evidence
`supporting a long-term latent effect. Several studies have presented data
`regarding the risk of developing breast cancer under age 45 by duration of
`OC use prior to e;1ge 25. The combined data fail to show a dose-response,
`indicating that early age of first OC use is not by itself a risk factor for
`development of breast cancer. The preponderance of data in studies
`estimating risk of breast cancer in women under 60 years of age by
`duration of OC use prior to first term pregnancy also failed to show an
`increased risk or a dose-response. However, analysis of the studies
`which estimated the relative risk of developing breast cancer in women
`under 45 years of age suggested that there was a trend of increasing risk
`with increasing duration of overall use, as well as increasing duration of
`use prior to first term pregnancy, with the increased risk in both groups
`becoming most evident after 8 years of use.
`Three large studies have suggested that prolonged use of high-estrogen(cid:173)
`dose OCs might increase the risk of developing breast cancer, but only
`when initially diagnosed at an early age.
`Because of the concern raised by these studies, Wingo et al. reanalyzed
`the extensive data obtained by the Cancer and Steroid Hormone study
`organized by the Centers for Disease Control (Table 118.1). These in(cid:173)
`vestigators found that women who used OCs h ad a slightly increased
`risk of developing breast. cancer between the ages of 20 and 34 compared
`to non-OC users. OC use did not alter . the risk of developing breast
`cancer between the ages of 35 and 44, and was associated with a slightly
`decreased risk of developing breast cancer between the ages of 45 and 54.
`Because breast cancer is more common between ages 45 and 54 than
`under 45, OC use could be associated with an increase of about 10 cases-
`of breast cancer per 100 000 women under age 45 but a decrease oHS- -
`cases per 100000 women in the 45-54-year age group.
`.
`These data are consistent with the belief that long-term use of hJgh·
`t cancer wa~
`· h b
`dose OCs could have promoted the age at whic
`reas
`otional effect
`Th.
`diagnosed clinically among susceptible women.
`IS prom
`· ble effect on the
`was transient, not persistent, and thus had no apprec1a
`. h
`ge60mtc
`d
`aggr~gate lifetime risk of developing breast cancer un er a
`population, despite the widespread use of OCs.
`h
`Because formulations w.ith low-dose estrogen ave
`
`b . ost
`' rn
`·
`
`been used
`
`Petitioner Exhibit 1026
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`

`

`Noncontraceptive effects of oral contraceptives
`
`807
`
`Table 118.1 Hypothetical annual age-specific breast cancer incidence rates in the
`USA in women aged 20- 54 in 1982 (from Wingo et al.)
`
`History of
`Age
`(years) OCuse
`
`OC use(%)
`
`Annual
`incidence
`RR
`per 100000
`(95% CI) women
`
`Rate
`difference
`per 100000
`women
`
`20-34 Never
`Ever
`
`24.0
`76.0
`
`All women
`
`100.0
`
`35-44 Never
`· Ever
`
`28.6
`71.4
`
`All women
`
`100.0
`
`45-54 Never
`Ever
`
`53.1
`46.9
`
`All women
`
`100.0
`
`Referent
`1.4
`(1.0-2.1)
`
`Referent
`1.1
`(0.9-1.3)
`
`Referent
`0.9
`(0.8- 1.0)
`
`8.5
`11.9
`
`11.1
`
`74.8
`82.2
`
`80.1
`
`177.5
`159.8
`
`169.2
`
`3.4
`
`7.4
`
`-17.7
`
`OC, Oral contraceptive; RR, relative risk; CI, confidence interval.
`
`women ingesting OCs only since 1983, the effect of these agents, if any,
`on early development of breast cancer can be determined only several
`years from now. However, the data reviewed thus far by the Food and
`Drug Administration resulted in a statement that no change in OC 'use or
`prescribing practice was warranted.
`In addition, there have been several studies of OC use and breast
`cancer risk in women at increased risk of developing the disease, those
`with a family history of breast cancer, as well as those with existing
`benign breast disease. The results of these studies indicate that OC use by
`each of these high-risk groups is not associated with any increased risk of
`developing breast cancer. In summary, epidemiologic data available to
`date indicate neither an increased nor decreased overall risk of breast
`cancer .in OC users with any type of formulation or with long-term use of
`these formulations.
`
`Cervical cancer
`
`The epidemiologic data obtained thus far indicate that long-term use of
`OCs is associated with an increased risk of preinvasive cervical neoplasia
`as well as both epidermoid and adenocarcinoma of the cervix, when
`
`Petitioner Exhibit 1026
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 5
`
`

