- Email: [email protected]
Use of oral contraceptives in women of older reproductive age
Meade
June 1988
Am J Obstet Gynecol
4. 5.
6. 7. 8. 9.
10.
11. 12.
and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30-t..Lg oestrogen preparations. Br Med J 1980;280: 1157-61. Royal College of General Practitioners. Oral contraceptives, venous thrombosis, and varicose veins. J R Coli Gen Pract 1978;28:393-9. Royal College of General Practitioners. Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet 1977; 1: 624. Kay CR. The happiness pill? J R Coli Gen Pract 1980;30:819. "Digest." British pill studies stress importance of relation between progestogen content and vascular disease. Fam Plan Perspect 1980; 12:262-4. Poller L, Thompson JM. Clotting factors during oral contraception: further report. Br Med J 1966;2:23-5. Stanwell-Smith R, Meade TW. Hormone replacement therapy for menopausal women: a review of its effect on haemostatic function, lipids, and blood pressure. Adv Drug React Ac Pois Rev 1984;4:187-210. Meade TW, Chakrabarti R, Haines AP, North WRS, Stirling Y. Haemostatic, lipid and blood-pressure profiles of women on oral contraceptives containing 50 f..Lg or 30 t..Lg oestrogen. Lancet 1977;2:948-51. Meade TW, Mellows S, Brozovic M, et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986;2:533-7. Henriksson P, Edhag 0. Orchidectomy versus oestrogen for prostatic cancer: cardiovascular effects. Br Med J 1986;2:413-5.
13. Henriksson P, Blomback M, Bratt G, Edhag 0, Eriksson A. Activators and inhibitors of coagulation and fibrinolysis in patients with prostatic cancer treated with oestrogen or orchidectomy. Thomb Res 1986;44:783-91. 14. Dalaker K, Hjermann I, Prydz H. A novel form of factor VII in plasma from men at risk for cardiovascular disease. Br J Haematol1985;61:315-22. 15. Gordon EM, Hellerstein HK, Ratnoff OD, Arafah BM, Yamashita TS. Augmented Hageman factor and prolactin 1 titers, enhanced cold activation of factor VII, and spontaneous shortening of prothrombin time in survivors of myocardial infarction.] Lab Clin Med 1987;109:409-13. 16. Miller GJ, Seghatchian MJ, Walter SJ, et al. An association between the factor VII coagulant activity and thrombin activity induced by surface/cold exposure of normal human plasma. Br J Haematol 1986;62:379-84. 17. Meade TW. The epidemiology of haemostatic and other variables in coronary artery disease. In: Verstraete M, Vermylenj, Lijnen HR, Arnoutj, eds. Thrombosis and haemostasis. Leuven: International Society on Thrombosis and Haemostasis and Leuven University Press, 1987:3760. 18. Meade TW, Chakrabarti R, Haines AP, North WRS, Stirling Y. Characteristics affecting fibrinolytic activity and plasma fibrinogen concentrations. Br Med J 1979; 1: 153-6. 19. Khaw K-T, Peart WS. Blood pressure and contraceptive use. Br Med J 1982;285:403-7.
Use of oral contraceptives in women of older reproductive age Daniel R. Mishell, Jr., MD Los Angeles, California Evidence of increased risk for cardiovascular disease in oral contraceptive users of older reproductive age is based on early data involving formulations containing higher doses of estrogen and progestin than those in use today. In addition, early studies included patients who would not receive oral contraceptives with today's more stringent prescribing criteria. When these data were carefully analyzed, a significant increase in myocardial infarction was noted only in oral contraceptive users with concomitant risk factors for cardiovascular disease. Analysis of other studies also showed a significant increase in the incidence of cardiovascular disease and mortality only in oral contraceptive users older than age 35 years who smoked. A recent long-term cohort study of women without risk factors for cardiovascular disease who mainly used oral contraceptives containing ,;so f..Lg estrogen showed no increased risk of myocardial infarction or cerebrovascular accident with oral contraceptive use. Use of oral contraceptives containing <50 f..Lg estrogen has not been shown to be associated with an increased risk of cardiovascular disease in healthy, nonsmoking women 35 to 45 years of age. (AM J OBSTET GYNECOL 1988;158:1652-7.)
Key words: Cardiovascular disease, oral contraceptives
From the Department of Obstetrics and G_~necology, University of Southern California School of Medicine. Reprint requests: Daniel R. Miskell, Jr., MD, Professor and Chairman, Department of Obstetrics and Gynecology, University of Southern California School of Medicine, 1240 N. Mission Road, Rm. L-1009, Los Angeles, CA 90033.
1652
In the United States most women of older reproductive age (35 to 45 years) who do not wish to conceive have available only four methods of pregnancy prevention: sterilization, barrier techniques, the progesterone-releasing intrauterine contraceptive de-
Volume 158 Number 6, Part 2
Use of OCs in women of older reproductive age 1653
Table I. Percent myocardial infarction according to risk factors, compared with controls Risk factor
0 1 Oral contraceptives Hyperlipidemia Smoking Hypertension Diabetes
2
Table II. Circulatory disease mortality rates (per 100,000 woman years) by age, smoking status, and oral contraceptive use
Myocardial infarction
Controls
18.9
64.0
5.4 5.4 16.2 6.8 1.4 27.0 18.9
4.5 0.5 16.5 9.5 0.0 4.5 0.5
From Mann JI, Doll R, Thorogood M, et al. Risk factors for myocardial infarction in young women. Br J Prev Soc Med 1976;30:94-100.
vice (IUD), and periodic abstinence. Each of these techniques has certain disadvantages. Surgical sterilization, even if performed by laparoscopy, is a major operative procedure requiring general anesthesia. Many women decide against sterilization because of the cost, inconvenience, and anesthetic risk of the procedure. Many of the barrier techniques, such as condoms and spermicides, must be used shortly before sexual intercourse and thus have a relatively high use-failure rate. Many women do not use these and other barrier techniques, such as the sponge and diaphragm, because of the inconvenience. Of the IUDs, the only one currently available in the United States is the progesterone-releasing IUD, which is costly, not easily obtained, and must be reinserted annually. The m
Mortality rate (No. of deaths) Age (yr)
Ever users
15-24 0.0 Nonsmokers Smokers 10.5 25-34 Nonsmokers 4.4 Smokers 14.2 35-44 Nonsmokers 21.5 Smokers 63.4 >45 Nonsmokers 52.4 206.7 Smokers
IControls
(0) (1)
0.0 (0) 0.0 (0)
(2) (6)
2.7 (1) 4.2 (1)
Ever users vs controls (95% confidence limits) Relative risk
1.6 3.4
(7) 6.4 (2) (18) 15.2 (3)
3.3 4.2*
(4) 11.4 (1) (17) 27.9 (2)
4.6 7.4*
From Royal College of General Practitioners' Oral Contraceptive Study. Further analysis of mortality in oral contraceptive users. Lancet 1981;1:541-3. *Significantly different.
