Paradigm's Lost,¹ 2003: Lessons from the placebo-controlled Women's Health Initiative:

Estrogen-progestin should not be used in menopausal women to prevent coronary heart disease.

WHI

• 16,608 postmenopausal women, ages 50-79, conjugated ethinyl estradiol 0.625 mg plus MPA 2.5 mg, or placebo.
• Primary efficacy outcome CHD
• After mean follow-up of 5.2 years, terminate trial, because risks exceeded benefits.
• EP does not confer cardiac protection and may increase the risk of CHD, especially in the 1st year after starting HRT. The treatment should not be prescribed for prevention of CHD

WHI AND STROKE

• Excess of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of CHD, use of hormones, statins, or aspirin

WHI: BREAST CANCER AND MAMMOGRAPHY

• Relatively short term EP increases incident breast cancers, which are diagnosed at a more advanced age, compared to placebo.
• EP substantially increases the percentage of women with abnormal mammograms.
• EP may stimulate breast cancer growth and hinder breast cancer diagnosis

WHI-GYNECOLOGIC CANCERS

• Continuous EP may increase the risk of ovarian cancer while producing endometrial cancer rates similar to placebo.
• The increased burden of endometrial biopsies required to assess vaginal bleeding further limits acceptability of EP regimens.
• Caution should be used when using continuous EP therapy

WHI- FRACTURE AND BONE MINERAL DENSITY

• EP increases bone mineral density and reduces the risk of fracture, present in all subgroups of women examined.
• When considering the effects of HRT on other important disease outcomes in a global model, there was no net benefit, even in women considered to be a high risk for fracture.

WHI-QUALITY OF LIFE

• EP did not have a clinically meaningful effect on health-related quality of life.
• Among post-menopausal women, 65 or older, EP did not improve cognitive function when compared to placebo. There was a small increased risk of clinically meaningful cognitive decline in the EP group.

References:

Manson JE, et al
Estrogen plus progestin and the risk of coronary heart disease
N Engl J Med. 2003 Aug 7;349(6):523-34

Wasserhiel-Smoller S, et al
Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial
JAMA. 2003 May 28;289(20):2673-84

Chlebowski RT, et al
Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial
JAMA. 2003 June25;289(24):3243-53

Anderson GL, et al
Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative Randomized Trial
JAMA. 2003Oct1;290(13):1739-48

Cauley JA, et al
Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative Randomized Trial
JAMA. 2003 Oct1;290(13):1729-38

Rapp SR, et al
Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Randomized Trial

Hays J, et al
Effects of estrogen plus progestin on health-related quality of life
N Engl J Med. 2003 May 8;348(19): 1839054

Hlatky MA, et al
Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy: results from the Heart and Estrogen/Progestin Replacement Study (HERS) trial

1 Credit for the title to David Herrington MD

---

Please see article above

Estrogen Supplementation in Post Menopausal Women

Jewish Hospital Cholesterol Center, Charles J. Glueck MD, Director, James E. Lang MD, Associate Director. Jewish Hospital Cholesterol Center, 3200 Burnet Ave, Cincinnati, Ohio 45229. 

Phone: 513-585-7800 Fax: 513-585-7950
E-mail: glueckch@healthall.com or cglueck@fuse.net  
web: http://www.jewishhospitalcincinnati.com/cholesterol/index.html

Frequently Asked Questions:

1. A placebo-controlled clinical trial data now provides us with the answers to the following major questions:

a. Does unopposed estrogen reduce myocardial infarction and stroke event rate?

b. Is unopposed estrogen therapy associated with increased cancer event rates, or increased blood clotting event rates, or other side effects?

c. Does estrogen/progestin therapy reduce myocardial infarction and stroke event rate?

d. Is estrogen/progestin therapy associated with increased cancer event rates, or increased blood clotting event rates, or other side effects?

Scientific Update, 9/27/2000. Failure of estrogen replacement therapy (ERT) to reduce coronary heart disease, coupled with an increase in atherothrombotic events.

Jewish Hospital Cholesterol Center, Charles J. Glueck MD, Director, James E. Lang MD, Associate Director, LeAnn Coberly MD Assistant Medical Director. Jewish Hospital Cholesterol Center, 3200 Burnet Ave, Cincinnati, Ohio 45229. 

