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Angina and normal coronary arteries in women: Gynecologic findings
Angina and normal coronary arteries in women: Gynecologic findings Philip M. Sarrel, MD", David Lindsay, MA: Giuseppe M.e. Ro sano, MDc, and Philip A. Poole-Wilson, MDc New Haven , Connecticut, and London, England OBJECTIVES: Our aim was to evaluate the hypotheses that women with severe angina and normal coronary arteries (syndrome X) have an increased incidence of hysterectomy and show a posit ive card iac response to 1713-estradiol replacement therapy. STUDY DESIGN: The gynecologic histories of 30 women with synd rome X were determined. Anginal and 1713-estradiol insufficiency symptoms were recorded daily for 1 month. Subsequently, 20 of the women underwent hyperemic response testing before and after 2 months of estrogen replacement therapy. Hyperem ic response results were compared with those of 12 asymptomatic post-menopausal women not receiving estrogen replacement therapy. Symptoms were recorded daily during estrogen replacement therapy. RESULTS: A total of 18 women (60%) underwent hysterectomy. All were experiencing hot flushes . Hyperemic response was diminished in women with syndrome X compared with controls. Hyperemic response increased and anginal sympto ms decreased during estrogen replacement therapy. CONCLUSION : The incidence of hysterectomy was increased and estrogen replacement therapy alleviated cardiac symptoms and enhanced hyperem ic response in a group of women with syndrome X. (AM J OSSTET G VNECOL 1992;167:467-72 .)
Key word s: Angina, estrogen , hysterectomy, vasodilatory reserve, syndrome X Women with severe angina, exercise electrocardiogram changes suggesting ischemia, an d norma l coronary ar teries (referred to as syndrome X or microvascular angina) present a challenging medical problem. These pa tients ha ve an exce llent prognosis with re gard to myocardial infarction and card iovascular mortality.1 Neverthe less, existing cardiovascu lar medications are freque ntly ineffective in rel ieving pain , and follow-up studies indicate that man y patients have significant limitation of daily activities because of pain ! Patients with thi s condition ha ve shown a diminished hyperemic respo nse, suggesting the chest pain to be a ma nifestat ion of a more wides pread vascular disorder.' O ne of the earliest observations about angina in women was mad e by Sir William Osler: who in 1892 pointed out that anginal pain without coronary artery di sease was more common in women than in men , carried a good prognosis, and was characterized by discom fort that was often lon g-lasting. LaCroix et al.,' in From the Departments of Obstetrics and Gynecology and Psychiatry, Yale University School of M edicine: the Royal Brompton and N ational Heart Hospital,' and the Department of Cardiac M edicine, Nat ional Heart and Lung In stitute?.• D.L. is a British H eart Foundat ion Junior Fellow. R eceivedfor publication October 17, 1991 ; revised February 6, 1992; accepted February 13,1 992 . Reprint requests: Philip M. So rrel, MD , Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar St ., N ew Haven, CT 06510 . 6 /1 /37267
a re cent national study reported by the Epidemiology Branch of the Na tional Institutes of Health, fou nd among white women aged 25 to 54 years tha t diag nosed angina occurs twice as often as it does amo ng agematched white men . In spite of the clinical diagnosis of angina pectoris, >50% of women undergoing coronary angiography hav e normal coronary arteries com pared to < 10% of men." For these women an etiologic explanation for th e ches t pain re mains elusive and a variety of noncard iac causes have been po stulated . Angina pectoris in wome n is freq ue ntl y associated with ot her con d itions of vascu lar disorder. T hese include hot flushes," Raynaud's phenornenon.t " an d rnigraine." In th e stud y of LaCroix et al. 20 .5% of the women with ang ina also experienced severe d yspnea, .... . requir ing the su bject to stop for breath when walking on level ground .'" In contrast, only 4.5% of the men in th e same age grou p experienc ed seve re dyspnea . Kronenberg ' reported that 16% of 438 perimenopa usa l and postmenopausal women ex perience d significant ches t pressure and 28 % experience d cranial pressure when hot flushes occur red. Among women with Raynaud's pheno me non , an increased incide nce of variant angina and migraine has been reported." 10 The association of ang ina and coronary artery di sease with loss of ovarian func tion has been described in ma ny articles in the med ical literature. Wuest et al." reported th at women who underwen t bilateral oopho-
