HORMONE REPLACEMENT THERAPY (HRT): THE GOOD, THE BAD, AND THE UGLY

WOMEN AND HEART DISEASE

• MI, stroke, and other coronary heart disease have killed more women than men each year since 1984
• In 1995, 455,000 men and 505,000 women died from Coronary Heart Disease
• Diseases of the heart and blood vessels kill more American women than the next 16 causes of death combined, including all cancers
• CHD occurs in 1 out of 8 women ages 45 to 64, and in 1 out of 3 over age 65
• In women 55 to 64 years old with CHD, 36% are disabled and in women over age 75, more than 55% are disabled
• For postmenopausal women, lifetime risk of death from CHD is 31%, compared to hip fracture (2.8/%), breast cancer (2.8%)
• Hospital mortality from MI is higher in women (16%) than men (11%)
• Women have poorer outcomes after MI than men, whether or not they receive thrombolytic therapy.
  • with thrombolytic therapy: in hospital mortality was 9.3% in women and 4.5% in men
  • without thrombolytic therapy: mortality in women was 16% and 10.9% in men

HEART DISEASE RISK FACTORS IN WOMEN

In 1991, in women ages 20-74 years:

• more than 33% have hypertension
• more than 25% have total cholesterol greater than 240 mg/dl
• 53% of non-hispanic white women older than 20 have borderline-high or high cholesterol
• more than 25% smoke cigarettes (smoking triples the risk of MI and lowers the age of initial MI; women who smoke fewer than 5 cigarettes/day have twice the risk of CHD over non-smokers)
• more than 25% of women are obese (greater than 20% over ideal body weight)

ATHEROSCLEROSIS IS AN EQUAL OPPORTUNITY KILLER

Five placebo-controlled clinical trials reveal that the best way to reduce and prevent coronary heart disease and stroke in women is statin drugs, not estrogen replacement therapy. The major, placebo-controlled, statin drug trials are as follows:

1. Care: Pravachol vs placebo (people with previous MI)
   Major coronary events fell 46% in women and 20% in men.
    
2. 4S: Simvastatin vs placebo (people with previous CHD)
   Major CHD events fell 35% in women.
    
3. POSCH: Partial ileal bypass in women
   31% reduction in CHD morbidity/mortality
   30% reduction in Coronary Artery Bypass CABG
   58% reduction in angioplasty.
    
4. LCAS: Fluvastatin (people with previous CHD)
   benefit in women as well as in men
    
5. AFCAPS/TexCAPS: 997 women (without clinically evident CHD, with average serum cholesterol levels)
   Lovastatin 20-40 mg/day reduced cardiovascular events in men and women, women better than men (after 5.2 years followup)

American Heart Association Science Advisory: HRT and CHD

Recommendation 1: Before ever giving estrogen-containing oral contraceptives, estrogen replacement therapy, Evista, or Tamoxifen, or in women already on such therapy, screen using the serologic resistance to activated protein C assay, and genotype for the prothrombin gene, or genotype for both the prothrombin and V Leiden mutations by cDNA-PCR assay (MDL lab [513-475-6631]). In women already on ERT, or pregnant, the assay of choice is the cDNA-PCR test, since it is not effected by exogenous estrogen, unlike the serologic test.

Recommendation 2: In women, heterozygous for the Factor V Leiden mutation, and/or heterozygous for the prothrombin gene mutation, HRT is contraindicated.

After years of taking the opposite tack, the American Heart Association (AHA) is recommending that HRT should not be initiated for secondary prevention of cardiovascular disease (CVD) in postmenopausal women.

The recommendation follows clinical trials suggesting there is no cardiovascular benefit. In fact, when women with documented atherosclerosis began to take HRT, there was an increased risk of cardiovascular disease events.

