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Contraceptive steroids, age, and the cardiovascular system
Contraceptive steroids, age, and the cardiovascular system EARL R. PLCNKETT, M.D .. PH.D., F.R.C.P.(C.)* London, Ontario, Canada There is evidence that women who use oral contraceptives may be at slightly greater risk of cardiovascular complications as their age increases beyond 35 years. Popular opinion has held that these risks were largely estrogen-related. At the same time, however, postmenopausal women taking natural estrogen alone or in association with minimal amounts of progestogen have not exhibited these increased risks when compared with untreated control subjects. New clinical data indicate that there is a progestogen dose-related decrease in high-density lipoprotein cholesterol. There is also some evidence that relates progestogen dosage to morbidity rates from circulatory disease. Therefore the smallest dose of both estrogen and progestogen consistent with contraceptive efficacy and reasonable cycle control must be sought for all steroid combinations. This applies particularly to oral contraception for the woman beyond 35 years of age. (AM. J. OBSTET. GYNECOL. 142:747, 1982.)
To PH Y s 1 c 1 AN s in general medicine, the term "steroid" refers to adrenocortical hormones, while to those of us in gynecology it implies estrogens and progestogens. This imprecision permitted either estrogens or progestogens to become synonymous with the combined oral contraceptiYe (OC). The loose terminology has created a misunderstanding about the impact of estrogens alone and has contributed to the delay in studying the metabolic effects of these hormones individually. The potential application of these hormones now extends from puberty until about 60 years or until death. In recent years a curious inconsistency has become apparent. Risks, particularly relating to circulatory complications, were found to increase in the middle of the third decade among women taking the OC. At the same time, postmenopausal women, who usually take so-called natural estrogens without progestogens, did not appear to suffer the same risk. Because the estrogen of the OC had become synonymous with vascular
From the Department of Obstetric; and Gynecology, Univenity of Western Ontario. Reprint requests: Earl R. Plunkett, M.D., Ph.D., F.R.C.P.(C.), Professor and Chairman, Department of Ob.1tetric1 and Gynecology, Univenity of Western Ontario, London, Ontario N6A 5Cl, Canada. *Chairman and Director, Canadian Committee to the Federal Minista of Health (Canada) on Human Reproduction. 0002-9378/82/060747+05$00.50/0 © 1982 The C. V. Mosby Co.
complications, many assumed that the difference lay between synthetic and natural hormones. \Vhile there may be a qualitative difference in metabolic impact, such discrepancies could be related to potency. There is about a 12- to 15-vear gap in our abilitv to prm·ide oral contraception without raising even modestly the relative risk. Currently. women tend to discontinue the pill at age 35 years either voluntarilv or on medical advice. The combined impact of smoking and the OC does indeed raise the risks markedh, especial!\ after age 35 years. Let us re\·iew the risks, clinical problems. and possible solutions for the woman who requires estrogen or estrogens and progestogens after age 35 years. There are many estimates of mortality risks in response to OC use. In 1979, Tietze and Lew it' presented such data that were based upon an updated, computerized mathematical model deri\·ed from the statistics of a number of clinical studies. Tietze and Lewit point out the increasing risks associated with pregnancy and increasing age. The maternal mortality rate ranges between 9.:j and 12.1 per 100,000 live births in women 15 to 29 years of age and increases to -!3.7 in the late third decade and to 6H.2 in the ·-lO- to .f.f-year-old group. Nonsmoking users of OCs between ages 15 and 29 years exhibit a mortalitY rate between 0.6 and 1.6 per 100,000 woman-years; this increases to 9 and 17.7 in the ~~5- to 39-year and -tO- to -++-year age groups, respectively. When smoking and pill use are combined.