United States will not prescribe OCs for healthy women older than age 35 years. The rationale for these decisions is based on old epidemiologic data. It is the purpose of this communication to review more recent epidemiologic studies and a recently published animal study that indicate that the current common practice of not prescribing OCs for older women may no longer be valid. Epidemiologic basis for not prescribing oral contraceptives for older women
The current product insert for OCs states that the mortality associated with their use in nonsmokers older than 40 years of age is higher than with any other method of contraception in this age group. This statement is derived from a study published by Tietze' in 1977, and a figure from this paper, derived from computerized data, appears in the product information brochure for many OCs. The data generated were based on several case control studies published by Mann et aJ.2·' and on two British cohort studies from the Oxford Family Planning Association 6 and the Royal College of General Practitioners 7 published between 1975 and 1977. These studies reported that women older than 35 to 40 years who used OCs had a significantly greater risk for fatal myocardial infarction or other cardiovascular cause of death than did women not using OCs. Between 1977 and 1981, additional case control studies 8• 10 and data from the Walnut Creek cohort study" confirmed that older women using OCs had a greater incidence of cardiovascular disease, particularly myocardial infarction, than controls did.
1654
Mishell
June 1988 Am J Obstet Gynecol
Table III. Walnut Creek Contraceptive Drug Study: Effect of oral contraceptive use on risk of diseases of circulatory system Standard rates Never used OCs
Disease
Acute myocardial infarction Ischemic heart disease Subarachnoid hemorrhage Cerebral thrombosis Arterial thrombosis Pulmonary embolism Thrombophlebitis
Current OC users
I
Relative risk
I
Past OC users
Current OC users
I
Past OC users
0.23
0.27
0.20
l.l
0.8
0.79
1.09
0.90
1.4
1.1
0.04
0.43
0.10
10.1 *
2.3*
0.24 0.24 0.38 0.51
0.53 0.76 0.22 0.42
0.29 0.24 0.29 0.48
2.2* 3.2* 0.6 0.8
1.2 1.0 0.0 1.8
From Ramcharan S, Pellegrin FA, Ray RM, et al. The Walnut Creek Contraceptive Drug Study: a prospective study of the side effects of oral contraceptives, vol. 3. Bethesda, Maryland: National Institutes of Health. 1981, NIH publication no 81-564. *Not significant overall; significant only in smokers 2::40 years of age.
Table IV. Oral contraceptive use in women aged 40 to 44 years dying of myocardial infarction Myocardial infarction n
Never used OCs Current OC users Ex-users of OCs
78 18 10
l
Table V. Circulatory disease* mortality rates with oral contraceptive use Duration of OC use (mo)
Controls
%
n
73.6 17.0 9.4
86 7 9
I
% 84.3 6.0 8.8
From Mann JI, Inman WH, Thorogood M. Oral contraceptive use in older women and fatal myocardial infarction. Br Med J 1976;2:445-7.
All of these studies were performed using OC formulations and prescribing criteria that were much different than those currently used. Each of the three cohort studies was initiated in 1968, when the dosage of both the estrogen and progestin component of the formulation was much greater than that currently prescribed. Likewise, the case control studies published in the late 1970s reflected data for women using higher dose formulations than those now used. The OC formulations with <50 IJ.g estrogen were not introduced until 1974 and were used by less than one fourth of OC users until 1980. Furthermore, until these studies were published the contraindications for OC use were also different from those currently advised. Prior to 1976 OCs were prescribed for women of any age, including those who smoked and those who had other risk factors for cardiovascular disease, such as preexisting hypertension, diabetes, and hypercholesterolemia. When some of these epidemiologic studies were analyzed for the pres-
0 1-24 25-48 49-72 73-96 o::97
Rate (per 100,000 women years)
7.0 32.5 23.5 28.4 32.3 20.4
(10) (5) (4) (5) (5) (4)
Relative risk
1.0 4.6 3.4 4.1 4.6 2.9
From Royal College of General Practitioners' Oral Contraceptive Study. Further analysis of mortality in oral contraceptive users. Lancet 1981; I :541-3. *International Classification of Diseases, Injuries, and Causes of Death, 390-458.
ence of these independent risk factors for myocardial infarction, it was found that a significantly increased risk of myocardial infarction occurred only in OC users with these risk factors that could cause narrowing of the lumen of the coronary arteries. In a reanalysis of their data, Mann et al. 2 · 12 found that the frequency of use of OCs in women older than 40 years of age without these risk factors who died of myocardial infarction was nearly identical to the frequency of OC use in the control group (Table 1). The incidence of OC use in the women with myocardial infarction was only higher in women with a history of one or more of these independent risk factors than in the controls. Analysis of circulatory disease mortality rates in the Royal College of General Practitioners' prospective study published in 1981 revealed that a significant increase in circulatory disease mortality occurred only in OC users older than age 35 years who also smoked, whereas the risk of mortality from circulatory disease
Use of OCs in women of older reproductive age 1655
Volume 158 Number 6, Part 2
1.5
•
1.0
Males
•
•
Males
1.5 r - 0.63
0.5 1.5
•
0.5
1.5
r - 0.49
•
'E
.s.