Phone: 513-585-7800 Fax: 513-585-7950
E-mail: glueckch@healthall.com or cglueck@fuse.net  
web: http://www.jewishhospitalcincinnati.com/cholesterol/index.html

Recently, the first major, placebo-controlled clinical trial of estrogen replacement therapy (ERT) in the secondary prevention of coronary heart disease (CHD) has been reported (the HERS study).¹  Over an average 4.1 years of followup, ERT failed to reduce the overall rate of CHD events, but increased thromboembolic events by 289% and gall bladder disease by 38%.¹ In the Estrogen and Atherosclerosis (ERA) trial,² 309 postmenopausal women with at least 1 coronary artery stenosis >30% were randomized to premarin 0.625 mg/day (n=100), premarin plus medroxyprogesterone acetate 2.5 mg/day (n=104), or placebo (n=105). After mean followup of 3.2 years, there was no difference between the three groups in coronary artery disease progression measured by change in the mean minimal lumen diameter by quantitative coronary angiography.  Moreover, the change in mean minimal lumen diameter from baseline to follow-up, a measure of disease progression, did not differ significantly among the 3 treatment groups. Preliminary data from the data and safety monitoring board of a third prospective, placebo-controlled, randomized clinical trial, the Woman's Health Initiative Hormone Replacement Trial (WHI-HRT),^3,4 like HERS¹ and ERA,² revealed no cardiovascular benefit from ERT (Lenfant, NHLBI statement, 4/17/00). The WHI-HRT included 16,609 postmenopausal women with a uterus taking estrogen combined with progestin, 10,739 women with a hysterectomy taking estrogen alone, and a placebo group.^3,4 During the first two years of the WHI-HRT there was a small increase in the number of myocardial infarctions, strokes, and thromboemboli in women taking active hormones compared to placebos. These increased events, however, did not meet statistical criteria for stopping the trial (Lenfant, NHLBI statement, 4/17/00). Along with HERS¹ and ERA², WHI-HRT^3,4 was the third prospective, placebo-controlled, randomized clinical trial which suggested that ERT is not cardio-protective in postmenopausal women with CHD, and substantially increases thromboembolism.

Our recent cross-sectional study⁵ of interactions between the thrombophilic Factor V Leiden gene mutation, ERT, and ATCVD in 423 women referred for hyperlipidemic therapy may provide some insight into the unexpected failure of ERT to reduce CHD in the HERS,¹ ERA,² and WHI-HRT^3,4 studies. We reported an interaction between ERT-mediated thrombophilia and the thrombophilic Factor V Leiden mutation for ATCVD.⁵ Independent of other risk factors for ATCVD, ATCVD events were more likely in two subgroups of women, not taking ERT (ERT minus [-]) and without the Factor V Leiden gene mutation (Leiden gene mutation minus [-]) or ERT users (ERT plus [+]) and Leiden gene mutation present (Leiden plus [+]).⁵ ERT was protective against ATCVD in Leiden gene mutation - women; 24% of Factor V Leiden gene mutation - women on ERT had sustained ATCVD vs 43% of those not on ERT (p=.001).⁵ We speculated⁵ that when ERT-mediated thrombophilia is superimposed on the heritable thrombophilic Factor V Leiden mutation, ATCVD is promoted, and any putative^1-4 ERT associated reduction in ATCVD is overshadowed. We speculated⁵ that ERT might reduce ATCVD in women without the Factor V Leiden gene mutation, and suggested,^5-7 as have others,^8-12 that women with the Factor V Leiden gene mutation not be given ERT, so as to reduce thromboembolic events,¹ and (speculatively) ATCVD.

Recently, we have shown that exogenous estrogen interacts with a common heritable trait, the prothrombin gene mutation, which is present in at least 6% of American women.¹³

In a consecutive case series, cross-sectional study of 275 women referred for therapy of hyperlipidemia, (75 [27%] on estrogen replacement therapy [ERT]), our specific aim was to determine whether ERT-mediated thrombophilia and heterozygosity for the thrombophilic 20210 G/A prothrombin gene mutation interacted as risk factors for atherothrombotic cardiovascular disease (ATCVD).¹³ Of the 275 women, 100 (36%) had ATCVD; 10 (3.6%) were heterozygous for the 20210 G/A prothrombin gene mutation. In women without the 20210 G/A prothrombin gene mutation, 15 of 71 (21%) on ERT had  ATCVD vs 78 of 194 (40%) not on ERT (X² = 8.31, p=.004). By stepwise logistic regression, in 261 women with ATCVD risk factor data, positive explanatory variables for ATCVD included the 20210 G/A prothrombin mutation (risk odds ratio 5.8, 95% confidence intervals [CI] 1.4-30.2, p=.021) and a 20210 G/A prothrombin gene mutation*ERT interaction term (risk odds ratio 2.70, 95% CI 1.4-5.4, p=.004). ATCVD events were more likely in two subgroups of women (ERT - and 20210 G/A prothrombin gene mutation -) or (ERT + and 20210 G/A prothrombin gene mutation +), p=.004. Other positive explanatory variables for ATCVD events included age (p=.004), triglycerides (p=.012), lipoprotein (a) (p=.03), and homocysteine (p=.032). ERT may be protective against ATCVD when the thrombophilic 20210 G/A prothrombin gene mutation is absent, whereas the 20210 G/A prothrombin gene mutation may increase risk for ATCVD, particularly in the presence of ERT. We suggest that the 20210 G/A prothrombin gene mutation be measured in all women on ERT or before beginning ERT to identify those heterozygous for the thrombophilic  prothrombin gene mutation (4%) in whom ERT is contraindicated because of increased risk for ATCVD and thromboembolism, and a second, much larger group of women without the 20210 G/A prothrombin gene mutation (96%) in whom ERT may possibly reduce risk for ATCVD.