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the rates in the latter two groups increase to 31.3 and 60.9, respectively. Tietze and Lewit indicated that barrier contraception with therapeutic abortion as "backup" is the safest approach to the problem. Mortality data relating to the intrauterine contraceptive device (IUD), presumably supported by termination, indicate similar safety with rates in the I A to 2. 7 range. If social. emotional, and moral philosophies could be discounted. then Tietze's numbers would provide at least some of the answers. We would still have to face. however, the effects of termination upon subsequent pregnancies and the potential effect of IUD-related peh·ic infiammatory disease on future fertility. For women ages :15 to 48 vears. tubal sterilization is a safe and efficient alternative. Unfortunately, these are the years when episodic anovulation and dysfunctional uterine bleeding become more common. Although many women prefer to avoid permanent sterilization. those who choose this option may find it necessary to resume using the OC to control bleeding. Others who have undergone surgery, including bilateral oophorectomy, or who have undergone spontaneous ovarian failure also may require estrogen with or without progestin. Obviously, there is a large number of women who, for reasons other than contraception, require consideration. The risk factors demand special attention in this age group. One of the major sources of data on risk factors and the OC is the ongoing study of the Royal College of General Practitioners (RCGP). 2 Within 14 months of study conception in 1968, 23,000 "users" of OCs and 23,000 nonuser controls were entered. In 1977, the RCGP:J published mortality data based on 56 users and 43 controls. The major causes of death among the users were circulatory, with a relative risk (RR) of 4.7 over the controls. That report indicated that the RR rose to 9.7 when the oral contraceptive had been taken for more than 5 years. This latter observation may not be true in the light of newer, expanded data. The most recent mortality figures from that study, published in March, 1981, analyzed the mortality data of 156 "ever users" and 93 controls. 4 Again, circulatory complications were the major problem, with an overall relative risk of 4.2. Mortality from cancer showed no difference, with rates of 30.0 for ever users and 31.5 for controls. Accidents and violence accounted for a mortality rate of 18.2 per 100,000 women-years in the ever users and 12.6 among controls. The overall mortality rate from all causes was 87.7 in the OC group and 64.4 in the controls, with a relative overall risk of 1.4. The various categories of circulatory disease among
~larch !5, I \!~2 .\n1. ]. OhsteL Gynecol.
current and tormer users and controls revealed an overall mortalitv rate of 28.6 for current users (RR .c 1.0). 30.9 for former users (RR = .f.3), and 7.2 tor controk An interesting aspect to these data involves the risb of those who had discontinued use n·rsu;, tho~e ,,·ho continued the OC until death. The RR l!lr nonrheumatic heart disease and hypertetbion was 6.-J. and 2.0 for current and former users, respectively. On the other hand, in cerebrovascular deaths the current user-; exhibited a relative risk of 2.0. while former users had an RR of 3.6. It is rather surprising that the relatin· risks of circulaton· diseases remain elevated after discontinuation of steroids. This suggests that the disease process mav have begun before the medication 1\:ts stopped. ludeed, whether recognized or not. rhc decision mav have been prompted by early symptom.,. The mortality related to cardiovascular disease again confirms an increased risk with age and/or smoking. Ever users who were nonsmokers experienced a mortality rate of 0 at less than 25 years of age, rising to 52 A per 100,000 woman-vears (RR = 4.6) after age .f!'i years. Among ever usen, who smoked. the rate was I 0.:) at less than 25 years of age and rose to 206.7 (RR = 7 A 1 at age .f5 vears and beyond. In addition. of the I 7 encr users who died of subarachnoid hemorrhage, 15 were age 35 vears or older. Because other risk factors mav he more likely to apply to the older woman, I will comment on two of these. In the RCGP mortality data of 1977. evidence suggested that longer use of the OCs enhanced rhe risk of mortalitv/ Recent data indicate no real difference between those on medication for less than 2 or more than H years." On the other hand, increasing paritv, although standardized for age, smoking, and socioeconomic status, was associated with an increasing mortality rate from circulatory problems. In March, 1981, Vessey and colleagues;; presented a brief update of the mortality data from the Oxford Family Planning Association study. This project also began in 1968 and entered more than 17,000 cases during the next 6 years. Fifty-six percent used OCs, 25% barrier methods, and 19% the I LD. Of the HI deaths reviewed, OC users displa\ed a mortality rate of 12.3 per 100,000 women-years as opposed to a rate of 29.9 in the RCGP report. A number of possible explanations for the differences come to mind. Since cases were entered into the Oxford stud~ for more than 4 years beyond the closing of the RCGP project, the actual subject ages may be younger in the Oxford data. Furthermore, there is the possibility that pills of lower dosage are more prevalent in the more recent study. Of course, as the studv progresses and
Volume 142 C\!umber 6, Part 2
Contraceptive steroids, age, and cardiovascular system