`

`808 Chapter 118
`
`compared with matched control groups. Confounding factors, such as the
`woman's age at first sexual intercourse, the number of sexual partners,
`exposure to human papillomavirus (possibly greater among users of
`OCs), cytologic screening (more frequent among OC users), and the use
`of barrier contraceptives or spermicides (primarily by women in the
`control group) as well as cigarette smoking (an independent risk factor for
`this disease) could have influenced these results. Most of these studies
`made statistical corrections for .these confounding factors, and in many of
`them the control group did not use barrier methods of contraception.
`As shown in Schlesselman' s review, the overall pattern of epi(cid:173)
`demiologic results suggests an approximate doubling of risk of develop(cid:173)
`ment of carcinoma-in-situ with use of OCs for more than 1 year, with
`thr~e studies showing increasing risk with increasing duration of use. The
`data for invasive cervical cancer suggest no increased ri'sk with <5 years
`of OC use, but a gradually increasing risk after 5 years' use, which results
`in a twofold increase with 10 years of use. Data from the Royal College of
`General Practitioners cohort study by Beral et al. support the results
`of these case-control studies, since there was a steadily increasing risk of
`both preinvasive and invasive cancer of the cervix with increasing dura(cid:173)
`tion of OC use. Thus, although it is uncertain whether OCs themselves
`increase the risk of cervical cancer, act as a cocarcinogen, or have no
`effect, users of OCs as a group are at high risk for cervical neoplasia and
`require at least annual screening of cervical cytology, especially if they
`have used OCs for more than 5 years.
`
`Endometrial cancer
`
`OCs contain progestins as well as an estrogen and the progestins inhibit
`the synthesis of estrogen receptors in the endometrium and thus inhibit
`·the growth-promoting mitotic action of estrogen upon endometrial tissue,
`At least 11 studies have been published on the relation between OCs and
`endometrial cancer, and nine of these studies have indicated that the use
`of these agents has a p~otective effect against endometrial cancer, the
`third most common cancer among US women. Women who use OCs for
`at least a year have an age-adjusted relative risk of 0.5 of-developjn&g--:'..,......._
`endometrial cancer between ages 40 and 55 as compared with nonusers.
`This protective effect is related to duration of use, increasing from a 20%
`reduction in risk with 1 year of. use to a 40% reduction with 2 years of use
`to .a 60% reduction with 4 years of use. This protective effect appears
`within 10 years of. initial use and persists for at least 15 years . af~
`stopping use of OCs, at least until age 60. The greatest protectiv~ efte~:
`in nulliparous women (relative risk 0.2) or women of low panty, wh
`have the greatest risk of acquiring this disease.
`
`Petitioner Exhibit 1026
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 6
`
`