References

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, In Press, 2000

2. Do we have proven, safe, and effective approaches to prevent heart attack and stroke in post-menopausal women?

YES!! There is abundant, placebo-controlled, clinical trial data using many of the Statin drugs, Mevacor, Zocor, and Pravachol, as well as older data with Niacin and Bile Acid Binding resins which shows that:

• lowering LDL cholesterol below 130 mg/dl in the absence of pre-existing heart disease, or below 100 mg/dl in the presence of pre-existing heart disease will reduce the likelihood of heart attack and stroke about 30 to 60%.
• Postmenopausal women actually respond better than men to such drugs, with greater lowering of LDL cholesterol and a greater reduction in heart attack and stroke event rates.
• By measuring total cholesterol, LDL cholesterol, triglyceride, HDL cholesterol, Lp(a), and homocysteine in women (and men), and by measuring blood pressure, cigarette smoking, and with tests for diabetes, we can easily identify those people who are at high risk and we can easily, safely, and effectively treat them WITHOUT ANY CONSIDERATION OF ESTROGEN THERAPY.

3. Are estrogens contraindicated in some women?

YES!! Because they can sharply raise triglycerides in women with increased triglycerides, causing pancreatitis, stroke, and heart attack, they are contraindicated in the following women:

• All women with fasting plasma triglycerides >500 mg/dl.
• Most women with fasting plasma triglycerides >300 mg/dl.

Before starting post menopausal estrogens, or if already on postmenopausal estrogens without a previous fasting triglyceride level determination, measure fasting triglycerides.

• Women heterozygous for either the mutant Factor V Leiden gene or prothrombin gene mutation (Molecular Diagnostics Laboratories (MDL)) (about 6% of unselected American women). The mutant Factor V Leiden gene causes resistance to activated protein C, which increases the risk of blood clots. Since at least 6% of unselected American women (and men) have the V Leiden mutation, we and others now suggest that a measurement of resistance to activated protein C be made before either post-menopausal estrogens or oral contraceptives containing estrogens are given. 6% of American women are heterozygous for the prothrombin gene mutation and we suggest that this be measured before estrogen replacement therapy is perscribed.

4. Is heart disease a major problem in women?

YES!!

• Heart disease is the leading cause of death in postmenopausal women.
• Over 240,000 women die with heart attacks each year.
• Heart attacks account for 22% of all deaths among women.
• About 50% of all deaths from heart attack occur in women.
• Long term, placebo-controlled, clinical trials on hormone replacement therapy and risk of coronary heart disease in women have not yet been completed.

5. Is estrogen replacement the only therapy for osteoporosis?

NO!!

There are two newly available, non hormonal, pharmacological approaches to treatment of osteoporosis:

a.  Fosamax

b.  Nasal calcitonin

They are very effective and safe, provided that they are used precisely according to directions.

6. Where is estrogen known/proven to be useful?

• Prevention/amelioration of perimenopausal and menopausal hot flashes, and sweats.
• Prevention/amelioration of osteonecrosis.
• Amelioration of dyspareunia (painful vaginal intercourse) due to menopausal changes in the vaginal epithelium.

Cholesterol Center, Jewish Hospital. 1/30/97 Charles J Glueck MD, Medical Director, James E. Lang MD, Associate Medical Director.

 

The Major Statin Drugs, Pravastatin, Simvastatin, Atorvastatin:

Pravastatin (Pravachol), a safe, potent HMG-COA reductase inhibitor. This compound, from the same family of compounds as Mevacor, is an effective and safe cholesterol lowering drug. In recent multi-center studies (Clinical Cardiology 1991;14:146-151), Pravachol was effective in lowering the "bad" cholesterol, i.e., LDL cholesterol, slightly elevated the "good" cholesterol, HDL-C, and, at the highest dose, lowered triglycerides:

Pravachol (Pravastatin)

Dose	LDL-C(reduction)	HDL-C(increase)	TG(decrease)
5 mg/day	-19.2 %	+5.2 %	-14.1 %
10 mg/day	-22.4	+6.6	-14.9
20 mg/day	-32.4	+2.4	-11.4
40 mg/day	-34.1	+11.7	-23.9

Pravachol acts similarly to, but more potently than, Mevacor. Pravachol acts predominantly to lower LDL cholesterol. At higher doses (40 mg/day), it moderately increases triglycerides, and modestly increases HDL-C.