more data accumulate, greater agreement may become evident in certain of these mortality categories. As indicated at the beginning, we find increasing risks of major circulatory diseases among users of steroid contraceptives from age 30 years onward. At the same time, physicians have continued to prescribe noncontraceptive estrogens for postmenopausal women. In spite of such treatment being used widely in women ages ~5 to 65 years and older, over a span of 40 years the epidemic of circulatory catastrophes has not appeared. In a report of the Boston Collaborative Drug Surveillance Program 6 in 197 4, an epidemiologic survey indicated major differences in the incidence of venous thromboembolism among women taking OCs, women taking estrogen for menopausal reasons, and nontreated patients. For comparison I have converted the data to an incidence based upon a common denominator of 100,000. The results are as follows: 9.34 per 100,000 population of nonusers, 18.18 per 100,000 taking menopausal estrogen, and 68.06 per 100,000 taking oral contraceptives (estrogen plus progestogen). In the 1979 report based upon the Walnut Creek Contraceptive Drug Study, Petitti and associates 7 could show no increased risk for myocardial infarction, subarachnoid hemorrhage, "other" stroke, or venous thromboembolism among those taking menopausal estrogens. It is worth noting that among the controls (who took no estrogen) there were two subjects with m\ocardial infarction who were receiving only progestogens. In this study, though, the RR for users ofOCs was only O.H for myocardial infarction and 0.6 for "other" strokes: it was 6.3 and 6.7 for subarachnoid hemorrhage and venous thrombosis, respectively. 1n the four vascular disease categories the RR for use of menopausal estrogens ranged between a low of 0. 7 and a high of only 1.6. In a retrospective study of 610 hypoestrogenic patients, Hammond and co-workers 8 carefully categorized the state of health at the time of entry and any new health problems that developed over the following 5 years. Half of these patients were treated with conjugated equine estrogen, and the others remained untreated. ;-..- o difference was noted in the incidence of hvpertension or weight gain. Although at entry the incidence of cardiovascular disease was the same in the two populations, a significant excess of such disease appeared in the nontreated as opposed to estrogentreated women after 5 years. It should be pointed out that the mean age at entry of the estrogen-treated subjects was 42.9 years while that of the untreated controls was 49.6 years. Because this is bv no means a random design, it would be wrong
to conclude that estrogen decreased the risk. Nevertheless, since 28.5% of the controls developed circulatory diseases, compared with 9.3% of the estrogen group (p < 0.001), there is certainly no evidence of increased risk. Nachtigal! and colleagues 9 describe a double-blind, random, 10-year study of 84 carefully matched pairs of women in which those treated received 2.5 mg of conjugated equine estrogen in cycles with 7 days of medroxyprogesterone at 10 mg. The mean blood pressures did not differ significantly, nor did body weight or blood glucose levels. The beta lipoproteins were lowered by estrogen. Most importantly, there were three myocardial infarctions among the controls and only one in the treated group. Again, the authors make no claim for an estrogen-protective effect, but there was no increased risk. These and many other studies have failed to demonstrate a significant risk of vascular disease during menopausal estrogen therapy. The fact that the Nachtigal! series included 7 days of medroxyprogesterone deserves comment. Hirvonen and associates 10 studied the effect of adding progestogen in sequential fashion to a cyclic estradiol valerate regimen. Three groups of six postmenopausal women received estrogen only in the first cycle. During the second and third cycles, progestogens were added for the last 7 days. The daily dose was 10 mg of medroxyprogesterone, 10 mg of norethindrone (NET) acetate, and 0.5 mg ofl-norgestrel for Groups 1, 2, and 3, respectively. Total cholesterol decreased in the first "estrogen" cycle and continued to decline further with the addition of the three progestogens. High-density lipoprotein cholesterol (HDL-C) increased slightly in the first cycle but diminished significantly with addition of the progestogens. The authors preferred medroxyprogesterone since it did not depress the HDL-C as much as the other progestogens. They overlooked the fact that the doses of NET acetate and l-norgestrel were very large. Indeed, we have found that a dose of 3 7.5 J.Lg (not 500) of /-norgestrel is sufficient to suppress the endometrium over a more prolonged time of treatment. Since the major purpose of adding progestogen is to prevent endometrial hyperplasia and minimize risks of cancer, 10 days of low-dose progestogen have been found to be more effective than large doses over shorter periods. Hirvonen and colleagues helped to demonstrate that progestogen could add to the risk of vascular complications during noncontraceptive estrogen treatment. Nevertheless, the doses of progestogen used were excessive in at least two ofthe groups. Based on data from the RCGP study, Kay 11 showed evidence of a dose rela-
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Plunkett
tionship between the progestogen content of OCs and ( irculatorv complications. There i.-. considerable e1idence that decreasing I-lDIA. len~ls and/or HDL-C/total cholesterol ratio is :t-;s"ciated "·it h increased risk of arteriosclerotic circulaton disordns. Therefore, the impact of OCs upon these indin's demands consideration, especialh· in the older subjcch. Larsson-( :ohn and associates 1" presented com paratin: data relating to the effect of four formulations on these parameters. These consisted of ethim·l estradiol/ f-norgcst rei in the following microgram proportions: ~0/:.!:"iO. c\0/:2~>0, :)()/ 130, and a triphasic preparation. The latter consisted of 30/50 for 6 davs, W/7S for 5 ([;l\ s, and :HI/I :23 f()r I 0 davs. ·fhe mean dailv dose therefore 11 as '\:2.:1/9 l.li. llw llDL-C: \\·as measured before and at I, 3, and ti lllonth-; alter treatment. Depression of the 1:dnes 11as gTcdtc-.t in the t110 preparations containing :230 ~J-g of progcqogcn and unchanged with the low-content t riphasic formulation. The HDL-C/total cholesterol ratio 1\;ts signiftt:tnth depressed lJI the larger doses (p < 0 .()()I) and mtKh less so ( p < (J.05) bv the :W/150 and triphasic preparations. Hriggs and Briggs 1" recentlv reported similar lipid data im oh ing :)0 or :15 ~J-g of ethim I estradiol and difkrent progestins. There were two l\ET formulations, and again. the larger dose had a greater effect on the HDL-C. total cholesterol. and trigln:erides. Comment
!he lll<>'it significant complication of oral contraception is till' increased risk of circulatory disease, 1rhich ma1 lw e~pt csscd a;, mvoe ol the most consistent ;l!ld significtnt. !he medical profession has tended to equate oral u>tllraccptivc (estrogen plus progestogen) effects with estmgen. Recause of the risk with OC use in women be1ond :\0 to :l!'i vcars of age, there has been an effort to sh"11· that still older women (postmenopausal) \\"CIT at l'l ct1 greater risk of cardioYasndar disease during noncont r;tccptin· estrogen therapY. Ait hough further
\larch 15, 191>2
Am . .J. Obstet. Gvnecol.