The AHA recommendations are needed because physicians have asked for clarification of the data surrounding HRT, said Lori Mosca, MD, PhD, lead author of the AHA science advisory and director of preventive cardiology at New York Presbyterian Hospital in New York City. "For many years, cardiologists and other health care providers who take care of women have assumed that HRT protects the heart," Mosca said. "At this time there is not sufficient evidence to make that claim. Our purpose is to clarify the role of hormones in heart disease prevention." The two key trials cited in the recommendation are the Heart and Estrogen/Progestin Replacement Study (HERS) and the Estrogen Replacement and Atherosclerosis (ERA) Trial.

In HERS, researchers found that after an average of 4.1 years of follow-up, there was no difference in the primary outcome of nonfatal myocardial infarction and coronary death between the women taking hormone and those on a placebo. In fact, they found a 52% increase in cardiovascular events in the first year in the HRT group compared with the placebo group.

The ERA trial, to test the effect of estrogen replacement therapy (ERT) and HRT on the progression of atherosclerosis in postmenopausal women with documented coronary stenosis, showed no benefit from either one (N Engl J Med. 2000;343:522-529).

The Heart Association recommends that physicians treating women with CVD on HRT should decide to continue or stop long-term therapy based on established noncoronary benefits and risks and patient

preference. It also recommended that if a woman with CVD who is undergoing HRT develops an acute event, such as myocardial infarction, or is immobilized, it is prudent to consider discontinuing HRT or to consider

anticoagulants while she is hospitalized to minimize the risk of developing a blood clot. Whether or not to restart HRT should then be based on established noncoronary benefits and risks, as well as patient preference.

USE FOR PRIMARY PREVENTION

The AHA cited an analysis showing an approximate 35% reduction in CHD events among uses of ERT and of HRT. But the AHA said there is insufficient data to suggest that HRT should be initiated only for primary prevention of CVD, and that it would withhold firm clinical recommendations for use of HRT for primary prevention until results are published from ongoing clinical trials.

WOMEN'S HEALTH INITIATIVE DATA

Last year, investigators informed participants in an ongoing trial, the Women's Health Initiative, that during the study's first 24 months there was a small increase in the number of myocardial infarctions, strokes, and blood clots in women taking HRT or ERT compared with those taking placebo. This June, the investigators informed participants that the data through February 28, 2001, still showed that a small number, less than one half of 1% per year, continue to have acute cardiovascular events.

For primary prevention of CVD, the AHA recommends the tried-and-true approach: women should attempt to reduce their risk factors through lifestyle modifications as smoking cessation, increased exercise, and weight loss, and, if needed, medications to improve cholesterol levels and lower elevated blood pressure.

COAGULATION PROBLEMS AND ERT:

• Osteonecrosis of the hip (adults and children) and jaw (adults). Factor V Leiden and prothrombin gene mutations have been shown to interact with ERT to promote osteonecrosis.
• A major risk factor for retinal vein thrombosis (adults) and for non arteritic ischemic optic neuropathy (NAION). Factor V Leiden mutation and the prothrombin gene mutation have been shown to interact with ERT to promote retinal vein thrombosis and retinal artery thrombosis.
• A major risk factor for first trimester miscarriage and for major complications of pregnancy. Physiologic hyperestrogenemia of pregnancy interacts with Factor V Leiden and prothrombin gene mutations.
• A major risk factor when interacting with estrogen for venous and arterial thrombosis.

ESTROGEN-INDUCED HYPERTRIGLYCERIDEMIA AND PANCREATITIS

Q: Are estrogens or SERMS (Evista, Tamoxifen) contraindicated in some women?

A: Yes! Most women with triglycerides greater than 300 mg/dl should never take estrogens or SERMS.

• when fasting triglycerides are greater than 500 mg/dl estrogen is absolutely contraindicated
• when fasting triglycerides are greater than 300 mg/dl relatively contraindicated

Q: Why?

A: Women with inherited high triglycerides who take either estrogen or SERMS increased risk for pancreatitis, heart attack, and stroke. Triglycerides in these women can rise above 1000 mg/dl and the estrogen prevents the triglyceride-lowering medications from working.

Q: If the triglycerides are normal, are there any other reasons to avoid taking estrogen?