`

`Noncontraceptive effects of oral contraceptives 809
`
`Ovarian cancer
`
`The incidence of developing ovarian cancer is directly related to the
`number of times a woman ovulates in her lifetime. Thus, inhibition of
`ovulation by both pregnancy and OCs reduces the risk of ovarian cancer.
`At least 30 published reports relate the use of OCs with subsequent
`development of ovarian cancer and each of these shows a reduction in
`risk, specifically of the most common type - epithelial ovarian cancers.
`OCs reduce the risk of the four m?ffi histologic types of epithelial ovarian
`cancer: (1) se!ous; (2) mucinous; (3) endometri~id; and (4) clear celL The
`relative risk of ovarian cancer is 0.6 for women who use OCs for 3 or
`more years, and as little as 6 months of use provides protection. The
`magnitude of the decrease in risk is directly related to the duration of use,
`increasing from a SO% reduction with 4 years' use to a 60-80% reduction
`with 7 or more years' use. The protective effect begins within 10 years of
`first use and continues for at least 15 years after the use of OCs ends, at
`least until age 60. As with endometrial cancer, the protective effect occurs
`only in women of low parity (four children or less), who are at greatest
`risk for this type of cancer.
`
`Liver adenoma and cancer
`
`The development of a benign hepatocellular adenoma is a rare occurrence
`in long-term users of OCs. The increased risk of this tumor was associated
`with prolonged use of high-dose formulations, particularly those con(cid:173)
`taining mestranol. Although two British studies reported an increased
`risk of liver cancer among users of OCs, the number of patients was small
`and the res!llts could have been influenced by confounding factors. Data
`from a large multicenter epidemiologic study coordinated by the World
`Health Organization found no increased risk of liver cancer associated
`with OC users in countries with a high prevalence rate of this neoplasm.
`This study found no change in risk with increasing duration of use or
`time since first or last use. The rate of death from this disease has
`remained unchang~d in the USA over the past 25 years, a period when
`millions of women have used these agents.
`
`PitUitary adenoma
`
`OCs mask the predominant symptoms produced by prolactinoma, amen(cid:173)
`orrhea, and galactorrhea. When OC use is discontinued these symptoms
`occur, suggesting a causal relation. However, data from three studies
`indicate that the incidence of pituitary adenoma among users of OCs is
`not higher than that among matched controls.
`
`..
`
`Petitioner Exhibit 1026
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 7
`
`

`

`') Chapter 118
`
`Malignant melanoma
`
`Several epidemiologic studies have been undertaken to assess the relation
`of OC use and the development of malignant melanoma. The results are
`conflicting, since an increased risk, a decreased risk, and no effect have
`all been reported. In a review by Prentice and Thomas, the summary
`relative risk for eight case-control studies was 1.0 and for three cohort
`studies 1.4, an insignificant increase. Thus there is no convincing evi(cid:173)
`dence that OC use increases the risk of developing malignant melanoma.
`In summary, there is an increased risk of cervical neoplasia among OC
`users (but no correlation has_ been established), as well as development
`of a benign liver adenoma. The incidence of breast cancer, pituitary
`adenomas, and melanoma is the same in OC users and control groups
`and there is a decreased risk of two lethal cancers - endometrial cancer
`and ovarian cancer- with reduction in risk persisting after OC use is
`discontinued.
`
`Reproductive effects
`
`The magnitude and duration of the delay in the return of fertility are
`greater for women discontinuing use of OCs with 50 ~g of estrogen or
`more than with those containing lower doses of estrogen. However,
`Bracken et al. reported that use of the low-dose formulations still resulted
`in a reduction in conception rates for at least the first six cycles after
`discontinuation. In women stopping use of OCs in order to conceive,
`the probability of conception is lowest in the first month after stopping
`their use and increases steadily thereafter. There is little, if any, effect of
`duration of OC use upon the length of delay of subsequent conception
`but the magnitude of the delay to return of conception after OC use is
`grea ter among older premenopausal women.
`Thus, for 2-3 years after the discontinuation of contraceptives in order
`to conceive, the rate of return of fertility is lower for users of OCs than for
`women who have used barrier methods. Eventually the percentage of
`women who conceive after ceasing to use each of these contraceptive
`methods becomes the same. Thus, the use of OCs does not cause per(cid:173)
`manent infertility.
`Because the resumption of ovulation is delayed for variable periods
`after OCs are stopped, it is difficult to estimate the expected date of
`delivery if conception takes place before spontaneous menses return. For
`this reason, when women stop OCs in order to conceive, it is probably
`best that they use barrier ·methods for about 1- 2 months until regular
`cycles resume. If conception occurs before resumption of spontaneous
`mensus, gestational age should be estimated by serial sonograP.hy. Neither
`
`Petitioner Exhibit 1026
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 8
`
`