data are required, no convincing evidence has emerged that such is the case. Menopausal women are usual II treated with natural estrogen only or estrogen in cor1 junction with minimal doses of progestogen. The lack of demonstrated complications compared with OC usc. therefore, must be related to such factors a;, dmagc of estrogen (biological potency), natural 1crsus s1nthetic estrogens (qualitative difference), total lack or minimal use of progestogens, or a reversal of intrinsic response to estrogen in the women more than 1:-: vears of age when compared to those 35 to Hi vear" nt age. Clinical data are now appearing which mmpare risks of circulatory disease in response to two or I hree dit~ ferent doses of the same progestogen combined with identical or similar amounts of the same estrogen. The higher levels of progestogen appear to correlate with greater risks. These findings are further substantiated ll\ the metabolic effects of progestogen <>ll HDL-C and the HDL-C/total cholesterol ratio. .\It hough opinion differs about the qualitati1·e differC!Ke in metabolic effects between natural and svntheti( estrogens, at most this is of secondarv importance. The difference in dosage ami biological ctkctin~nes.-, between the two tvpcs of estrogens is also probabh of lesser consequence. It makes no sense to ~uggest arelersal in the metabolic response to estrogens in older women. For the more mature woman who needs contraception, surgical sterilization is likelv the >afest and most practical approach. Intrauterine de1 ices and other harrier methods with therapeutic abortion as h.Kkup might serve others. Smdies are required to prmc the efficacv, acceptabilitY, and safety olfornwlations with smaller progestogen doses. :\ow. certainlv, those older women who need steroid contraceptinn should he checked for e~isting risk factors. a
REFERENCES I. Tict1.c. C .. and l.ewit. S.: Life risks associated with relersihlc methods of fertility regulation, Int. .J. Gynecol. Ohstet. 16:"1'i6, 1979. 2. Roval College of General Practitioners: Oral Contracepti,·es and Health, London, 197-l, Putnam. :1. Beral, V .. principal author: Mortalitv among oral-
contraceptive users, Royal College of General Practitioners' Oral Contraception Study, Lancet 2:727, 1977. CL Layde, P.M., and Beral, V., principal aurhors: Royal College of General Practitioners' Oral Contraception Study: Further analysis of mortalitv in oral contraceptive users, Lancet 1:541, 1981.
\'olume 142 !\"umber 6, Part 2
5. Vessey, M.P., McPherson, K., and Yeates, D.: Mortality in oral contraceptive users, Lancet 1:549, 1981. (Letter to the editor.) 6. A report from the Boston Collaborative Drug Surveillance Program: Surgically confirmed gallbladder disease, venous thromboembolism and breast tumours in relation to postmenopausal estrogen therapy, N. Engl. ]. Med. 290:15, 1974. 7. Petitti, D. B., Wingerd, J., Pellegrin, F., et al.: Risk of vascular disease in women: Smoking, oral contraceptives, noncontraceptive estrogens and other factors, ]. A. M.A. 242:1150, 1979. H. Hammond, C. B.,Jelovsek, F. R., Lee, K. L., eta!.: Effects of long-term estrogen therapy, AM. J. 0BSTET. GYNECOL. 133:525, 1979. 9. :"Jachtigall, l.. E., Nachtigall, R. H., Nachtigal!, R. D.,
Contraceptive steroids, age, and cardiovascular system
10.
I I. 12.
13.