467
468 Sarral at al.
rectomy and did not receive hormone replacement therapy showed an increased prevalence of severe atherosclerotic disease at autopsy, and Robinson et al." found that castrated women showed a higher incidence of angina as compared with that of controls who had not had surgery. Although myocardial infarction and cardiovascular disease are most clearly associated with bilateral salpingo-oophorectomy," elevated risks of cardiovascular disease have been reported even after simple hysterectomy," and loss of ovarian hormone production after simple hysterectomy has been suggested as an etiologic factor. 16 The possibility that ovarian insufficiency might be associated with syndrome X in women led to a gynecologic endocrine evaluation of 30 patients with this condition. The patients were seen at the Royal Brompton and National Heart Hospital in London, where their gynecologic histories and signs and symptoms of ovarian insufficiency were evaluated. Twenty of these women subsequently participated in a pilot study to determine whether 17~-estradioltreatment would have a positive effect on cardiac symptoms and measures of cardiovascular function. Patients and methods
Thirty consecutive female patients previously diagnosed with syndrome X were recruited for this study. Before our investigations all of the women had been evaluated for chest pain by their family physicians and at least two consulting cardiologists. These physicians had concurred that the nature of the women's pain fit the criteria for a diagnosis of angina pectoris. The women were seen in the Cardiac Medicine Clinic of the Royal Brompton and National Heart Hospital in London. They were interviewed by a research team consisting of a cardiologist (DL or GR) and a gynecologist (PS). This interview further confirmed the presence of angina-type chest pain. In fact, all the women had a history of severe angina, a positive exercise test (ST segment depression> I mm during treadmill testing), and normal coronary arteries at the time of coronary catheterization. The women were receiving a variety of cardiac medications including coronary vasodilators, calcium channel-blocking agents, ~-adrenergic-block ing agents, and cardiac glycosides. The cardiac history was reviewed, and as complete an obstetric and gynecologic history as possible was elicited. A blood sample was drawn for determination of serum estradiol and follicle-stimulating hormone (FSH) concentrations. The control group comprised II women without chest pain or hot flushes (age 52.6 :':: 4.5 years, mean ± SD). The women in the control group were not receiving hormone replacement therapy although all were postmenopausal, showing estradiol concentrations <25 pg/ml and FSH levels >40 mIU/m!. The women in the control group were not taking any cardiac medi-
August 1992 Am J Obstet Gynecol
cations. Patients with a history of hypertension were excluded from both groups. After informed consent was obtained, all cardiac medications were discontinued for at least I week except for sublingual glyceryl trinitrates. Glyceryl trinitrate treatment was discontinued for a minimum of 24 hours before the first study visit. The subjects in both groups were not allowed to smoke cigarettes or drink tea or coffee within 4 hours of the study. Ten of the women with syndrome X either were taking or recently had been taking hormone replacement therapy. These medications were all discontinued for at least 6 weeks before the initial hyperemic response was measured. The subjects reclined in a semirecumbent position on a couch, and blood pressure was recorded from the left arm. Hyperemic response was measured with a laser Doppler probe applied to the pulp of the right middle finger. The room temperature was maintained at 70° F. After a period of stabilization, arterial flow in the fingertip was determined for a 2-minute period. Limb blood flow was then occluded for 5 minutes with a sphygmomanometer inflated to 200 mm Hg. The laser Doppler probe continued to monitor flow through the period of occlusion and for 3 minutes after release of the cuff pressure. All of the women maintained a daily diary for 1 month, during which they recorded the frequency and intensity of chest pain, sleep disturbance, headache, anxiety reactions, and depression. A rating scale ranging from 0 (no symptoms) to 4 (severe symptoms) was used. A minimum of a two-level change in a symptom (e.g., from 4 to 2) defined a "significant change." At the follow-up visit, 20 of the women diagnosed with syndrome X agreed to participate in a 2-month trial in which they wore 17~-estradiol skin patches (Estraderm TTS) delivering 50 fJ.g/ day for the first month and 100 fJ.g/day for a second month. The estradiol patches were changed twice weekly and were applied to the buttocks according to the usual prescription guidelines. The women agreed to discontinue cardiac medications except for sublingual nitrates. The diaries were maintained throughout this period, and the hyperemic response test was repeated at the end of the trial. The 10 women initially evaluated who were not included in the estradiol trial were those who were not willing to return for repeat visits because of the inconvenience of coming to the clinic in London, did not wish to receive estrogen treatment, or had return appointments after recruitment for the estrogen treatment study was completed. Findings and results
Hormonal and nonanginal vascular findings are summarized in Fig. I. The mean age of the women was 52 years (range 46 to 63, SD ± 6). Twelve of the women had experienced a natural menopause at a mean :':: SD
Syndrome X: Gynecologic findings 469
Volume 167 Xumber 2
100
100%
-
r--
100%
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80 -
C ~Ql
60%
r--
60
43%
-
Q.
40
20
Hysterectomy·
Estradiol <25pg/mL
Hotllushes
Migraine headaches
Fig. 1. Hormone and vascular findings in 30 women with syndrome X. Mean ± SD age of women was 52 ± 6 years. Average ± SD time from hysterectomy to onset of cardiac symptoms was 7.7 ± 5.7 years.