0
C1l
.•
• Intravaginal Ring
1.0
r - 0.54
0.48
0.5 0
(ii
1.5
E
Control Females
1.0
~
c
0.5 0
1.0
Intravaginal Ring
•
•
0.50
0.5
1.5
Oral Contraceptive
1.0 0.5 0
= 0.75
0
Control Females
1.0
1.5
•
0.5
0
Intimal Area
•
1.0
r - 0.57
0 1.5 1.0
• Oral Contraceptive • r = 0.62
0.5
20
40
60
80
100 Plasma HDL Cholesterol ( mg/ dl)
Fig. 1. Relationship between plasma HDL-C concentrations and extent of coronary artery atherosclerosis among four experimental groups. For all r values, p ,;;; 0.05. (From Adams MR, Clarkson TB, Koritnik DR, et al. Fertil Steril 1987; 47:1010-8.)
was not significantly increased for nonsmoking OC users of any age, even those older than age 45 years 13 (Table II). The final report of the Walnut Creek Contraceptive Drug Study showed that there was no difference in the incidence of myocardial infarction in current or past OC users and women who never used OCs" (Table III). Although there was found to be a significant increase in the incidence of cerebral arterial vascular disease among OC users in this study, it occurred only in women older than age 40 years who also smoked. Thus even in these older epidemiologic studies, where the amount of steroids in the formulation used was higher than that used today, an increased incidence of cardiovascular disease in OC users occurred only in women who smoked or had other independent risk factors. Cause of cardiovascular disease associated with oral contraception
The cause of the cardiovascular disease occurring in certain users ofOCs appears to be thrombosis, and thus is related to the estrogen component and not to atherosclerosis, which could be related to the progestogen component of the formulation. Evidence for this statement is based on the following three facts:
0
10 Total Plasma Cholesterol: HDL Cholesterol
Fig. 2. Relationship between plasma total cholesterol/HDL-C concentrations among four experimental groups. For all r values, p < 0.05 and extent of coronary artery atherosclerosis. (From Adams MR, Clarkson TB, Koritnik DR, et al. Fertil Steril 1987;47: 1010-8.)
1. Nearly all of the published epidemiologic studies indicate that there is no increased risk of myocardial infarction in ex-users of OCs. In the large study by Mann et a!! the incidence of myocardial infarction in ex-users of OCs was nearly identical to that in the control group, and the great majority of other studies have shown similar results (Table IV). 2. The incidence of cardiovascular disease is not correlated with the duration of OC use. In the 1981 analysis of the Royal College study the increased risk of mortality from circulatory disease was not found to be significantly different among those who had used OCs for less than 2 years and those who had used them for more than 8 years or for varying intermediate durations 13 (Table V). 3. A recent study of cynomolgus macaque monkeys indicates that OCs may have a protective effect against the development of atherosclerosis, even though the ingestion of certain OCs is associated with decreased levels of high-density lipoproteincholesterol (HDL-C). 14 In this well-performed study, four groups of monkeys were fed an atherogenic diet for 2 years. The groups consisted of (1) control males, (2) control females, (3) females in whom an intravaginal ring that released only levonorgestrel was constantly
1656 Mishell
June 1988 Am J Obstet Gynecol
Table VI. Extent of coronary artery atherosclerosis in animals with plasma total cholesterol/HDL-C <25 Mean plasma total Coronary artery cholesterol/ HDL-C intimal area
Males (n = 14) Control females (n = 14) Oral contraceptive
11.9±1.5 10.3 ± 1.2 12.0 ± 2.2
0.532 ± 0.114* 0.329 ± 0.085t 0.059 ± 0.034
15.0 ± 1.7
0.503 ± 0.156*
(n = 9)
Intravaginal ring (n = 11)
From Adams MR, Clarkson TB, Koritnik DR, et al. Contraceptive steroids and coronary artery atherosclerosis in cynomolgus macaques. Fertil Steril 1987;47:1010-8. Values represent mean ± SEM. *p < 0.03 compared with oral contraceptive. tp < 0.05 compared with oral contraceptive.
Table VII. Ratio of observed to expected events by estrogen dose in the United Kingdom, 1974 to 1977 Ethinyl estradiol Event
50 pg
30 /Lg
Venous deaths Nonvenous deaths Ischemic heart disease Cerebrovascular accident Pregnancy
1.40 1.52 1.48 1.20 0.62
0.65 0.53* 0.54* 0.80 1.33*
From Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30-f.tg oestrogen preparations. Br Med J 1980;280: 1157-61. *p < 0.05.
used, and (4) females who ingested an OC formulation containing ethinyl estradiol and norgestrel in a dosage comparable to the human dose. At the end of 2 years it was found that HDL-C levels were lowered significantly in both treatment groups; the animals wearing the intravaginal ring and those ingesting OCs compared with female controls. In both the treatment groups, the total cholesterol/HDL-C ratios were significantly higher in the treatment groups than in the control females. At the end of 2 years the animals were killed, and the area of atherosclerosis in the coronary arteries was carefully measured. Although the area of atherosclerosis correlated negatively with the HDL-C levels (Fig. 1) and positively with the cholesterol/HDL-C levels (Fig. 2), the group ingesting the formulation with both norgestrel and ethinyl estradiol had a significantly smaller area of atherosclerosis than did the control females (Table VI). Inasmuch as the animals wearing the levonorgestrel-releasing intravaginal ring that did not
contain ethinyl estradiol had an increased area of atherosclerosis compared with the control females, it appears that the ethinyl estradiol in the OCs protects gainst atherosclerosis. Because the estrogenic component of the formulation causes thrombosis, further indirect evidence indicating that the cardiovascular disease is related to 1 thrombosis is provided in that the incidence of both arterial and venous cardiovascular disease is directly correlated with the amount of estrogen ingested in the formulation. Several investigators have shown that the amount of hepatic globulin synthesis is directly correlated with the amount of ethinyl estradiol ingested. 15 · 16 Meade et al. 17 reported that a significantly greater increase in factors VII and X and fibrinogen occurred in women ingesting formulations containing 50 j.Lg ethinyl estradiol than in those using formulations with 30 j.Lg ethinyl estradiol. In addition to studies linking the incidence of venous thrombosis with the amount of estrogen ingested in the formulation, both Mann 18 and Meade et al. 17 have reported that the incidence of cerebral thrombosis, coronary thrombosis, ischemic heart disease, and arterial venous disease, including nonvenous deaths, is correlated with the dose of estrogen ingested. Meade et al. reported that the observed/ expected ratio of arterial vascular disease is significantly less among women ingesting formulations with 30 f.Lg estrogen than those ingesting formulations with 50 f.Lg (Table VII). Recent epidemiologic data