751
et a!.: Estrogen replacement therapy. II. A prospective study in the relationship to carcinoma and cardiovascular and metabolic problems, Obstet. Gynecol. 54:74, I 979. Hirvonen, E., Malkonen, M., and Mannen, V.: Effects of different progestogens on lipoproteins during postmenopausal replacement therapv, :"1. Engl. ]. Med. 304:560, 1981. Kay, C. R.: The happiness pill? James MacKenzie Lecture,]. R. Coli. Gen. Pract. 30:8,1980. Larsson-Cohn. U., Fagreus, L., Wallentin, L., et al.: In Greenblatt, R., editor: The Development of a New Triphasic Oral Contraceptive, Lancaster, England, 1980, MTP Press Ltd, pp. 69-77. Briggs, M .. and Briggs, M.: A randomized study of metabolic effects of four low estrogen contraceptives: Results after six cycles, Contraception 23:463, I 981.
To PH Y s 1 c 1 AN s in general medicine, the term "steroid" refers to adrenocortical hormones, while to those of us in gynecology it implies estrogens and progestogens. This imprecision permitted either estrogens or progestogens to become synonymous with the combined oral contraceptiYe (OC). The loose terminology has created a misunderstanding about the impact of estrogens alone and has contributed to the delay in studying the metabolic effects of these hormones individually. The potential application of these hormones now extends from puberty until about 60 years or until death. In recent years a curious inconsistency has become apparent. Risks, particularly relating to circulatory complications, were found to increase in the middle of the third decade among women taking the OC. At the same time, postmenopausal women, who usually take so-called natural estrogens without progestogens, did not appear to suffer the same risk. Because the estrogen of the OC had become synonymous with vascular
From the Department of Obstetric; and Gynecology, Univenity of Western Ontario. Reprint requests: Earl R. Plunkett, M.D., Ph.D., F.R.C.P.(C.), Professor and Chairman, Department of Ob.1tetric1 and Gynecology, Univenity of Western Ontario, London, Ontario N6A 5Cl, Canada. *Chairman and Director, Canadian Committee to the Federal Minista of Health (Canada) on Human Reproduction. 0002-9378/82/060747+05$00.50/0 © 1982 The C. V. Mosby Co.
complications, many assumed that the difference lay between synthetic and natural hormones. \Vhile there may be a qualitative difference in metabolic impact, such discrepancies could be related to potency. There is about a 12- to 15-vear gap in our abilitv to prm·ide oral contraception without raising even modestly the relative risk. Currently. women tend to discontinue the pill at age 35 years either voluntarilv or on medical advice. The combined impact of smoking and the OC does indeed raise the risks markedh, especial!\ after age 35 years. Let us re\·iew the risks, clinical problems. and possible solutions for the woman who requires estrogen or estrogens and progestogens after age 35 years. There are many estimates of mortality risks in response to OC use. In 1979, Tietze and Lew it' presented such data that were based upon an updated, computerized mathematical model deri\·ed from the statistics of a number of clinical studies. Tietze and Lewit point out the increasing risks associated with pregnancy and increasing age. The maternal mortality rate ranges between 9.:j and 12.1 per 100,000 live births in women 15 to 29 years of age and increases to -!3.7 in the late third decade and to 6H.2 in the ·-lO- to .f.f-year-old group. Nonsmoking users of OCs between ages 15 and 29 years exhibit a mortalitY rate between 0.6 and 1.6 per 100,000 woman-years; this increases to 9 and 17.7 in the ~~5- to 39-year and -tO- to -++-year age groups, respectively. When smoking and pill use are combined.
747
748
Plunkett
the rates in the latter two groups increase to 31.3 and 60.9, respectively. Tietze and Lewit indicated that barrier contraception with therapeutic abortion as "backup" is the safest approach to the problem. Mortality data relating to the intrauterine contraceptive device (IUD), presumably supported by termination, indicate similar safety with rates in the I A to 2. 7 range. If social. emotional, and moral philosophies could be discounted. then Tietze's numbers would provide at least some of the answers. We would still have to face. however, the effects of termination upon subsequent pregnancies and the potential effect of IUD-related peh·ic infiammatory disease on future fertility. For women ages :15 to 48 vears. tubal sterilization is a safe and efficient alternative. Unfortunately, these are the years when episodic anovulation and dysfunctional uterine bleeding become more common. Although many women prefer to avoid permanent sterilization. those who choose this option may find it necessary to resume using the OC to control bleeding. Others who have undergone surgery, including bilateral oophorectomy, or who have undergone spontaneous ovarian failure also may require estrogen with or without progestin. Obviously, there is a large number of women who, for reasons other than contraception, require consideration. The risk factors demand special attention in this age group. One of the major sources of data on risk factors and the OC is the ongoing study of the Royal College of General Practitioners (RCGP). 2 Within 14 months of study conception in 1968, 23,000 "users" of OCs and 23,000 nonuser controls were entered. In 1977, the RCGP:J published mortality data based on 56 users and 43 controls. The major causes of death among the users were circulatory, with a relative risk (RR) of 4.7 over the controls. That report indicated that the RR rose to 9.7 when the oral contraceptive had been taken for more than 5 years. This latter observation may not be true in the light of newer, expanded data. The most recent mortality figures from that study, published in March, 1981, analyzed the mortality data of 156 "ever users" and 93 controls. 4 Again, circulatory complications were the major problem, with an overall relative risk of 4.2. Mortality from cancer showed no difference, with rates of 30.0 for ever users and 31.5 for controls. Accidents and violence accounted for a mortality rate of 18.2 per 100,000 women-years in the ever users and 12.6 among controls. The overall mortality rate from all causes was 87.7 in the OC group and 64.4 in the controls, with a relative overall risk of 1.4. The various categories of circulatory disease among
~larch !5, I \!~2 .\n1. ]. OhsteL Gynecol.