age of 49.5 ± 4 years (range 47 to 55). Eighteen of the 30 women underwent hysterectomy at an average age of 41 years. Sixteen of the 18 hysterectomies were abdominal procedures, and two women had vaginal hysterectomy for uterine prolapse and urinary incontinence. We were not able to determine the gynecologic diagnoses in many of the women as they themselves were unsure. However, it did appear that essentially all of the procedures were necessary, with the most frequent indications being uterine fibromyomas or excessive bleeding or both. Nine of the 18 women had ovaries removed at the time of surgery. Seventeen of the 30 women had received hormone replacement therapy at some time. However, only 10 of the women were taking hormone replacement therapy when first seen in this study. Nine of the 10 women using hormones had undergone hysterectomy, and eight of these women had bilateral oophorectomy. Seven women had discontinued hormone replacement therapy, including four who had been given estrogen plus progestin. These four women stopped hormone replacement therapy because of intolerable chest pain that developed during the time they were taking the progestin. Angina developed at a mean ± SD duration of 7.7 ± 5.7 years after hysterectomy. All the women, including those taking hormone replacement therapy, were experiencing hot flushes. In five of these women the flushes were mild (level 2), but 25 women rated the flushes as severe (level 4) in the monthly diaries. Sleep was disrupted in all of the women, usually because of awakening with hot flushes. All the women reported that at least some of their hot flushes were accompanied by chest pressure or pain. Thirteen of the 30 women had migraine headaches. Serum estradiol and FSH concentrations were <25 pglml and >40 mIU Iml, respectively, in all of the women.
Hyperemic response results before 17~-estradiol treatment in the syndrome X women are compared with those of an age-matched, pain-free control group in Fig. 2. The ratio of postocclusion blood flow level to the preocclusion level was calculated at 20-second intervals for 2 minutes. It can be seen that the women with syndrome X do not show any response above baseline (i.e., they do not appear to have a vasodilator reserve), whereas the control group shows a significant response over the entire 2 minutes. Calculation of the ratio of the maximum response level to the baseline flow level (MBR) gave a value of 1.08 for those with syndrome X and 2.3 for the control group. After estradiol treatment for 2 months, the MBR of the women with syndrome X was 2.07. The posttreatment MBR is compared with pretreatment and control group findings in Fig. 3. Response levels were almost doubled after estradiol treatment and approached the levels of the control group without angina. Nineteen of the 20 women reported marked improvement (a minimum of a two-level decrease in the anginal symptom rating) or complete disappearance of chest pain. Cessation of hot flushes correlated with decrease or disappearance of chest pain. All of the women reported a decrease in the use of glyceryl trinitate tablets. Unfortunately, the diaries did not include quantification of glyceryl trinitate usage, and therefore we are not able to report the decline in usage with precision.
Comment These findings suggest an association between hysterectomy, ovarian insufficiency, and the development of syndrome X. The average age of the patients studied was 52; in Great Britain, 8% to 12% of women in this age group have undergone hysterectomy with or with-
470 Sarral at al.
August 1992
Am
35
J Obstet Gynecol
- - Controls ---- Syndrome X
3
25 ell
.~
Qi
2
~
.0
B o
15
~
II:
----------~----------~-----------+---------! 05
o - t - - - - , - - - . - - - - . , - - - - - - -I . - - - -I , - - - . -I - - - - ,I 140 120 100 o 20 40 60 80 Seconds after cuff release
Fig. 2. Hyperemic response of 20 women with syndrome X compared with that of 12 control subjects. (See text for details of test.)
1200
H
1000
800
!l
"0
~
600
~
400 200 MBR
=
23
MBR = 108
MBR =207
Syndrome X (before treatment)
Syndrome X (after treatment)
0 Controls
Fig. 3. MBR of hyperemic response in women with syndrome X before and after treatment with 1713-estradiol compared with that of control subjects.
out removal of the ovaries." In the current series 60% had undergone hysterectomy. All of the hysterectomies appear to have been indicated procedures. Although the evidence in the medical literature re lating hysterectomy to the development of coronary artery disease is more clearly associated with bilateral salpingo-oophorectomy," studies indicate that simple hysterectomy is also reported to incur an elevated cardiovascular risk. As noted, the study of Siddle et al. " implies that the loss of ovarian hormone production with simple hysterectomy may be comparable to that occurring when the ovaries are removed . In the latter instance hormone replacement therapy is more likely to be initiated soon after the surgery. Unfortunately, when the ovaries are retained, it can be mistakenly assumed that normal ovarian function always ensues and there is no need for hormone replacement therapy. Moreover, most patients are lost to follow-up after hysterectomy, since neither gynecologists nor patients believe that continuing gynecologic care is necessary. In
the current series only three women returned to their gynecologists for continuing follow-up after their scheduled postoperative visits. Nonetheless, most of the women with retained ovaries described symptoms of ovarian insufficiency to their primary care physicians. However, since their ovaries had not been removed, their ph ysicians did not attribute the symptoms to ovarian insufficiency, and onl y one woman received hormone replacement therapy. Cardiac symptoms developed within 7 years of the hysterectomy. Chest pain is not considered a reliable indicator of angina pectoris in women." The cardiologists involved in the characterization of the chest pain in the women in our series determined to the best of their abilities that the pain was of cardiac origin, and the positive results of exercise tests would seem to confirm the impression of ischemic disease. The finding of a decreased vasodilatory reserve capacity in the syndrome X women compared with the age-matched control women suggests the problem to be due to altered cor-
Syndrome X: Gynecologic findings 471
Volume 167 Number 2
onary hemodynamics in association with pathophysiologic changes other than atherosclerotic plaque formation. All the women showed symptoms of estradiol deficiency. Twenty-five of 30 were experiencing >20 hot flushes each day. Chest pain frequently accompanied the hot flushes. Further evidence of a more widespread vascular disturbance was seen among 13 (43%) of the women who also experienced migraine headaches (Fig. I).