A: Yes! All women heterozgyous for the mutant Factor V Leiden gene or for the prothrombin gene should avoid taking estrogen or SERMS.

Q: Why?

A: When estrogen and probably SERMS are given to V Leiden or Prothromin gene heterozygotes, the risk of blood clots rises to 40 times that of the general population.
 

HRT, BREAST CANCER, ENDOMETRIAL CANCER

With every medication there are benefits and risks. The benefits of HRT include prevention of osteoporosis and easing of menopausal symptoms (night sweats, hot flashes, vaginal dryness, etc). In the past, it was felt that HRT reduced risk of heart attack and stroke. As summarized above, new evidence shows that HRT may increase coronary heart disease event rates, particularly in women heterozygous for the V Leiden or Prothrombin gene mutations (11% of the Caucasian population). The risks of HRT, beyond elevation of triglycerides, and increased risk of venous thrombosis involve cancer of the breast, endometrium, and ovaries.

The relative risk of breast cancer is moderately elevated in current and recent HRT users, and increases by about 2.3% per year with longer duration of use. The effect drops after cessation, and largely but not totally disappears after about 5 years. Unopposed estrogen use is strongly related to increased enometrial cancer, but cyclic estrogen-progestin use appears to reduce this side effect if progestins are used for at least 14 days per cycle. Unfortunately, however, combined HRT is associated with increased risk of breast cancer as opposed to estrogen alone.

References

Women and Heart Disease:

1. Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. J Am Med Assn 280:605-613, 1998.
2. Herrington DM, Reboussin DM, Brosnihan KB, et al: Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Eng J Med 343:522-529, 2000.
3. McGowan JA, Pottern L. Commentary on the Women's Health Initiative. Maturitas 2000;34:109-112.
4. Design of the Women's Health Initiative clinical trial and observational study. The women's health initiative study group. Control Clin Trials 19:61-109, 1998.
5. Glueck CJ, Wang P, Fontaine RN, et al: Effect of exogenous estrogen on atherothrombotic vascular disease risk related to the presence or absense of the Factor V Leiden mutation (resistance to activated protein C). Am J Cardiol 84:549-554 1999.
6. Glueck CJ, McMahon RE, Bouquot J, et al: Heterozygosity for the Leiden mutation of the Factor V gene, a common pathoetiology for osteonecrosis of the jaw, with thrombophilia augmented by exogenous estrogens. J Lab Clin Med 130:540-543, 1997.
7. Glueck CJ, McMahon RE, Bouquot JE, et al: Exogenous estrogen may exacerbate thrombophilia, impair bone healing, and contribute to development of chronic facial pain. Cranio, Craniomandibular Practice 16:143-153,1998.
8. Henkens CM, Bom VJ, Seinen AJ, et al: Sensitivity to activated protein C; influence of contraceptives and sex. Thromb Haemost 73:402-404,1996.
9. Caine YG, Bauer KA, Barzegar S, et al: Coagulation activation following estrogen administration to postmenopausal women. Thromb Haemost 68:392-395,1992.
10. Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med 127:895-903, 1997.
11. Bauersachs R, Lindhoff-Last E, Erhly AM, et al: Significance of hereditary thrombophilia for risk of thrombosis with oral contraceptives. Zentralbl Gynakol 118:262-270, 1996.
12. Rosendaal FR, Siscovick DS, Schwartz SM, et al: Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 89:2817-21, 1997.
13. Glueck CJ, Wang P, Fontaine RN, Sieve-Smith L, Lang JE. Interaction of estrogen replacement therapy with the thrombophilic 20210 G/A prothrombin gene mutation for atherothrombotic vascular disease. A cross-sectional study of 275 hyperlipidemic women. Metabolism 2001;50:360-365.
14. Glueck CJ, Wang P, Fontaine RN, Sieve-Smith L, Lang J. Estrogen replacement therapy, thrombophilia, and atherothrombosis. Metabolism, In Press, 2002.