`

`Noncontraceptive effects of oral contraceptives 811
`
`the rate of spontaneous abortion nor the incidence of chromosomal
`abnormalities in abortuses is increased in women who conceive in the
`first or subsequent months after ceasing to use OCs.
`Several cohort and case-control studies of large ·numbers of babies
`born to women who stopped using OCs have been undertaken. These
`studies indicate that these infants have no greater chance of being born
`with any type of birth defect than infants bom to women in the general
`. population, even if conception occurred in the fu·st month after the
`medication was discontinued. If these steroids are ingested during the
`first few months of pregnancy, a recent review by Bracken and Vita of
`all the prospective epidemiologic studies with a control group of wol?en
`not using OCs reported that there was no increased risk of congenital
`malformations overall among the offspring of OC users. Furthennore
`there was no increased risk of congenital heart defects or limb reduction
`defects in OC users. An increased risk of these anomalies had been
`reported in early case-control studies of women ingesting OCs after
`conception. However, the results. could have been influenced by recal!
`bias. A statement warning of a possible teratogenic effect of ingestion of
`OCs during pregnancy has been deleted from current product labeling for
`OCs.
`
`Metabolic effects
`
`Different metabolic effects of contraceptive steroids are produced by
`the estrogenic component,. ethinylestradiol, as well as the progestill.
`In general, the severity of these adverse metabolic effects is directly
`correlated with the dosage and potenq (biologic activity) of steroid in the
`formulation. During the past 30 years the amount of both the estrogenic
`and progestogenic, component of formulati9ns has decreased markedly
`and has been accompanied by a lower incidence and severity of the
`adverse metabolic effects.
`
`Protein
`
`·
`
`The synthetic estrogens used in OCs increase the hepatic production of
`several globulins, some of which are involved in the coagulation process.
`Another globulin, angiotensinogen, may be converted to angiotensin and
`increa~e blood pressure in some users .. The circulating levels of each of
`these globulins correlate directly with the amount of estrogen in tl1e OC
`formulation. Epidemiologic studies have shown that the incidence of both
`venous and arterial thrombosis is also directly related to the dose of
`estrogen.
`Angiotensinogen levels are lower in women who ingest formulations
`
`Petitioner Exhibit 1026
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 9
`
`

`

`t
`
`812 Chapter 118
`
`with 30-35 !lg ethinylestradiol than in those who ingest formulations with
`50 11g. However, there is still a significant mcrease in blood pressure in
`women who receive the lower dosage. Thus, blood pressure should
`be monitored in all users of OCs. Indirect evidence suggests that the
`progestin component 1).1ay also affect blood pressure. However, women
`who receive progestins without estrogen do not have an increase in blood
`pressure over time, indicating that the estrogen component is the major
`factor in causing elevated blood pressure in certain users of OCs.
`
`Carbohydrate
`
`When formulations with a high ·dose of progestin are administered,
`4- 16% of women (depending on their age) have an abnormal response
`to the glucose tolerance test. The incidence of abnormal test results
`is related to the dose and potency of the progestin, since estrogen does
`not affect carbohydrate metabolism. SomE;! studies have shown that
`formulations with a low dose of progestin do not significantly alter levels
`of glucose, insulin, or glucagon after a glucose load in healthy women or
`in those with a history of gestational diabetes. However, other studies
`indicate that the multiphasic formulations with norgestrel, but not those
`with norethindrone, produce some deterioration of glucose tolerance in
`normal women, as well as in those with a history of gestational diabetes.
`When one is prescribing these agents for women with a history of
`glucose intolerance, it is preferable to use formulations with a low dose of
`a progestin. Kjos et al. have shown that women with a previous history
`. of gestational diabetes. i~gesting these agents have no greater risk of
`developing diabetes than a control group using other methods of con(cid:173)
`traception. Data from 20 years' experience with use of mainly high-dose
`formulations in the large Royal College of General Practitioners study
`revealed no increased risk of developing diabetes mellitus among current
`OC users (relative risk 0.80) or former OC users (relative risk 0.82), even
`among those women who had used OCs for 10 years or longer.,
`
`Lipids
`
`Adverse alterations in high-density lipoprotein (HDL) cholesterol and
`low-density lipoprotein (LDL) cholesterol are produced by-alHke-pr~·-,___ __ -1
`gestins currently used in OCs available in the USA, and the degree of
`change in the levels of these cholesterols is related to the amount and
`potency of the progestin. Because the estrogen component has an effect
`opposite to that of the progestin, a decrease in HDL d1olesterol levels
`50 ug of estrogen
`.
`.
`.
`.
`.
`t · ·
`after the mgestion of vanous formulations con ammg
`r
`trel Studies haw
`.
`· ·
`has been noted only for a formulation contatrung norges
`·
`
`Petitioner Exhibit 1026
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 10
`
`