The pretreatment hyperemic response results in the syndrome X women indicate diminished vasodilator reserve capacity. This finding confirms the observations of others who have concluded that reduced hyperemic response in syndrome X indicates the anginal symptoms to be a manifestation of a widespread vascular disorder.' The hyperemic response in the forearm to the release of arterial occlusion has been extensively studied. Sudden increase in blood flow in an artery is thought to stimulate the release of endothelial-derived relaxing factor (EDRF), and the hyperemic response is thought to reflect vasorelaxation induced by EDRF acting on the vascular smooth muscle.' Our finding of increased hyperemic response after 1713-estradiol treatment is consistent with those of others, including Williams et al.." who reported that coronary vascular response to acetylcholine stimulation (another EDRF-mediated vasodilator response) in ovariectomized monkeys is increased after 1713-estradiol implants. Hemodynamic changes reported after treatment with 1713-estradiol include restoration of vasomotor control, increased cardiac output, and decreased vascular resistance." Increased hyperemic response correlated in our study with an increased vasodilator reserve as the syndrome X patients showed significant improvement in cardiac symptoms. Estrogen replacement therapy in postmenopausal women has been shown to reduce cardiovascular morbidity and mortality." Although effects on lipid metabolism appear to contribute significantly to this cardioprotection, the hemodynamic effects of 1713-estradiol also appear to be of significance. The current study shows an association between signs and symptoms of ovarian insufficiency and disturbed vascular function in women with syndrome X. The part of the study assessing the effects of 1713-estradiol treatment on cardiac symptoms and hyperemic response should be considered a pilot investigation into a potential mechanism through which estrogen treatment provides cardioprotection. This study indicates that estradiol deficiency may induce pathophysiologic changes contributing to anginal symptoms in women diagnosed with syndrome X. The high prevalence of hysterectomy and the inadequacy of hormone replacement therapy observed in this study suggest the need for careful gynecologic endocrine evaluation of women presenting with this syndrome. A
double-blind, placebo-controlled study of the effects of 1713-estradiol on cardiovascular parameters in women with syndrome X should determine which hormone effects account for the improvements seen thus far. REFERENCES 1. Hutchinson S], Poole-Wilson PA, Henderson AH. Angina with normal coronary arteries: a review, Q j Med 1989;72:677-88. 2. Ockene IS, Shay Mj, Alpert jS, Weiner BH, Dalen jE. Unexplained chest pain in patients with normal coronary arteriograms. N Englj Med 1980;303:1249-52. 3. Sax FL, Cannon RO, Hanson C, Epstein SE. Impaired forearm vasodilator reserve in patients with microvascular angina. Evidence of a generalized disorder of vascular function. N Englj Med 1987;317:1366-70. 4. Osler W. Lectures on angina pectoris and allied states. New York: Appleton, 1901. 5. LaCroix AZ, Haynes SG, Savage DD, Havlik RJ. Rose questionnaire angina among United States black, white, and Mexican-American women and men. Am j Epidemiol 1989; 129:669-86. 6. Kennedy jW, Kaiser GC, Fischer LD, et al. Clinical and angiographic predictors of operative mortality from the collaborative study in coronary artery surgery (CASS). Circulation 1981;63:793-802. 7. Kronenberg F. Hot flashes. Epidemiology and physiology. Ann N Y Acad Sci 1990;592:52-86. 8. Leppert J, Aberg H, Ringqvist I, Sorensson S. Raynaud's phenomenon in a female population: prevalence and association with other conditions. Angiology 1987;38: 871-7. 9. Zahavi I, Chagnac A, Hering R, et aI. Prevalence of Raynaud's phenomenon in patients with migraine. Arch Intern Med 1984;144:742-4. 10. Atkinson AR, Appenzeller 0, Hemicrania and Raynaud's phenomenon: manifestation of the same disease? Headache 1976;16:1-2. 11. Welsh KMA, Darnley D, Simkins RT. The role of estrogen in migraine: a review and hypothesis. Cephalalgia 1984;4:227-36. 12. WuestJH, Dry TJ, Edwards JE. The degree of coronary atherosclerosis in bilaterally oophorectomized women. J Am Heart Assoc 1953;7:801-9. 13. Robinson RW, Higano N, Cohen WD. Increased incidence of coronary heart disease in women castrated prior to the menopause. Arch Intern Med 1959;104:908-13. 14. Stampfer MJ, Colditz GA, Willett WC. Menopause and heart disease: a review. Ann N Y Acad Sci 1990;592:192203. 15. Gordon T, Kannel WB, Hjortland MC, McNamara PM. Menopause and coronary heart disease: the Framingham study. Ann Intern Med 1978;89:157-61. 16. Siddle N, Sarrel P, Whitehead M. The effect of hysterectomy on the age at ovarian failure: identification of a subgroup of women with premature loss of ovarian function and literature review. Fertil Steril 1987;47:94-100. 17. McPherson K, WennbergJE, Hovindo B, et al. Small-area variations in the use of common surgical procedures: an international comparison of New England, England, and Norway. N EnglJ Med 1982;307:1310-4. 18. Tobin JN, Wassertheil-Smollers, Wexler JP, et al. Sex bias in considering coronary bypass surgery. Ann Intern Med 1987;197:19-25. 19. WilliamsJK, Adams MR, Klopfenstein HS. Estrogen modulates responses of atherosclerotic coronary arteries. Circ Res 1990;81:1680-7. 20. Magness RR, Rosenfeld CR. Local and systemic estradiol1713: effects on uterine and systemic vasodilation. Am J Physiol 1989;256(suppl):E536-42. 21. Bush TL, Barrett-Conner E, Cowan LD, et al. Cardiovascular mortality and non-contraceptive use of estrogen in women. Circulation 1987;75:1102-9.