current and tormer users and controls revealed an overall mortalitv rate of 28.6 for current users (RR .c 1.0). 30.9 for former users (RR = .f.3), and 7.2 tor controk An interesting aspect to these data involves the risb of those who had discontinued use n·rsu;, tho~e ,,·ho continued the OC until death. The RR l!lr nonrheumatic heart disease and hypertetbion was 6.-J. and 2.0 for current and former users, respectively. On the other hand, in cerebrovascular deaths the current user-; exhibited a relative risk of 2.0. while former users had an RR of 3.6. It is rather surprising that the relatin· risks of circulaton· diseases remain elevated after discontinuation of steroids. This suggests that the disease process mav have begun before the medication 1\:ts stopped. ludeed, whether recognized or not. rhc decision mav have been prompted by early symptom.,. The mortality related to cardiovascular disease again confirms an increased risk with age and/or smoking. Ever users who were nonsmokers experienced a mortality rate of 0 at less than 25 years of age, rising to 52 A per 100,000 woman-vears (RR = 4.6) after age .f!'i years. Among ever usen, who smoked. the rate was I 0.:) at less than 25 years of age and rose to 206.7 (RR = 7 A 1 at age .f5 vears and beyond. In addition. of the I 7 encr users who died of subarachnoid hemorrhage, 15 were age 35 vears or older. Because other risk factors mav he more likely to apply to the older woman, I will comment on two of these. In the RCGP mortality data of 1977. evidence suggested that longer use of the OCs enhanced rhe risk of mortalitv/ Recent data indicate no real difference between those on medication for less than 2 or more than H years." On the other hand, increasing paritv, although standardized for age, smoking, and socioeconomic status, was associated with an increasing mortality rate from circulatory problems. In March, 1981, Vessey and colleagues;; presented a brief update of the mortality data from the Oxford Family Planning Association study. This project also began in 1968 and entered more than 17,000 cases during the next 6 years. Fifty-six percent used OCs, 25% barrier methods, and 19% the I LD. Of the HI deaths reviewed, OC users displa\ed a mortality rate of 12.3 per 100,000 women-years as opposed to a rate of 29.9 in the RCGP report. A number of possible explanations for the differences come to mind. Since cases were entered into the Oxford stud~ for more than 4 years beyond the closing of the RCGP project, the actual subject ages may be younger in the Oxford data. Furthermore, there is the possibility that pills of lower dosage are more prevalent in the more recent study. Of course, as the studv progresses and
Volume 142 C\!umber 6, Part 2
Contraceptive steroids, age, and cardiovascular system
more data accumulate, greater agreement may become evident in certain of these mortality categories. As indicated at the beginning, we find increasing risks of major circulatory diseases among users of steroid contraceptives from age 30 years onward. At the same time, physicians have continued to prescribe noncontraceptive estrogens for postmenopausal women. In spite of such treatment being used widely in women ages ~5 to 65 years and older, over a span of 40 years the epidemic of circulatory catastrophes has not appeared. In a report of the Boston Collaborative Drug Surveillance Program 6 in 197 4, an epidemiologic survey indicated major differences in the incidence of venous thromboembolism among women taking OCs, women taking estrogen for menopausal reasons, and nontreated patients. For comparison I have converted the data to an incidence based upon a common denominator of 100,000. The results are as follows: 9.34 per 100,000 population of nonusers, 18.18 per 100,000 taking menopausal estrogen, and 68.06 per 100,000 taking oral contraceptives (estrogen plus progestogen). In the 1979 report based upon the Walnut Creek Contraceptive Drug Study, Petitti and associates 7 could show no increased risk for myocardial infarction, subarachnoid hemorrhage, "other" stroke, or venous thromboembolism among those taking menopausal estrogens. It is worth noting that among the controls (who took no estrogen) there were two subjects with m\ocardial infarction who were receiving only progestogens. In this study, though, the RR for users ofOCs was only O.H for myocardial infarction and 0.6 for "other" strokes: it was 6.3 and 6.7 for subarachnoid hemorrhage and venous thrombosis, respectively. 1n the four vascular disease categories the RR for use of menopausal estrogens ranged between a low of 0. 7 and a high of only 1.6. In a retrospective study of 610 hypoestrogenic patients, Hammond and co-workers 8 carefully categorized the state of health at the time of entry and any new health problems that developed over the following 5 years. Half of these patients were treated with conjugated equine estrogen, and the others remained untreated. ;-..- o difference was noted in the incidence of hvpertension or weight gain. Although at entry the incidence of cardiovascular disease was the same in the two populations, a significant excess of such disease appeared in the nontreated as opposed to estrogentreated women after 5 years. It should be pointed out that the mean age at entry of the estrogen-treated subjects was 42.9 years while that of the untreated controls was 49.6 years. Because this is bv no means a random design, it would be wrong