The data derived from the epidemiologic data summarized previously, on which current oral contraception prescribing practice is based, are no longer relevant. This statement is based on the following conclusions: First, potential OC users are now screened for risk factors. Oral contraceptives are generally not prescribed for women who have hypertension, diabetes, or hypercholesterolemia or for women older than age 35 years who smoke. Each of these conditions can cause arterial narrowing and increase the chance of thrombus formation. Second, according to data reported by the U.S. FooL and Drug Administration, the use of OC formulations with <50 f.Lg estrogen has been steadily increasing in the United States since they were introduced in 1974. According to these data the estimated percentage of total OC prescriptions that were written for formulations with <50 j.Lg estrogen increased from 5% in 1975 to 28% in 1980, to 52% in 1983, and reached 75% in 1987. A cohort study of OC use and cardiovascular disease was instituted by Porter et al. 19. 21 in 1979; the results have appeared in three publications. In these studies
Volume 158 Number 6, Part 2
the incidence of cardiovascular disease was determined in healthy users of OCs enrolled in a prepaid health plan in Washington State. Data excluded from analysis included those for women who had been treated for hypertension or diabetes or had a history of thromboembolism, heart attack, cerebrovascular accident, recent surgery, or chronic illness that could predispose the women to arterial or venous thrombosis. Data for OC users who smoked were not excluded from analysis. The first report analyzed data on a population base of more than 40,000 women aged 18 to 44 years studied from 1977 to 1979.' 9 In this time period there were no heart attacks in the more than 10,000 Qsers of OCs or in the more than 30,000 controls. Seven women, all nonusers ofOCs, had cerebrovascular accidents during this period. There was a significantly increased risk (RR = 8.3) for venous thrombosis among OC users compared with nonusers. The second report of the study provided data on the two cohorts of women between 1980 and 1982!" During this period in which more than 65,000 women were studied, one nonuser of OCs had a myocardial infarction, and seven had cerebrovascular accidents. None of the OC users had a myocardial infarction, and only one user had a cerebrovascular accident. The risk ratio for OC use and cerebrovascular accident was 0.9. Although the risk of diagnosis of venous thrombosis was significantly higher in OC users than in nonusers, the relative risk dropped from 8.3 to 2.8, most likely related to a 23% increase in use of formulations containing <30 t-Lg estrogen in the latter time period. The latest report of this study analyzed mortality among OC users during the 6 years from 1977 to 1982. During this time 11 nonusers of OCs died of cardiovascular diseases; no users died of cardiovascular disease. Comment
The data reported from recent epidemiologic studies indicate that the use of OC formulations containing <50 t-Lg estrogen by healthy, nonsmoking women, including those in the group 35 to 44 years of age, is not associated with an increased risk of arterial cardiovascular disease, specifically myocardial infarction and cerebrovascular accidents. Furthermore, the recent study using monkeys 14 supports the concept that the use of OCs containing estrogen may help protect older premenopausal women against the development of coronary atherosclerosis, just as exogenous estrogen administered helps to protect postmenopausal women from myocardial infarction. 22 Physicians may conclude from these studies that it is not contraindicated to use low estrogen dose OCs in healthy, nonsmoking, premenopausal women between 35 and 45 years of age
Use of OCs in women of older reproductive age
1657
who are at risk of pregnancy and who do not wish to use other methods of contraception. REFERENCES 1. Tietze C. New estimates of mortality associated with fertility control. Fam Plann Perspect 1977;9:74-6. 2. Mann Jl, Inman WH, Thorogood M. Oral contraceptive use in older women and fatal myocardial infarction. Br Medj 1976;2:445-7. 3. Mannjl, Inman WH. Oral contraceptives and death from myocardial infarction. Br Med J 1975;2:245-8. 4. Mann JI, Thorogood M, Walter WE, et al. Oral contraceptives and myocardial infarction in young women. Br Med J 1975;3:631-2. 5. Mann Jl, Vessey M, Thorogood M, et al. Myocardial infraction in young women with special reference to oral contraceptive practice. Br Med J 1975;2:241-5. 6. Vessey MP, McPherson K, Johnson B. Mortality among women participating in the Oxford Family Planning Association contraceptive study. Lancet 1977;2:731-3. 7. Royal College of General Practitioners' Oral Contraceptive Study. Mortality among oral contraceptives users. Lancet 1977;2:727-31. 8. Jick H, Dinan B, Rothman KJ. Oral contraceptives and nonfatal myocardial infarction. JAMA 1978;239: 1403-6. 9. Shapiro S, Slone D, Rosenberg L, et al. Oral contraceptive use in relation to myocardial infarction. Lancet 1979; 1:743-6. 10. Slone D, Shapiro S, Kaufman DW, et al. Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N Eng! J Med 1981 ;305:420-4. II. Ramcharan S, Pellegrin FA, Ray RM, et al. The Walnut Creek Contraceptive Drug Study: a prospective study of the side effects of oral contraceptives, vol 3. Bethesda, Maryland: National Institutes of Health: 1981; NIH publication no 81-564. 12. Mann JI, Doll R, Thorogood M, Vessey MP, Waters WE. Risk factors for myocardial infarction in young women. Br J Prev Soc Med 1976;30:94-100. · 13. Royal College of General Practitioners' Oral Contraceptive Study. Further analysis of mortality in oral contraceptive users. Lancet 1981;1:541-3. 14. Adams MR, Clarkson TB, Koritnik DR, et al. Contraceptive steroids and coronary artery atherosclerosis in cynomolgus macaques. Fertil Steril 1987;47:1010-8. 15. Meade TW. Oral contraceptives, clotting factors, and thrombosis. AMj 0BSTET GYNECOL 1982;142:758-61. 16. Moore DE, Kawagoe S, Davajan V, et al. An in vivo system in man for quantitation of estrogenicity. I I. Pharmacologic changes iri. binding capacity of serum corticosteroidbinding globulin induced by conjugated estrogens, mestranol, and ethinyJ estradiol. AM j 0BSTET GYNECOL 1978; 130;482-6. 17. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30-f.l.g oestrogen preparations. Br Med J 1980;280: 1157-61. 18. Mann JI. Progestogens in cardiovascular disease: an introduction to the epidemiologic data. AM J OBSTET GvNECOL 1982;142:752-7. 19. Porter JB, Hunter JR, Danielson DA, et al. Oral contraceptives and nonfatal vascular disease: recent experience. Obstet Gynecol 1982;59:299-302. 20. Porter JB, Hunter JR, Jick H, et al. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol 1985;66: l-4. 21. Porter JB, Hershel J, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987;70:29-32. 22. Stampfer MJ, Willet WC, Colditz GA. Postmenopausal estrogen use and heart disease. N Eng! J Med 1986; 315:125.
June 1988
Am J Obstet Gynecol
4. 5.
6. 7. 8. 9.
10.