Key word s: Angina, estrogen , hysterectomy, vasodilatory reserve, syndrome X Women with severe angina, exercise electrocardiogram changes suggesting ischemia, an d norma l coronary ar teries (referred to as syndrome X or microvascular angina) present a challenging medical problem. These pa tients ha ve an exce llent prognosis with re gard to myocardial infarction and card iovascular mortality.1 Neverthe less, existing cardiovascu lar medications are freque ntly ineffective in rel ieving pain , and follow-up studies indicate that man y patients have significant limitation of daily activities because of pain ! Patients with thi s condition ha ve shown a diminished hyperemic respo nse, suggesting the chest pain to be a ma nifestat ion of a more wides pread vascular disorder.' O ne of the earliest observations about angina in women was mad e by Sir William Osler: who in 1892 pointed out that anginal pain without coronary artery di sease was more common in women than in men , carried a good prognosis, and was characterized by discom fort that was often lon g-lasting. LaCroix et al.,' in From the Departments of Obstetrics and Gynecology and Psychiatry, Yale University School of M edicine: the Royal Brompton and N ational Heart Hospital,' and the Department of Cardiac M edicine, Nat ional Heart and Lung In stitute?.• D.L. is a British H eart Foundat ion Junior Fellow. R eceivedfor publication October 17, 1991 ; revised February 6, 1992; accepted February 13,1 992 . Reprint requests: Philip M. So rrel, MD , Department of Obstetrics and Gynecology, Yale University School of Medicine, 333 Cedar St ., N ew Haven, CT 06510 . 6 /1 /37267
a re cent national study reported by the Epidemiology Branch of the Na tional Institutes of Health, fou nd among white women aged 25 to 54 years tha t diag nosed angina occurs twice as often as it does amo ng agematched white men . In spite of the clinical diagnosis of angina pectoris, >50% of women undergoing coronary angiography hav e normal coronary arteries com pared to < 10% of men." For these women an etiologic explanation for th e ches t pain re mains elusive and a variety of noncard iac causes have been po stulated . Angina pectoris in wome n is freq ue ntl y associated with ot her con d itions of vascu lar disorder. T hese include hot flushes," Raynaud's phenornenon.t " an d rnigraine." In th e stud y of LaCroix et al. 20 .5% of the women with ang ina also experienced severe d yspnea, .... . requir ing the su bject to stop for breath when walking on level ground .'" In contrast, only 4.5% of the men in th e same age grou p experienc ed seve re dyspnea . Kronenberg ' reported that 16% of 438 perimenopa usa l and postmenopausal women ex perience d significant ches t pressure and 28 % experience d cranial pressure when hot flushes occur red. Among women with Raynaud's pheno me non , an increased incide nce of variant angina and migraine has been reported." 10 The association of ang ina and coronary artery di sease with loss of ovarian func tion has been described in ma ny articles in the med ical literature. Wuest et al." reported th at women who underwen t bilateral oopho-