`

`Noncontraceptive effects of oral contraceptives 813
`
`measured lipid levels before and after the ingestion of several low-dose
`estrogen-progestin formulations, including the triphasic formulation
`containing levonorgestrel. These found no adverse alterations in the
`levels of HDL or LDL cholesterol or in the ratio of total cholesterol to
`HDL cholesterol. In two prospective randomized studies of ~e 3 tri(cid:173)
`phasic formulations currently being marketed in the USA, it has been
`reported that each had similar effects which were clinically insignificant
`upon carbohydrate and lipid metabolism, including changes in HDL,
`HDLz and LDL cholesterol. Studies with formulations containing the
`three newly synthesized progestins indicate that these also produce no
`alteration in lipid or carbohydrate metabolism. Thus, the most recently
`developed low-dose OCs have no adverse effects on carbohydrate or lipid
`metabolism.
`
`I
`
`Other metabolic effects
`
`The symptoms most frequently produced by the estrogenic component
`include nausea (a central nervous system effect), breast tenderness, and
`fluid retention, which usually does not exceed 1-2kg body weight, due
`to decreased sodium excretion. Minor, clinically insignificant changes in
`circula ti.ng vitamin levels also occurred after ingestion of the higher(cid:173)
`dosage OCs. These changes include a decrease in levels of the B-complex
`vitamins and ascorbic acid and increases in levels of vitamin A. Even with
`use of the high-steroid,dose agents, dietary vitamin supplementation was
`not necessary as the changes in circulating vitamin levels were small and
`clinically insignificant. Estrogen can also cause chloasma (pigmentation of
`the malar eminences), which is accenh1ated by sunlight and usually takes
`a long time to disappear after OCs are discontinued. The incidence of all
`these estrogenic side-effects is much lower now than occurred previously
`because the formulations in use today contain only one-fifth as much
`estrogen as the formulations used irt the 1960s.
`The estrogen component of OC agents also accelerates the develop(cid:173)
`ment of the symptoms of gallbladder disease in young women but does
`not increase the overall incidence of cholelithiasis. In a very large, re(cid:173)
`trospective cohort study by Strom et al., the risk ratio for gallbladder
`disease in OC users was only 1.14, which barely achieved statistical
`significance. Among women _using formulations with less than SO 11g of
`estrogen, the risk ratio for gallbladder disease was 0.97.
`Data from studies of postmenopausal women receiving estrogen
`therapy alone, as well as estrogen- progestin sequential therapy, indicate
`that estrogen alone improves the mood of.women, whereas the addition
`of a progestin !flcreases the amount of depression, . irritability, tension,
`and fatigue. These studies also indicate that the progestin component
`
`j
`
`j
`~
`'
`i,
`
`'I .. ·,. .,
`
`"
`
`· .. ...
`
`Petitioner Exhibit 1026
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 11
`
`

`

`~ 814 Chapter 118
`
`may be the major cause of the adverse mood changes and tiredness
`observed in some women after ingestion of OCs. It has not been defi(cid:173)
`nitely established, however/ whether estrogen or progestin is the major
`factor in producing adverse mood changes. Possibly both are involved.
`The progestins, because they are structurally related to testosterone,
`also produce certain adverse androgenic effects, including weight gain,
`acne, and a symptom perceived by some women as nervousness. Some
`women gain a considerable amount of weight when.they take OCs, and
`this weight gain is produced l?Y the anabolic effect of the progestin·
`component. Although estrogens decrease sebum production, progestins
`increase sebum production and can cause acne to develop or worsen.
`Thus patients who have acne should be given a formulation with a low
`progestin: estrogen ratio.~Jbe final symptom produced by the progestiit
`component is failure - of withdrawal bleeding or amenorrhea. Because
`the progestins decrease the synthesis of estrogen receptors in the endo(cid:173)
`metrium, endometrial growth is decreased, and some women have
`failure of withdrawal bleeding. Although this symptom is not important
`medicaily, since bleeding serves as a signal that the woman is not preg(cid:173)
`nant, it is desirable to have some amount of periodic withdrawal bleeding
`during the days she is not taking these steroids.
`Both steroid components can act together to produce irreguJar bleed(cid:173)
`ing. Breakthrough bleeding (which is usually produced by insufficient
`estrogen, too much progestin, or a combination of both), as well as failure
`of withdrawal bleeding, can be alleviated by increasing the amount
`of estrogen· in the formulation or by switching to a more estrogenic
`formulation. Many women taking OCs complain of an increased frequency
`of headaches. The exact relation, if any, between OC use and headaches
`has not been determined.
`
`Cardiovascular effects
`
`One must be concerned about the adverse changes in lipid levels produced
`by the progestin component of certain high-progestin-dose OC formu(cid:173)
`lations. However, the cause of the increased incidence of both venous
`and arterial cardiovascular disease, including myocardial infarction, in
`users of OCs appears to be thrombosis and not atherosclerosis.
`Estrogens can increase blood viscosity by raising plasma fibrinogen
`levels as well as hematocrit. The synthetic progestins also increase blood
`viscosity by raising hematocrit and decreasing erythrocyte deformability.
`Increased blood viscosity, produced by either of these two steroid-do~e­
`related mechanisms, could cause an increased incidence of thrombOSIS(cid:173)
`This could explain the findings in several epidemiologic studies, indud-
`
`Petitioner Exhibit 1026
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 12
`
`