11. 12.
and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30-t..Lg oestrogen preparations. Br Med J 1980;280: 1157-61. Royal College of General Practitioners. Oral contraceptives, venous thrombosis, and varicose veins. J R Coli Gen Pract 1978;28:393-9. Royal College of General Practitioners. Effect on hypertension and benign breast disease of progestogen component in combined oral contraceptives. Lancet 1977; 1: 624. Kay CR. The happiness pill? J R Coli Gen Pract 1980;30:819. "Digest." British pill studies stress importance of relation between progestogen content and vascular disease. Fam Plan Perspect 1980; 12:262-4. Poller L, Thompson JM. Clotting factors during oral contraception: further report. Br Med J 1966;2:23-5. Stanwell-Smith R, Meade TW. Hormone replacement therapy for menopausal women: a review of its effect on haemostatic function, lipids, and blood pressure. Adv Drug React Ac Pois Rev 1984;4:187-210. Meade TW, Chakrabarti R, Haines AP, North WRS, Stirling Y. Haemostatic, lipid and blood-pressure profiles of women on oral contraceptives containing 50 f..Lg or 30 t..Lg oestrogen. Lancet 1977;2:948-51. Meade TW, Mellows S, Brozovic M, et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986;2:533-7. Henriksson P, Edhag 0. Orchidectomy versus oestrogen for prostatic cancer: cardiovascular effects. Br Med J 1986;2:413-5.
13. Henriksson P, Blomback M, Bratt G, Edhag 0, Eriksson A. Activators and inhibitors of coagulation and fibrinolysis in patients with prostatic cancer treated with oestrogen or orchidectomy. Thomb Res 1986;44:783-91. 14. Dalaker K, Hjermann I, Prydz H. A novel form of factor VII in plasma from men at risk for cardiovascular disease. Br J Haematol1985;61:315-22. 15. Gordon EM, Hellerstein HK, Ratnoff OD, Arafah BM, Yamashita TS. Augmented Hageman factor and prolactin 1 titers, enhanced cold activation of factor VII, and spontaneous shortening of prothrombin time in survivors of myocardial infarction.] Lab Clin Med 1987;109:409-13. 16. Miller GJ, Seghatchian MJ, Walter SJ, et al. An association between the factor VII coagulant activity and thrombin activity induced by surface/cold exposure of normal human plasma. Br J Haematol 1986;62:379-84. 17. Meade TW. The epidemiology of haemostatic and other variables in coronary artery disease. In: Verstraete M, Vermylenj, Lijnen HR, Arnoutj, eds. Thrombosis and haemostasis. Leuven: International Society on Thrombosis and Haemostasis and Leuven University Press, 1987:3760. 18. Meade TW, Chakrabarti R, Haines AP, North WRS, Stirling Y. Characteristics affecting fibrinolytic activity and plasma fibrinogen concentrations. Br Med J 1979; 1: 153-6. 19. Khaw K-T, Peart WS. Blood pressure and contraceptive use. Br Med J 1982;285:403-7.
Use of oral contraceptives in women of older reproductive age Daniel R. Mishell, Jr., MD Los Angeles, California Evidence of increased risk for cardiovascular disease in oral contraceptive users of older reproductive age is based on early data involving formulations containing higher doses of estrogen and progestin than those in use today. In addition, early studies included patients who would not receive oral contraceptives with today's more stringent prescribing criteria. When these data were carefully analyzed, a significant increase in myocardial infarction was noted only in oral contraceptive users with concomitant risk factors for cardiovascular disease. Analysis of other studies also showed a significant increase in the incidence of cardiovascular disease and mortality only in oral contraceptive users older than age 35 years who smoked. A recent long-term cohort study of women without risk factors for cardiovascular disease who mainly used oral contraceptives containing ,;so f..Lg estrogen showed no increased risk of myocardial infarction or cerebrovascular accident with oral contraceptive use. Use of oral contraceptives containing <50 f..Lg estrogen has not been shown to be associated with an increased risk of cardiovascular disease in healthy, nonsmoking women 35 to 45 years of age. (AM J OBSTET GYNECOL 1988;158:1652-7.)
Key words: Cardiovascular disease, oral contraceptives
From the Department of Obstetrics and G_~necology, University of Southern California School of Medicine. Reprint requests: Daniel R. Miskell, Jr., MD, Professor and Chairman, Department of Obstetrics and Gynecology, University of Southern California School of Medicine, 1240 N. Mission Road, Rm. L-1009, Los Angeles, CA 90033.
1652
In the United States most women of older reproductive age (35 to 45 years) who do not wish to conceive have available only four methods of pregnancy prevention: sterilization, barrier techniques, the progesterone-releasing intrauterine contraceptive de-
Volume 158 Number 6, Part 2
Use of OCs in women of older reproductive age 1653
Table I. Percent myocardial infarction according to risk factors, compared with controls Risk factor
0 1 Oral contraceptives Hyperlipidemia Smoking Hypertension Diabetes
2
Table II. Circulatory disease mortality rates (per 100,000 woman years) by age, smoking status, and oral contraceptive use
Myocardial infarction
Controls
18.9
64.0
5.4 5.4 16.2 6.8 1.4 27.0 18.9
4.5 0.5 16.5 9.5 0.0 4.5 0.5
From Mann JI, Doll R, Thorogood M, et al. Risk factors for myocardial infarction in young women. Br J Prev Soc Med 1976;30:94-100.
vice (IUD), and periodic abstinence. Each of these techniques has certain disadvantages. Surgical sterilization, even if performed by laparoscopy, is a major operative procedure requiring general anesthesia. Many women decide against sterilization because of the cost, inconvenience, and anesthetic risk of the procedure. Many of the barrier techniques, such as condoms and spermicides, must be used shortly before sexual intercourse and thus have a relatively high use-failure rate. Many women do not use these and other barrier techniques, such as the sponge and diaphragm, because of the inconvenience. Of the IUDs, the only one currently available in the United States is the progesterone-releasing IUD, which is costly, not easily obtained, and must be reinserted annually. The m
Mortality rate (No. of deaths) Age (yr)
Ever users
15-24 0.0 Nonsmokers Smokers 10.5 25-34 Nonsmokers 4.4 Smokers 14.2 35-44 Nonsmokers 21.5 Smokers 63.4 >45 Nonsmokers 52.4 206.7 Smokers
IControls
(0) (1)
0.0 (0) 0.0 (0)
(2) (6)
2.7 (1) 4.2 (1)
Ever users vs controls (95% confidence limits) Relative risk
1.6 3.4
(7) 6.4 (2) (18) 15.2 (3)
3.3 4.2*
(4) 11.4 (1) (17) 27.9 (2)
4.6 7.4*
From Royal College of General Practitioners' Oral Contraceptive Study. Further analysis of mortality in oral contraceptive users. Lancet 1981;1:541-3. *Significantly different.