Osteonecrosis of the Hip, Venous thrombosis

1. Glueck CJ et al. Heterozygosity for the Leiden mutation of the factor V gene, a common pathoetiology for osteonecrosis of the jaw. J Lab Clin Med 1997;130:540-543.
2. Glueck CJ, McMahon RE, Bouquot JE, Triplett D. Exogenous estrogen therapy may exacerbate thrombophilia, impair bone healing, and contribute to development of chronic facial pain. Cranio, The Journal of Craniomandibular Practice 1998;16:143-153.
3. Glueck CJ, Friberg RA, Fontaine RN, Tracy T, Wang P. Hypofibrinolysis, thrombophilia, osteonecrosis. Clinical Orthopedics 2001;386:19-33.
4. Glueck CJ, Frieberg RA, Fontaine RN et al: Anticoagulant therapy for osteonecrosis associated with heritable hypofibrinolysis and thrombophilia. Expert opinion on Investigational Drugs 2001;10:1309-1316.
5. Levesque H et al. Estrogen therapy and venous thromboembolic disease. Reve Med Interne 1997;18 (suppl 6): 620S-625S.
6. Weitz IC et al. Tamoxifen-associated venous thrombosis and activated protein C resistance due to factor V Leiden. Cancer 1997;79:2024-2027.
7. Hennekens CM et al. Sensitivity to activated protein C; influence of oral contraceptives and sex. Thromb Haemost 1996;73:402-404.
8. Caine YG, Bauer KA, Barzegar S, et al. Coagulation activation following estrogen administration to postmenopausal women. Thrombosis and Haemostasis 1992;68:392-395.
9. Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Annals of Int Med 1997;127:895-903.
10. Glueck CJ, Freiberg, R, Gruppo R, Crawford A, Roy D, Brandt G, McMahon RE, Bouquot J, Tracy T, Stroop D, Wang P, Becker A. Thrombophilia and Hypofibrinolysis: Reversible Pathogenetic Etiologies of Osteonecrosis in Adults and in Children (Legg-Perthes Disease). AOA International Symposium on Osteonecrosis. In Urbaniak JR, Jones JP Jr (eds). Osteonecrosis: Etiology, diagnosis, and treatment. Rosemont IL, American Academy of Orthopedic Surgeons, 1997;pp 105-110.
11. Glueck CJ, Brandt G, Gruppo R, Crawford A, Roy D, Tracy T, Stroop D, Wang P, Becker A. Resistance to activated protein C and Legg-Perthes Disease. Clinical Orthopedics 1997;338:139-152
12. Brandt G, Gruppo R, Glueck CJ, Stroop D, Becker A, Pillow A, Wang P. Sensitivity, specificity, and predictive value of modified assays for activated protein C resistance in children. Thrombosis Haemostasis 1998;79:567-570.
13. Gruppo R, Glueck CJ, Wall E, Roy D, Wang P. Legg-Perthes disease in three siblings, 2 heterozygous and 1 homozygous for the Factor V Leiden Mutation. Journal of Pediatrics 1998;132:885-888
14. Arruda VR, Belangero WD, Oxelo MC, Oliveira GB, Pagnano RG, Volpon JB, Annichino-Bizzacchi JM. Inherited risk factors for thrombophilia among children with Legg-Calve'-Perthes Disease. J Ped Orthop 1999;19:84-87.
15. Eldridge JC, Dilley A, Dorris J, et al: Thrombophilia due to protein C deficiency, protein S deficiency or resistance to activated protein C as a cause of Legg-Perthes disease. Pediatrics 102 (#3): 14A,1998.