467
468 Sarral at al.
rectomy and did not receive hormone replacement therapy showed an increased prevalence of severe atherosclerotic disease at autopsy, and Robinson et al." found that castrated women showed a higher incidence of angina as compared with that of controls who had not had surgery. Although myocardial infarction and cardiovascular disease are most clearly associated with bilateral salpingo-oophorectomy," elevated risks of cardiovascular disease have been reported even after simple hysterectomy," and loss of ovarian hormone production after simple hysterectomy has been suggested as an etiologic factor. 16 The possibility that ovarian insufficiency might be associated with syndrome X in women led to a gynecologic endocrine evaluation of 30 patients with this condition. The patients were seen at the Royal Brompton and National Heart Hospital in London, where their gynecologic histories and signs and symptoms of ovarian insufficiency were evaluated. Twenty of these women subsequently participated in a pilot study to determine whether 17~-estradioltreatment would have a positive effect on cardiac symptoms and measures of cardiovascular function. Patients and methods
Thirty consecutive female patients previously diagnosed with syndrome X were recruited for this study. Before our investigations all of the women had been evaluated for chest pain by their family physicians and at least two consulting cardiologists. These physicians had concurred that the nature of the women's pain fit the criteria for a diagnosis of angina pectoris. The women were seen in the Cardiac Medicine Clinic of the Royal Brompton and National Heart Hospital in London. They were interviewed by a research team consisting of a cardiologist (DL or GR) and a gynecologist (PS). This interview further confirmed the presence of angina-type chest pain. In fact, all the women had a history of severe angina, a positive exercise test (ST segment depression> I mm during treadmill testing), and normal coronary arteries at the time of coronary catheterization. The women were receiving a variety of cardiac medications including coronary vasodilators, calcium channel-blocking agents, ~-adrenergic-block ing agents, and cardiac glycosides. The cardiac history was reviewed, and as complete an obstetric and gynecologic history as possible was elicited. A blood sample was drawn for determination of serum estradiol and follicle-stimulating hormone (FSH) concentrations. The control group comprised II women without chest pain or hot flushes (age 52.6 :':: 4.5 years, mean ± SD). The women in the control group were not receiving hormone replacement therapy although all were postmenopausal, showing estradiol concentrations <25 pg/ml and FSH levels >40 mIU/m!. The women in the control group were not taking any cardiac medi-
August 1992 Am J Obstet Gynecol
cations. Patients with a history of hypertension were excluded from both groups. After informed consent was obtained, all cardiac medications were discontinued for at least I week except for sublingual glyceryl trinitrates. Glyceryl trinitrate treatment was discontinued for a minimum of 24 hours before the first study visit. The subjects in both groups were not allowed to smoke cigarettes or drink tea or coffee within 4 hours of the study. Ten of the women with syndrome X either were taking or recently had been taking hormone replacement therapy. These medications were all discontinued for at least 6 weeks before the initial hyperemic response was measured. The subjects reclined in a semirecumbent position on a couch, and blood pressure was recorded from the left arm. Hyperemic response was measured with a laser Doppler probe applied to the pulp of the right middle finger. The room temperature was maintained at 70° F. After a period of stabilization, arterial flow in the fingertip was determined for a 2-minute period. Limb blood flow was then occluded for 5 minutes with a sphygmomanometer inflated to 200 mm Hg. The laser Doppler probe continued to monitor flow through the period of occlusion and for 3 minutes after release of the cuff pressure. All of the women maintained a daily diary for 1 month, during which they recorded the frequency and intensity of chest pain, sleep disturbance, headache, anxiety reactions, and depression. A rating scale ranging from 0 (no symptoms) to 4 (severe symptoms) was used. A minimum of a two-level change in a symptom (e.g., from 4 to 2) defined a "significant change." At the follow-up visit, 20 of the women diagnosed with syndrome X agreed to participate in a 2-month trial in which they wore 17~-estradiol skin patches (Estraderm TTS) delivering 50 fJ.g/ day for the first month and 100 fJ.g/day for a second month. The estradiol patches were changed twice weekly and were applied to the buttocks according to the usual prescription guidelines. The women agreed to discontinue cardiac medications except for sublingual nitrates. The diaries were maintained throughout this period, and the hyperemic response test was repeated at the end of the trial. The 10 women initially evaluated who were not included in the estradiol trial were those who were not willing to return for repeat visits because of the inconvenience of coming to the clinic in London, did not wish to receive estrogen treatment, or had return appointments after recruitment for the estrogen treatment study was completed. Findings and results
Hormonal and nonanginal vascular findings are summarized in Fig. I. The mean age of the women was 52 years (range 46 to 63, SD ± 6). Twelve of the women had experienced a natural menopause at a mean :':: SD
Syndrome X: Gynecologic findings 469
Volume 167 Xumber 2
100
100%
-
r--
100%
-
80 -
C ~Ql
60%
r--
60
43%
-
Q.
40
20
Hysterectomy·
Estradiol <25pg/mL
Hotllushes
Migraine headaches
Fig. 1. Hormone and vascular findings in 30 women with syndrome X. Mean ± SD age of women was 52 ± 6 years. Average ± SD time from hysterectomy to onset of cardiac symptoms was 7.7 ± 5.7 years.
age of 49.5 ± 4 years (range 47 to 55). Eighteen of the 30 women underwent hysterectomy at an average age of 41 years. Sixteen of the 18 hysterectomies were abdominal procedures, and two women had vaginal hysterectomy for uterine prolapse and urinary incontinence. We were not able to determine the gynecologic diagnoses in many of the women as they themselves were unsure. However, it did appear that essentially all of the procedures were necessary, with the most frequent indications being uterine fibromyomas or excessive bleeding or both. Nine of the 18 women had ovaries removed at the time of surgery. Seventeen of the 30 women had received hormone replacement therapy at some time. However, only 10 of the women were taking hormone replacement therapy when first seen in this study. Nine of the 10 women using hormones had undergone hysterectomy, and eight of these women had bilateral oophorectomy. Seven women had discontinued hormone replacement therapy, including four who had been given estrogen plus progestin. These four women stopped hormone replacement therapy because of intolerable chest pain that developed during the time they were taking the progestin. Angina developed at a mean ± SD duration of 7.7 ± 5.7 years after hysterectomy. All the women, including those taking hormone replacement therapy, were experiencing hot flushes. In five of these women the flushes were mild (level 2), but 25 women rated the flushes as severe (level 4) in the monthly diaries. Sleep was disrupted in all of the women, usually because of awakening with hot flushes. All the women reported that at least some of their hot flushes were accompanied by chest pressure or pain. Thirteen of the 30 women had migraine headaches. Serum estradiol and FSH concentrations were <25 pglml and >40 mIU Iml, respectively, in all of the women.