United States will not prescribe OCs for healthy women older than age 35 years. The rationale for these decisions is based on old epidemiologic data. It is the purpose of this communication to review more recent epidemiologic studies and a recently published animal study that indicate that the current common practice of not prescribing OCs for older women may no longer be valid. Epidemiologic basis for not prescribing oral contraceptives for older women
The current product insert for OCs states that the mortality associated with their use in nonsmokers older than 40 years of age is higher than with any other method of contraception in this age group. This statement is derived from a study published by Tietze' in 1977, and a figure from this paper, derived from computerized data, appears in the product information brochure for many OCs. The data generated were based on several case control studies published by Mann et aJ.2·' and on two British cohort studies from the Oxford Family Planning Association 6 and the Royal College of General Practitioners 7 published between 1975 and 1977. These studies reported that women older than 35 to 40 years who used OCs had a significantly greater risk for fatal myocardial infarction or other cardiovascular cause of death than did women not using OCs. Between 1977 and 1981, additional case control studies 8• 10 and data from the Walnut Creek cohort study" confirmed that older women using OCs had a greater incidence of cardiovascular disease, particularly myocardial infarction, than controls did.
1654
Mishell
June 1988 Am J Obstet Gynecol
Table III. Walnut Creek Contraceptive Drug Study: Effect of oral contraceptive use on risk of diseases of circulatory system Standard rates Never used OCs
Disease
Acute myocardial infarction Ischemic heart disease Subarachnoid hemorrhage Cerebral thrombosis Arterial thrombosis Pulmonary embolism Thrombophlebitis
Current OC users
I
Relative risk
I
Past OC users
Current OC users
I
Past OC users
0.23
0.27
0.20
l.l
0.8
0.79
1.09
0.90
1.4
1.1
0.04
0.43
0.10
10.1 *
2.3*
0.24 0.24 0.38 0.51
0.53 0.76 0.22 0.42
0.29 0.24 0.29 0.48
2.2* 3.2* 0.6 0.8
1.2 1.0 0.0 1.8
From Ramcharan S, Pellegrin FA, Ray RM, et al. The Walnut Creek Contraceptive Drug Study: a prospective study of the side effects of oral contraceptives, vol. 3. Bethesda, Maryland: National Institutes of Health. 1981, NIH publication no 81-564. *Not significant overall; significant only in smokers 2::40 years of age.
Table IV. Oral contraceptive use in women aged 40 to 44 years dying of myocardial infarction Myocardial infarction n
Never used OCs Current OC users Ex-users of OCs
78 18 10
l
Table V. Circulatory disease* mortality rates with oral contraceptive use Duration of OC use (mo)
Controls
%
n
73.6 17.0 9.4
86 7 9
I
% 84.3 6.0 8.8
From Mann JI, Inman WH, Thorogood M. Oral contraceptive use in older women and fatal myocardial infarction. Br Med J 1976;2:445-7.
All of these studies were performed using OC formulations and prescribing criteria that were much different than those currently used. Each of the three cohort studies was initiated in 1968, when the dosage of both the estrogen and progestin component of the formulation was much greater than that currently prescribed. Likewise, the case control studies published in the late 1970s reflected data for women using higher dose formulations than those now used. The OC formulations with <50 IJ.g estrogen were not introduced until 1974 and were used by less than one fourth of OC users until 1980. Furthermore, until these studies were published the contraindications for OC use were also different from those currently advised. Prior to 1976 OCs were prescribed for women of any age, including those who smoked and those who had other risk factors for cardiovascular disease, such as preexisting hypertension, diabetes, and hypercholesterolemia. When some of these epidemiologic studies were analyzed for the pres-
0 1-24 25-48 49-72 73-96 o::97
Rate (per 100,000 women years)
7.0 32.5 23.5 28.4 32.3 20.4
(10) (5) (4) (5) (5) (4)
Relative risk
1.0 4.6 3.4 4.1 4.6 2.9
From Royal College of General Practitioners' Oral Contraceptive Study. Further analysis of mortality in oral contraceptive users. Lancet 1981; I :541-3. *International Classification of Diseases, Injuries, and Causes of Death, 390-458.
ence of these independent risk factors for myocardial infarction, it was found that a significantly increased risk of myocardial infarction occurred only in OC users with these risk factors that could cause narrowing of the lumen of the coronary arteries. In a reanalysis of their data, Mann et al. 2 · 12 found that the frequency of use of OCs in women older than 40 years of age without these risk factors who died of myocardial infarction was nearly identical to the frequency of OC use in the control group (Table 1). The incidence of OC use in the women with myocardial infarction was only higher in women with a history of one or more of these independent risk factors than in the controls. Analysis of circulatory disease mortality rates in the Royal College of General Practitioners' prospective study published in 1981 revealed that a significant increase in circulatory disease mortality occurred only in OC users older than age 35 years who also smoked, whereas the risk of mortality from circulatory disease
Use of OCs in women of older reproductive age 1655
Volume 158 Number 6, Part 2
1.5
•
1.0
Males
•
•
Males
1.5 r - 0.63
0.5 1.5
•
0.5
1.5
r - 0.49
•
'E
.s.