Osteonecrosis of the Jaws:

1. Glueck CJ, McMahon RE, Bouquot JE, Tracy T, Sieve-Smith L, Wang P. A Preliminary pilot study of treatment of thrombophilia and hypofibrinolysis and amelioration of the pain of osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:64-73.
2. Glueck CJ, McMahon RE, Bouquot JE, Tracy T, Sieve-Smith L, Wang P. A Preliminary pilot study of treatment of thrombophilia and hypofibrinolysis and amelioration of the pain of osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:64-73.
3. Glueck CJ, McMahon RE, Bouquot J, Triplett D, Gruppo R, Wang P. Heterozygosity for the Leiden mutation of the factor V gene, a common pathoetiology for osteonecrosis of the jaw, with thrombophilia augmented by exogenous estrogens. J Lab Clin Med 1997;130:540-543.
4. Glueck CJ, McMahon RE, Bouquot JE, Triplett D. Exogenous estrogen may exacerbate thrombophilia, impair bone healing, and contribute to development of chronic facial pain. Cranio, The Journal of Craniomandibular Practice 1998;16:143-153

Atherothrombosis: Arterial thrombosis

1. Glueck CJ, Fontaine RN, Gupta A, Alasmi M. Myocardial infarction in a 35 year old man with homocysteinemia, high plasminogen activator inhibitor activity, and resistance to activated protein C. Metabolism 1997;46:1470-1472
2. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L, Lang JE. Effect of exogenous estrogen on atherothrombotic vascular disease risk related to the presence or absence of the factor V Leiden mutation. Am J Cardiol 1999;84:549-554.
3. Glueck CJ, Wang P, Fontaine RN, Sieve-Smith L, Lang JE. Interaction of estrogen replacement therapy with the thrombophilic 20210 G/A prothrombin gene mutation for atherothrombotic vascular disease. A cross-sectional study of 275 hyperlipidemic women. Metabolism 2001;50:360-365.
4. Glueck CJ, Wang P, Fontaine RN, Sieve-Smith L, Lang J. Estrogen replacement therapy, thrombophilia, and atherothrombosis. Metabolism, In Press, 2002.

Retinal Vein Thrombosis, Non-arteritic optic neuritis (NAION):

1. Glueck CJ, Bell H, Vadlamani L, Gupta A, Fontaine RN, Wang P, Tracy T, Stroop D, Gruppo R Heritable thrombophilia and hypofibrinolysis. Arch Ophthalmol 1999;117:43-49.
2. Glueck CJ, Fontaine RN, Wang P. Interaction of heritable and estrogen-induced thrombophilia: possible pathoetiologies for ischemic optic neuropathy and ischemic strok. Thrombosis Haemostasis 2001;85:256-9

Triglycerides and estrogens

1. Glueck CJ, Lang J, Tracy T, Oakes N, Speirs J. Severe hypertriglyceridemia and pancreatitis when estrogen replacement therapy is given to hypertriglyceridemic women. J Lab Clin Med 1994;123:59-64.
2. Stone NJ. Estrogen-induced pancreatitis: a caveat worth remembering. J Lab Clin Med 1994;123:18-19
3. Glueck CJ, Streicher P, Wang P, Sprecher D, Falko JM. Treatment of severe familial hypertriglyceridemia during pregnancy with very low fat diet and omega-3 fatty acids. Nutrition 1996; 12: 203-205.
4. Glueck CJ, Lang JE. Lipoprotein Metabolism in the Elderly. The Merck Manual of Geriatrics, Abrams WB, Beers MH, Berkow RB, eds. Merck and Co, Rahway, NJ, 1995, pp 1023-1052.
5. Glueck CJ, Christopher C, Mishkel MA, et al: Pancreatitis, familial hypertriglyceridemia and pregnancy. Am J Obstet Gynecol 1980;136:755-761.
6. Glueck CJ, Scheel D, Fishback J, et al: Estrogen-induced pancreatitis in patients with previously covert familial type V hyperlipoproteinemia. Metabolism 1972;21:657-666.
7. Zorrilla E, Hulse M, Hernandez A, Gershberg H. Severe endogenous hypertriglyceridemia during treatment with estrogen and oral contraceptives. J Clin Endocrinol Metab 1968;28:1793-1796.
8. Davidoff F, Tishler S, Rosoff C. Marked hyperlipemia and pancreatitis associated with oral contraceptive therapy. NEJM 1973;289:552-555.
9. Hoogerbrugge N. Hypertriglyceridemia following oestrogen use. Ned Tijdschr Geneeskd 1997;141:1225-1227 (Dutch)
10. Stone NJ. Secondary causes of hyperlipidemia. Med Clin North Am 1994;78:117-141.
11. Parker WA. Estrogen-induced pancreatitis. Clin Pharm 1983;2:75-79.
12. Editorial. Pancreatitis from oral contraceptives. Br Med J 1973;4:688-689
13. Brunzell JD et al. The interaction of familial and secondary causes of hypertriglyceridemia: role in pancreatitis. Trans Assoc Am Physicians 1973; 86:245-254.