Hyperemic response results before 17~-estradiol treatment in the syndrome X women are compared with those of an age-matched, pain-free control group in Fig. 2. The ratio of postocclusion blood flow level to the preocclusion level was calculated at 20-second intervals for 2 minutes. It can be seen that the women with syndrome X do not show any response above baseline (i.e., they do not appear to have a vasodilator reserve), whereas the control group shows a significant response over the entire 2 minutes. Calculation of the ratio of the maximum response level to the baseline flow level (MBR) gave a value of 1.08 for those with syndrome X and 2.3 for the control group. After estradiol treatment for 2 months, the MBR of the women with syndrome X was 2.07. The posttreatment MBR is compared with pretreatment and control group findings in Fig. 3. Response levels were almost doubled after estradiol treatment and approached the levels of the control group without angina. Nineteen of the 20 women reported marked improvement (a minimum of a two-level decrease in the anginal symptom rating) or complete disappearance of chest pain. Cessation of hot flushes correlated with decrease or disappearance of chest pain. All of the women reported a decrease in the use of glyceryl trinitate tablets. Unfortunately, the diaries did not include quantification of glyceryl trinitate usage, and therefore we are not able to report the decline in usage with precision.
Comment These findings suggest an association between hysterectomy, ovarian insufficiency, and the development of syndrome X. The average age of the patients studied was 52; in Great Britain, 8% to 12% of women in this age group have undergone hysterectomy with or with-
470 Sarral at al.
August 1992
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35
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- - Controls ---- Syndrome X
3
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o - t - - - - , - - - . - - - - . , - - - - - - -I . - - - -I , - - - . -I - - - - ,I 140 120 100 o 20 40 60 80 Seconds after cuff release
Fig. 2. Hyperemic response of 20 women with syndrome X compared with that of 12 control subjects. (See text for details of test.)
1200
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Fig. 3. MBR of hyperemic response in women with syndrome X before and after treatment with 1713-estradiol compared with that of control subjects.
out removal of the ovaries." In the current series 60% had undergone hysterectomy. All of the hysterectomies appear to have been indicated procedures. Although the evidence in the medical literature re lating hysterectomy to the development of coronary artery disease is more clearly associated with bilateral salpingo-oophorectomy," studies indicate that simple hysterectomy is also reported to incur an elevated cardiovascular risk. As noted, the study of Siddle et al. " implies that the loss of ovarian hormone production with simple hysterectomy may be comparable to that occurring when the ovaries are removed . In the latter instance hormone replacement therapy is more likely to be initiated soon after the surgery. Unfortunately, when the ovaries are retained, it can be mistakenly assumed that normal ovarian function always ensues and there is no need for hormone replacement therapy. Moreover, most patients are lost to follow-up after hysterectomy, since neither gynecologists nor patients believe that continuing gynecologic care is necessary. In
the current series only three women returned to their gynecologists for continuing follow-up after their scheduled postoperative visits. Nonetheless, most of the women with retained ovaries described symptoms of ovarian insufficiency to their primary care physicians. However, since their ovaries had not been removed, their ph ysicians did not attribute the symptoms to ovarian insufficiency, and onl y one woman received hormone replacement therapy. Cardiac symptoms developed within 7 years of the hysterectomy. Chest pain is not considered a reliable indicator of angina pectoris in women." The cardiologists involved in the characterization of the chest pain in the women in our series determined to the best of their abilities that the pain was of cardiac origin, and the positive results of exercise tests would seem to confirm the impression of ischemic disease. The finding of a decreased vasodilatory reserve capacity in the syndrome X women compared with the age-matched control women suggests the problem to be due to altered cor-
Syndrome X: Gynecologic findings 471
Volume 167 Number 2
onary hemodynamics in association with pathophysiologic changes other than atherosclerotic plaque formation. All the women showed symptoms of estradiol deficiency. Twenty-five of 30 were experiencing >20 hot flushes each day. Chest pain frequently accompanied the hot flushes. Further evidence of a more widespread vascular disturbance was seen among 13 (43%) of the women who also experienced migraine headaches (Fig. I).