to conclude that estrogen decreased the risk. Nevertheless, since 28.5% of the controls developed circulatory diseases, compared with 9.3% of the estrogen group (p < 0.001), there is certainly no evidence of increased risk. Nachtigal! and colleagues 9 describe a double-blind, random, 10-year study of 84 carefully matched pairs of women in which those treated received 2.5 mg of conjugated equine estrogen in cycles with 7 days of medroxyprogesterone at 10 mg. The mean blood pressures did not differ significantly, nor did body weight or blood glucose levels. The beta lipoproteins were lowered by estrogen. Most importantly, there were three myocardial infarctions among the controls and only one in the treated group. Again, the authors make no claim for an estrogen-protective effect, but there was no increased risk. These and many other studies have failed to demonstrate a significant risk of vascular disease during menopausal estrogen therapy. The fact that the Nachtigal! series included 7 days of medroxyprogesterone deserves comment. Hirvonen and associates 10 studied the effect of adding progestogen in sequential fashion to a cyclic estradiol valerate regimen. Three groups of six postmenopausal women received estrogen only in the first cycle. During the second and third cycles, progestogens were added for the last 7 days. The daily dose was 10 mg of medroxyprogesterone, 10 mg of norethindrone (NET) acetate, and 0.5 mg ofl-norgestrel for Groups 1, 2, and 3, respectively. Total cholesterol decreased in the first "estrogen" cycle and continued to decline further with the addition of the three progestogens. High-density lipoprotein cholesterol (HDL-C) increased slightly in the first cycle but diminished significantly with addition of the progestogens. The authors preferred medroxyprogesterone since it did not depress the HDL-C as much as the other progestogens. They overlooked the fact that the doses of NET acetate and l-norgestrel were very large. Indeed, we have found that a dose of 3 7.5 J.Lg (not 500) of /-norgestrel is sufficient to suppress the endometrium over a more prolonged time of treatment. Since the major purpose of adding progestogen is to prevent endometrial hyperplasia and minimize risks of cancer, 10 days of low-dose progestogen have been found to be more effective than large doses over shorter periods. Hirvonen and colleagues helped to demonstrate that progestogen could add to the risk of vascular complications during noncontraceptive estrogen treatment. Nevertheless, the doses of progestogen used were excessive in at least two ofthe groups. Based on data from the RCGP study, Kay 11 showed evidence of a dose rela-
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tionship between the progestogen content of OCs and ( irculatorv complications. There i.-. considerable e1idence that decreasing I-lDIA. len~ls and/or HDL-C/total cholesterol ratio is :t-;s"ciated "·it h increased risk of arteriosclerotic circulaton disordns. Therefore, the impact of OCs upon these indin's demands consideration, especialh· in the older subjcch. Larsson-( :ohn and associates 1" presented com paratin: data relating to the effect of four formulations on these parameters. These consisted of ethim·l estradiol/ f-norgcst rei in the following microgram proportions: ~0/:.!:"iO. c\0/:2~>0, :)()/ 130, and a triphasic preparation. The latter consisted of 30/50 for 6 davs, W/7S for 5 ([;l\ s, and :HI/I :23 f()r I 0 davs. ·fhe mean dailv dose therefore 11 as '\:2.:1/9 l.li. llw llDL-C: \\·as measured before and at I, 3, and ti lllonth-; alter treatment. Depression of the 1:dnes 11as gTcdtc-.t in the t110 preparations containing :230 ~J-g of progcqogcn and unchanged with the low-content t riphasic formulation. The HDL-C/total cholesterol ratio 1\;ts signiftt:tnth depressed lJI the larger doses (p < 0 .()()I) and mtKh less so ( p < (J.05) bv the :W/150 and triphasic preparations. Hriggs and Briggs 1" recentlv reported similar lipid data im oh ing :)0 or :15 ~J-g of ethim I estradiol and difkrent progestins. There were two l\ET formulations, and again. the larger dose had a greater effect on the HDL-C. total cholesterol. and trigln:erides. Comment
!he lll<>'it significant complication of oral contraception is till' increased risk of circulatory disease, 1rhich ma1 lw e~pt csscd a;, mvoe
\larch 15, 191>2
Am . .J. Obstet. Gvnecol.