0
C1l
.•
• Intravaginal Ring
1.0
r - 0.54
0.48
0.5 0
(ii
1.5
E
Control Females
1.0
~
c
0.5 0
1.0
Intravaginal Ring
•
•
0.50
0.5
1.5
Oral Contraceptive
1.0 0.5 0
= 0.75
0
Control Females
1.0
1.5
•
0.5
0
Intimal Area
•
1.0
r - 0.57
0 1.5 1.0
• Oral Contraceptive • r = 0.62
0.5
20
40
60
80
100 Plasma HDL Cholesterol ( mg/ dl)
Fig. 1. Relationship between plasma HDL-C concentrations and extent of coronary artery atherosclerosis among four experimental groups. For all r values, p ,;;; 0.05. (From Adams MR, Clarkson TB, Koritnik DR, et al. Fertil Steril 1987; 47:1010-8.)
was not significantly increased for nonsmoking OC users of any age, even those older than age 45 years 13 (Table II). The final report of the Walnut Creek Contraceptive Drug Study showed that there was no difference in the incidence of myocardial infarction in current or past OC users and women who never used OCs" (Table III). Although there was found to be a significant increase in the incidence of cerebral arterial vascular disease among OC users in this study, it occurred only in women older than age 40 years who also smoked. Thus even in these older epidemiologic studies, where the amount of steroids in the formulation used was higher than that used today, an increased incidence of cardiovascular disease in OC users occurred only in women who smoked or had other independent risk factors. Cause of cardiovascular disease associated with oral contraception
The cause of the cardiovascular disease occurring in certain users ofOCs appears to be thrombosis, and thus is related to the estrogen component and not to atherosclerosis, which could be related to the progestogen component of the formulation. Evidence for this statement is based on the following three facts:
0
10 Total Plasma Cholesterol: HDL Cholesterol
Fig. 2. Relationship between plasma total cholesterol/HDL-C concentrations among four experimental groups. For all r values, p < 0.05 and extent of coronary artery atherosclerosis. (From Adams MR, Clarkson TB, Koritnik DR, et al. Fertil Steril 1987;47: 1010-8.)
1. Nearly all of the published epidemiologic studies indicate that there is no increased risk of myocardial infarction in ex-users of OCs. In the large study by Mann et a!! the incidence of myocardial infarction in ex-users of OCs was nearly identical to that in the control group, and the great majority of other studies have shown similar results (Table IV). 2. The incidence of cardiovascular disease is not correlated with the duration of OC use. In the 1981 analysis of the Royal College study the increased risk of mortality from circulatory disease was not found to be significantly different among those who had used OCs for less than 2 years and those who had used them for more than 8 years or for varying intermediate durations 13 (Table V). 3. A recent study of cynomolgus macaque monkeys indicates that OCs may have a protective effect against the development of atherosclerosis, even though the ingestion of certain OCs is associated with decreased levels of high-density lipoproteincholesterol (HDL-C). 14 In this well-performed study, four groups of monkeys were fed an atherogenic diet for 2 years. The groups consisted of (1) control males, (2) control females, (3) females in whom an intravaginal ring that released only levonorgestrel was constantly
1656 Mishell
June 1988 Am J Obstet Gynecol
Table VI. Extent of coronary artery atherosclerosis in animals with plasma total cholesterol/HDL-C <25 Mean plasma total Coronary artery cholesterol/ HDL-C intimal area
Males (n = 14) Control females (n = 14) Oral contraceptive
11.9±1.5 10.3 ± 1.2 12.0 ± 2.2
0.532 ± 0.114* 0.329 ± 0.085t 0.059 ± 0.034
15.0 ± 1.7
0.503 ± 0.156*
(n = 9)
Intravaginal ring (n = 11)
From Adams MR, Clarkson TB, Koritnik DR, et al. Contraceptive steroids and coronary artery atherosclerosis in cynomolgus macaques. Fertil Steril 1987;47:1010-8. Values represent mean ± SEM. *p < 0.03 compared with oral contraceptive. tp < 0.05 compared with oral contraceptive.
Table VII. Ratio of observed to expected events by estrogen dose in the United Kingdom, 1974 to 1977 Ethinyl estradiol Event
50 pg
30 /Lg
Venous deaths Nonvenous deaths Ischemic heart disease Cerebrovascular accident Pregnancy
1.40 1.52 1.48 1.20 0.62
0.65 0.53* 0.54* 0.80 1.33*
From Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30-f.tg oestrogen preparations. Br Med J 1980;280: 1157-61. *p < 0.05.
used, and (4) females who ingested an OC formulation containing ethinyl estradiol and norgestrel in a dosage comparable to the human dose. At the end of 2 years it was found that HDL-C levels were lowered significantly in both treatment groups; the animals wearing the intravaginal ring and those ingesting OCs compared with female controls. In both the treatment groups, the total cholesterol/HDL-C ratios were significantly higher in the treatment groups than in the control females. At the end of 2 years the animals were killed, and the area of atherosclerosis in the coronary arteries was carefully measured. Although the area of atherosclerosis correlated negatively with the HDL-C levels (Fig. 1) and positively with the cholesterol/HDL-C levels (Fig. 2), the group ingesting the formulation with both norgestrel and ethinyl estradiol had a significantly smaller area of atherosclerosis than did the control females (Table VI). Inasmuch as the animals wearing the levonorgestrel-releasing intravaginal ring that did not
contain ethinyl estradiol had an increased area of atherosclerosis compared with the control females, it appears that the ethinyl estradiol in the OCs protects gainst atherosclerosis. Because the estrogenic component of the formulation causes thrombosis, further indirect evidence indicating that the cardiovascular disease is related to 1 thrombosis is provided in that the incidence of both arterial and venous cardiovascular disease is directly correlated with the amount of estrogen ingested in the formulation. Several investigators have shown that the amount of hepatic globulin synthesis is directly correlated with the amount of ethinyl estradiol ingested. 15 · 16 Meade et al. 17 reported that a significantly greater increase in factors VII and X and fibrinogen occurred in women ingesting formulations containing 50 j.Lg ethinyl estradiol than in those using formulations with 30 j.Lg ethinyl estradiol. In addition to studies linking the incidence of venous thrombosis with the amount of estrogen ingested in the formulation, both Mann 18 and Meade et al. 17 have reported that the incidence of cerebral thrombosis, coronary thrombosis, ischemic heart disease, and arterial venous disease, including nonvenous deaths, is correlated with the dose of estrogen ingested. Meade et al. reported that the observed/ expected ratio of arterial vascular disease is significantly less among women ingesting formulations with 30 f.Lg estrogen than those ingesting formulations with 50 f.Lg (Table VII). Recent epidemiologic data