The pretreatment hyperemic response results in the syndrome X women indicate diminished vasodilator reserve capacity. This finding confirms the observations of others who have concluded that reduced hyperemic response in syndrome X indicates the anginal symptoms to be a manifestation of a widespread vascular disorder.' The hyperemic response in the forearm to the release of arterial occlusion has been extensively studied. Sudden increase in blood flow in an artery is thought to stimulate the release of endothelial-derived relaxing factor (EDRF), and the hyperemic response is thought to reflect vasorelaxation induced by EDRF acting on the vascular smooth muscle.' Our finding of increased hyperemic response after 1713-estradiol treatment is consistent with those of others, including Williams et al.." who reported that coronary vascular response to acetylcholine stimulation (another EDRF-mediated vasodilator response) in ovariectomized monkeys is increased after 1713-estradiol implants. Hemodynamic changes reported after treatment with 1713-estradiol include restoration of vasomotor control, increased cardiac output, and decreased vascular resistance." Increased hyperemic response correlated in our study with an increased vasodilator reserve as the syndrome X patients showed significant improvement in cardiac symptoms. Estrogen replacement therapy in postmenopausal women has been shown to reduce cardiovascular morbidity and mortality." Although effects on lipid metabolism appear to contribute significantly to this cardioprotection, the hemodynamic effects of 1713-estradiol also appear to be of significance. The current study shows an association between signs and symptoms of ovarian insufficiency and disturbed vascular function in women with syndrome X. The part of the study assessing the effects of 1713-estradiol treatment on cardiac symptoms and hyperemic response should be considered a pilot investigation into a potential mechanism through which estrogen treatment provides cardioprotection. This study indicates that estradiol deficiency may induce pathophysiologic changes contributing to anginal symptoms in women diagnosed with syndrome X. The high prevalence of hysterectomy and the inadequacy of hormone replacement therapy observed in this study suggest the need for careful gynecologic endocrine evaluation of women presenting with this syndrome. A
double-blind, placebo-controlled study of the effects of 1713-estradiol on cardiovascular parameters in women with syndrome X should determine which hormone effects account for the improvements seen thus far. REFERENCES 1. Hutchinson S], Poole-Wilson PA, Henderson AH. Angina with normal coronary arteries: a review, Q j Med 1989;72:677-88. 2. Ockene IS, Shay Mj, Alpert jS, Weiner BH, Dalen jE. Unexplained chest pain in patients with normal coronary arteriograms. N Englj Med 1980;303:1249-52. 3. Sax FL, Cannon RO, Hanson C, Epstein SE. Impaired forearm vasodilator reserve in patients with microvascular angina. Evidence of a generalized disorder of vascular function. N Englj Med 1987;317:1366-70. 4. Osler W. Lectures on angina pectoris and allied states. New York: Appleton, 1901. 5. LaCroix AZ, Haynes SG, Savage DD, Havlik RJ. Rose questionnaire angina among United States black, white, and Mexican-American women and men. Am j Epidemiol 1989; 129:669-86. 6. Kennedy jW, Kaiser GC, Fischer LD, et al. Clinical and angiographic predictors of operative mortality from the collaborative study in coronary artery surgery (CASS). Circulation 1981;63:793-802. 7. Kronenberg F. Hot flashes. Epidemiology and physiology. Ann N Y Acad Sci 1990;592:52-86. 8. Leppert J, Aberg H, Ringqvist I, Sorensson S. Raynaud's phenomenon in a female population: prevalence and association with other conditions. Angiology 1987;38: 871-7. 9. Zahavi I, Chagnac A, Hering R, et aI. Prevalence of Raynaud's phenomenon in patients with migraine. Arch Intern Med 1984;144:742-4. 10. Atkinson AR, Appenzeller 0, Hemicrania and Raynaud's phenomenon: manifestation of the same disease? Headache 1976;16:1-2. 11. Welsh KMA, Darnley D, Simkins RT. The role of estrogen in migraine: a review and hypothesis. Cephalalgia 1984;4:227-36. 12. WuestJH, Dry TJ, Edwards JE. The degree of coronary atherosclerosis in bilaterally oophorectomized women. J Am Heart Assoc 1953;7:801-9. 13. Robinson RW, Higano N, Cohen WD. Increased incidence of coronary heart disease in women castrated prior to the menopause. Arch Intern Med 1959;104:908-13. 14. Stampfer MJ, Colditz GA, Willett WC. Menopause and heart disease: a review. Ann N Y Acad Sci 1990;592:192203. 15. Gordon T, Kannel WB, Hjortland MC, McNamara PM. Menopause and coronary heart disease: the Framingham study. Ann Intern Med 1978;89:157-61. 16. Siddle N, Sarrel P, Whitehead M. The effect of hysterectomy on the age at ovarian failure: identification of a subgroup of women with premature loss of ovarian function and literature review. Fertil Steril 1987;47:94-100. 17. McPherson K, WennbergJE, Hovindo B, et al. Small-area variations in the use of common surgical procedures: an international comparison of New England, England, and Norway. N EnglJ Med 1982;307:1310-4. 18. Tobin JN, Wassertheil-Smollers, Wexler JP, et al. Sex bias in considering coronary bypass surgery. Ann Intern Med 1987;197:19-25. 19. WilliamsJK, Adams MR, Klopfenstein HS. Estrogen modulates responses of atherosclerotic coronary arteries. Circ Res 1990;81:1680-7. 20. Magness RR, Rosenfeld CR. Local and systemic estradiol1713: effects on uterine and systemic vasodilation. Am J Physiol 1989;256(suppl):E536-42. 21. Bush TL, Barrett-Conner E, Cowan LD, et al. Cardiovascular mortality and non-contraceptive use of estrogen in women. Circulation 1987;75:1102-9.