HRT, Cancer

1. Colditz GA. Hormones and breast cancer. Journal of Womens Health 1999;8:347-57
2. Lacey JV et al: Use of hormone replacement therapy and adenocarcinoma and squamous cell carcinomas of the uterine cervix. Gynecologic Oncology 2000;77:149-154.
3. Jasienska G, et al: Energetic factors, ovarian steroids, and the risk of breast cancer. European Journal of Cancer Prevention 2000;9:231-9.
4. Hill DA, et al: Continuous combined hormone replacement therapy and risk of endometrial cancer. Am J Ob Gyn 2000;183:1456-61.
5. Zeleniuch-Jacquette A, et al. Postmenopausal endogenous oestrogens and risk of endometrial cancer: results of a prospective study. JAMA 2000;283:485-91.
6. Lipman MF, et al. Indicators of lifetime estrogen exposure: effect on breast cancer incidence and interaction with raloxifene therapy in the multiple outcomes of raloxifene evaluation study participants. J Clin Oncol 2001;19:3111-6.
7. Ross KK, et al. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J NCI 2000;92:328-32
8. Genazzani AR, Gadducci A, Gambacciani M. Controversial issues in climacteric medicine II. Hormone replacement therapy and cancer. International Menopause Society Expert Workshop. 9-12 June 2001, Opera del Duomo, Pisa, Italy. Climacteric. 2001 Sep;4(3):181-93.
9. Mahavni V, Sood AK. Hormone replacement therapy and cancer risk. Curr Opin Oncol. 2001 Sep;13(5):384-9. Review.
10. La Vecchia C, Brinton LA, McTiernan A. Menopause, hormone replacement therapy and cancer. Maturitas. 2001 Aug 25;39(2):97-115. Review.
11. Barrett-Connor E, Stuenkel CA. Hormone replacement therapy (HRT)--risks and benefits.Int J Epidemiol. 2001 Jun;30(3):423-6. Review.
12. Newcomb PA, Trentham-Dietz A, Egan KM, Titus-Ernstoff L, Baron JA, Storer BE, Willett WC, Stampfer MJ. Fracture history and risk of breast and endometrial cancer. Am J Epidemiol. 2001 Jun 1;153(11):1071-8.
13. Shoupe D. HRT dosing regimens: continuous versus cyclic-pros and cons. Int J Fertil Womens Med. 2001 Jan-Feb;46(1):7-15. Review.
14. Pukkala E, Tulenheimo-Silfvast A, Leminen A. Incidence of cancer among women using long versus monthly cycle hormonal replacement therapy, Finland 1994-1997. Cancer Causes Control. 2001 Feb;12(2):111-5.
15. Persson I. Estrogens in the causation of breast, endometrial and ovarian cancers - evidence and hypotheses from epidemiological findings. J Steroid Biochem Mol Biol. 2000 Nov 30;74(5):357-64. Review.
16. Beral V, Banks E, Reeves G, Appleby P. Use of HRT and the subsequent risk of cancer. J Epidemiol Biostat. 1999;4(3):191-210; discussion 210-5. Review.
17. Sismondi P, Biglia N, Giai M, Ponzone R, Roagna R, Sgro L, Campagnoli C. HRT, breast and endometrial cancers: strategies and intervention options. Maturitas. 1999 Aug 16;32(3):131-9. Review.
18. Persson I, Weiderpass E, Bergkvist L, Bergstrom R, Schairer C. Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement. Cancer Causes Control. 1999 Aug;10(4):253-60.

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