data are required, no convincing evidence has emerged that such is the case. Menopausal women are usual II treated with natural estrogen only or estrogen in cor1 junction with minimal doses of progestogen. The lack of demonstrated complications compared with OC usc. therefore, must be related to such factors a;, dmagc of estrogen (biological potency), natural 1crsus s1nthetic estrogens (qualitative difference), total lack or minimal use of progestogens, or a reversal of intrinsic response to estrogen in the women more than 1:-: vears of age when compared to those 35 to Hi vear" nt age. Clinical data are now appearing which mmpare risks of circulatory disease in response to two or I hree dit~ ferent doses of the same progestogen combined with identical or similar amounts of the same estrogen. The higher levels of progestogen appear to correlate with greater risks. These findings are further substantiated ll\ the metabolic effects of progestogen <>ll HDL-C and the HDL-C/total cholesterol ratio. .\It hough opinion differs about the qualitati1·e differC!Ke in metabolic effects between natural and svntheti( estrogens, at most this is of secondarv importance. The difference in dosage ami biological ctkctin~nes.-, between the two tvpcs of estrogens is also probabh of lesser consequence. It makes no sense to ~uggest arelersal in the metabolic response to estrogens in older women. For the more mature woman who needs contraception, surgical sterilization is likelv the >afest and most practical approach. Intrauterine de1 ices and other harrier methods with therapeutic abortion as h.Kkup might serve others. Smdies are required to prmc the efficacv, acceptabilitY, and safety olfornwlations with smaller progestogen doses. :\ow. certainlv, those older women who need steroid contraceptinn should he checked for e~isting risk factors. a
REFERENCES I. Tict1.c. C .. and l.ewit. S.: Life risks associated with relersihlc methods of fertility regulation, Int. .J. Gynecol. Ohstet. 16:"1'i6, 1979. 2. Roval College of General Practitioners: Oral Contracepti,·es and Health, London, 197-l, Putnam. :1. Beral, V .. principal author: Mortalitv among oral-
contraceptive users, Royal College of General Practitioners' Oral Contraception Study, Lancet 2:727, 1977. CL Layde, P.M., and Beral, V., principal aurhors: Royal College of General Practitioners' Oral Contraception Study: Further analysis of mortalitv in oral contraceptive users, Lancet 1:541, 1981.
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5. Vessey, M.P., McPherson, K., and Yeates, D.: Mortality in oral contraceptive users, Lancet 1:549, 1981. (Letter to the editor.) 6. A report from the Boston Collaborative Drug Surveillance Program: Surgically confirmed gallbladder disease, venous thromboembolism and breast tumours in relation to postmenopausal estrogen therapy, N. Engl. ]. Med. 290:15, 1974. 7. Petitti, D. B., Wingerd, J., Pellegrin, F., et al.: Risk of vascular disease in women: Smoking, oral contraceptives, noncontraceptive estrogens and other factors, ]. A. M.A. 242:1150, 1979. H. Hammond, C. B.,Jelovsek, F. R., Lee, K. L., eta!.: Effects of long-term estrogen therapy, AM. J. 0BSTET. GYNECOL. 133:525, 1979. 9. :"Jachtigall, l.. E., Nachtigall, R. H., Nachtigal!, R. D.,
Contraceptive steroids, age, and cardiovascular system
10.
I I. 12.
13.
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et a!.: Estrogen replacement therapy. II. A prospective study in the relationship to carcinoma and cardiovascular and metabolic problems, Obstet. Gynecol. 54:74, I 979. Hirvonen, E., Malkonen, M., and Mannen, V.: Effects of different progestogens on lipoproteins during postmenopausal replacement therapv, :"1. Engl. ]. Med. 304:560, 1981. Kay, C. R.: The happiness pill? James MacKenzie Lecture,]. R. Coli. Gen. Pract. 30:8,1980. Larsson-Cohn. U., Fagreus, L., Wallentin, L., et al.: In Greenblatt, R., editor: The Development of a New Triphasic Oral Contraceptive, Lancaster, England, 1980, MTP Press Ltd, pp. 69-77. Briggs, M .. and Briggs, M.: A randomized study of metabolic effects of four low estrogen contraceptives: Results after six cycles, Contraception 23:463, I 981.