The data derived from the epidemiologic data summarized previously, on which current oral contraception prescribing practice is based, are no longer relevant. This statement is based on the following conclusions: First, potential OC users are now screened for risk factors. Oral contraceptives are generally not prescribed for women who have hypertension, diabetes, or hypercholesterolemia or for women older than age 35 years who smoke. Each of these conditions can cause arterial narrowing and increase the chance of thrombus formation. Second, according to data reported by the U.S. FooL and Drug Administration, the use of OC formulations with <50 f.Lg estrogen has been steadily increasing in the United States since they were introduced in 1974. According to these data the estimated percentage of total OC prescriptions that were written for formulations with <50 j.Lg estrogen increased from 5% in 1975 to 28% in 1980, to 52% in 1983, and reached 75% in 1987. A cohort study of OC use and cardiovascular disease was instituted by Porter et al. 19. 21 in 1979; the results have appeared in three publications. In these studies
Volume 158 Number 6, Part 2
the incidence of cardiovascular disease was determined in healthy users of OCs enrolled in a prepaid health plan in Washington State. Data excluded from analysis included those for women who had been treated for hypertension or diabetes or had a history of thromboembolism, heart attack, cerebrovascular accident, recent surgery, or chronic illness that could predispose the women to arterial or venous thrombosis. Data for OC users who smoked were not excluded from analysis. The first report analyzed data on a population base of more than 40,000 women aged 18 to 44 years studied from 1977 to 1979.' 9 In this time period there were no heart attacks in the more than 10,000 Qsers of OCs or in the more than 30,000 controls. Seven women, all nonusers ofOCs, had cerebrovascular accidents during this period. There was a significantly increased risk (RR = 8.3) for venous thrombosis among OC users compared with nonusers. The second report of the study provided data on the two cohorts of women between 1980 and 1982!" During this period in which more than 65,000 women were studied, one nonuser of OCs had a myocardial infarction, and seven had cerebrovascular accidents. None of the OC users had a myocardial infarction, and only one user had a cerebrovascular accident. The risk ratio for OC use and cerebrovascular accident was 0.9. Although the risk of diagnosis of venous thrombosis was significantly higher in OC users than in nonusers, the relative risk dropped from 8.3 to 2.8, most likely related to a 23% increase in use of formulations containing <30 t-Lg estrogen in the latter time period. The latest report of this study analyzed mortality among OC users during the 6 years from 1977 to 1982. During this time 11 nonusers of OCs died of cardiovascular diseases; no users died of cardiovascular disease. Comment
The data reported from recent epidemiologic studies indicate that the use of OC formulations containing <50 t-Lg estrogen by healthy, nonsmoking women, including those in the group 35 to 44 years of age, is not associated with an increased risk of arterial cardiovascular disease, specifically myocardial infarction and cerebrovascular accidents. Furthermore, the recent study using monkeys 14 supports the concept that the use of OCs containing estrogen may help protect older premenopausal women against the development of coronary atherosclerosis, just as exogenous estrogen administered helps to protect postmenopausal women from myocardial infarction. 22 Physicians may conclude from these studies that it is not contraindicated to use low estrogen dose OCs in healthy, nonsmoking, premenopausal women between 35 and 45 years of age
Use of OCs in women of older reproductive age
1657
who are at risk of pregnancy and who do not wish to use other methods of contraception. REFERENCES 1. Tietze C. New estimates of mortality associated with fertility control. Fam Plann Perspect 1977;9:74-6. 2. Mann Jl, Inman WH, Thorogood M. Oral contraceptive use in older women and fatal myocardial infarction. Br Medj 1976;2:445-7. 3. Mannjl, Inman WH. Oral contraceptives and death from myocardial infarction. Br Med J 1975;2:245-8. 4. Mann JI, Thorogood M, Walter WE, et al. Oral contraceptives and myocardial infarction in young women. Br Med J 1975;3:631-2. 5. Mann Jl, Vessey M, Thorogood M, et al. Myocardial infraction in young women with special reference to oral contraceptive practice. Br Med J 1975;2:241-5. 6. Vessey MP, McPherson K, Johnson B. Mortality among women participating in the Oxford Family Planning Association contraceptive study. Lancet 1977;2:731-3. 7. Royal College of General Practitioners' Oral Contraceptive Study. Mortality among oral contraceptives users. Lancet 1977;2:727-31. 8. Jick H, Dinan B, Rothman KJ. Oral contraceptives and nonfatal myocardial infarction. JAMA 1978;239: 1403-6. 9. Shapiro S, Slone D, Rosenberg L, et al. Oral contraceptive use in relation to myocardial infarction. Lancet 1979; 1:743-6. 10. Slone D, Shapiro S, Kaufman DW, et al. Risk of myocardial infarction in relation to current and discontinued use of oral contraceptives. N Eng! J Med 1981 ;305:420-4. II. Ramcharan S, Pellegrin FA, Ray RM, et al. The Walnut Creek Contraceptive Drug Study: a prospective study of the side effects of oral contraceptives, vol 3. Bethesda, Maryland: National Institutes of Health: 1981; NIH publication no 81-564. 12. Mann JI, Doll R, Thorogood M, Vessey MP, Waters WE. Risk factors for myocardial infarction in young women. Br J Prev Soc Med 1976;30:94-100. · 13. Royal College of General Practitioners' Oral Contraceptive Study. Further analysis of mortality in oral contraceptive users. Lancet 1981;1:541-3. 14. Adams MR, Clarkson TB, Koritnik DR, et al. Contraceptive steroids and coronary artery atherosclerosis in cynomolgus macaques. Fertil Steril 1987;47:1010-8. 15. Meade TW. Oral contraceptives, clotting factors, and thrombosis. AMj 0BSTET GYNECOL 1982;142:758-61. 16. Moore DE, Kawagoe S, Davajan V, et al. An in vivo system in man for quantitation of estrogenicity. I I. Pharmacologic changes iri. binding capacity of serum corticosteroidbinding globulin induced by conjugated estrogens, mestranol, and ethinyJ estradiol. AM j 0BSTET GYNECOL 1978; 130;482-6. 17. Meade TW, Greenberg G, Thompson SG. Progestogens and cardiovascular reactions associated with oral contraceptives and a comparison of the safety of 50- and 30-f.l.g oestrogen preparations. Br Med J 1980;280: 1157-61. 18. Mann JI. Progestogens in cardiovascular disease: an introduction to the epidemiologic data. AM J OBSTET GvNECOL 1982;142:752-7. 19. Porter JB, Hunter JR, Danielson DA, et al. Oral contraceptives and nonfatal vascular disease: recent experience. Obstet Gynecol 1982;59:299-302. 20. Porter JB, Hunter JR, Jick H, et al. Oral contraceptives and nonfatal vascular disease. Obstet Gynecol 1985;66: l-4. 21. Porter JB, Hershel J, Walker AM. Mortality among oral contraceptive users. Obstet Gynecol 1987;70:29-32. 22. Stampfer MJ, Willet WC, Colditz GA. Postmenopausal estrogen use and heart disease. N Eng! J Med 1986; 315:125.