`

`Noncontraceptive effects of oral contraceptives
`
`815
`
`ing the Royal College of General Practitioners study, that the incidence
`of both venous and arterial thrombotic events is directly related inde(cid:173)
`pendently to both the dose of estrogen and the dose of progestin.
`Neither epidemiologic studies of humans nor experimental studies
`with subhuman primates have observed an acceleration of atherosclerosis
`with the ingestion of OCs. Three large epidemiologic studies found that
`there is -no increased risk of myocardial infarction among former users of
`OCs. The incidence of cardiovascular disease is also not correlated with
`the duration of OC use.
`Studies suggest that the estrogen component of OCs may have a
`protective effect on coronary art~riosclerosis that would otherwise be
`accelerated by decreased levels of HDL cholesterol.
`The epidemiologic studies that reported an increased incidence of
`myocardial infarction in older users of OCs were published in the late
`1970s and thus used as a databa·se women who ingested only formulations
`with 50 1-1-g or more of estrogen. In these case-control and cohort studies, a
`significantly increased incidence. of myocardial infarction was found
`-mainly among older users who had risk factors that caused arterial nar(cid:173)
`rowing, particularly smoking, as well as preexisting hypercholesterolemia,
`hypeJ;tension, or diabetes mellitus.
`Data accumulated during the first 10 years of the Royal College of
`General Practitioners study, 1968- 1978, in which most users ingested
`fom1ulations with >50 f.lg of estrogen and high doses of progestin,
`showed that a significantly increased relative risk of death from circu(cid:173)
`latory disease occurred only among women over age 35 who also smoked. A
`more recent analysis of data· obtained during the first 20 years of this
`study, 1998-1988, revealed no significant increased relative risk of ~cute
`myocardial infarction among current or former OC users who did not
`smoke cigarettes. Even though most of the women in this study used
`high-dose formulations, a significantly increased risk of myocardial
`infarction occurred only among both mild (<15 cigarettes a day) and
`heavy cigarette smokers, with the latter group having a greater relative
`risk. In this and other studies, cigarette smoking was an independent risk
`factor for myocardial infarction, but the use of OCs by cigarette smokers
`greatly enhanced their risk of developing a myocardial infarction, with
`the two factors acting synergistically.
`Although epidemiologic data from studies performed in the 1970s
`indicated that a possible causal relation existed between ingestion of high(cid:173)
`dose OC formulations and cerebrovascular accident (CVA, stroke), the
`data were conflicting. Some studies showed a significantly increased risk
`of thrombotic CV A, others an increased risk of hemorrhagic CV A, and
`others no significantly increased risk of either entity. Furthermore, as
`with myocardial infarction, the studies showing a significantly increased
`
`Petitioner Exhibit 1026
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 13
`
`

`

`816 Chapter 118
`
`risk of CV A in OC users indicated that the increased risk was mainly
`limited to older women who also smoked and/or were hypertensive.
`Data from the epidemiologic studies of