The drug works by reducing synthesis of cholesterol in the liver and the intestine, and thus forces the liver to catabolize (chop up) more LDL cholesterol to provide adequate cholesterol for the liver cells. Because the body makes most of its cholesterol at night, the drug works best if taken with the evening meal or at bedtime. The maximal effect is seen quickly, within 4 weeks.

Side Effects:

Like Mevacor, since this drug works in the liver, a small number of patients will develop asymptomatic increases in liver enzymes. These resolve quickly when the drug is discontinued, and are not serious.

The compound may be rarely associated with increased likelihood of headache, and possibly with increased likelihood of skin rash.

When given in conjunction with Gemfibrozil (Lopid), there is a small likelihood of increased risk of muscle pain or tenderness, and if this happens, the drugs should be immediately stopped, and call made to us (513-585-7800).

Pravachol should not be given along with the following drugs because of increased likelihood of adverse reactions (liver):

1. The antibiotic Erythromycin or any erythromycin derivative.

2. Nicotinic Acid

3. Cyclosporine (may possibly be used, but only with very close follow-up)

The safety of the drug during pregnancy is not known (for the fetus), and the drug should never be taken if there is any chance of pregnancy.

OUTCOME STUDIES: The West of Scotland Study, a primary prevention study, has shown that Pravachol significantly reduces the risk of non fatal myocardial infarction (31%), and the risk of death from all cardiovascular causes by 32%, while reducing all cause mortality significantly (21%). Plac I and Plac II studies, secondary prevention studies with Pravachol, have shown up to 60% reduction in CHD (Coroonary Heart Disease) events.

Simvastatin (Zocor), a safe, potent, HMG-COA reductase inhibitor.

This compound, from the same family of compounds as Mevacor, is an effective and safe cholesterol lowering drug. In recent multi-center studies Zocor was effective in lowering the "bad" cholesterol, LDL cholesterol, slightly elevated the "good" cholesterol, HDL-C, and, at the highest dose, lowered triglycerides:

Dose	LDL-C(reduction)	HDL-C(increase)	TG(decrease)
5 mg/day	-22 %	8 %	-6 %
10 mg/day	-27	9	-10
20 mg/day	-34	12	-14
40 mg/day	-40	13	-20

Like Mevacor, the drug acts predominantly to lower LDL cholesterol, but is much more potent than Mevacor. At higher doses (40 mg/day), it moderately lowers triglycerides, and increases HDL-C modestly. The triglyceride lowering and HDL-C elevating effects may be most marked in patients who have triglycerides >250 mg/dl, and HDL-C <35 mg/dl.

The drug works by reducing synthesis of cholesterol in the liver and possibly in the intestine, and thus forces the liver to catabolize (chop up) more LDL cholesterol to provide adequate cholesterol for the liver cells. Because the body makes most of its cholesterol at night, the drug works best if taken with the evening meal. The maximal effect is seen quickly, within 4 weeks.

Side Effects:

Since this drug works in the liver, a small number of patients will develop asymptomatic increases in liver enzymes. These resolve quickly when the drug is discontinued, and are not serious. In about 0.6% of patients, the drug needs to be discontinued because of drug-related clinical adverse events, and in about 0.8% for drug-related laboratory adverse events, usually liver function tests persistently greater than 3 times the upper normal limit. About 5% of patients will develop elevations of the skeletal muscle enzyme, CPK, but only very rarely does this drug, when given by itself, produce muscle pain, weakness, or tenderness (myopathy).

The compound may be rarely associated with increased likelihood of headache. When given in conjunction with Gemfibrozil (Lopid), there is an increased, but still small likelihood of muscle pain, weakness, or tenderness, and if this happens, both Zocor and Lopid should be immediately stopped, and a call be made immediately to us (513-585-7800).

Zocor should not be given along with the following drugs because of increased likelihood of adverse reactions (liver):

1. The antibiotic Erythromycin or any erythromycin derivative.

2. Nicotinic Acid

3. Cyclosporine (may possibly be used, but only with very close follow-up)

The safety of the drug during pregnancy is not known (for the fetus), and the drug should never be taken if there is any chance of pregnancy.

OUTCOME STUDIES: In the 4 S study, Simvastatin therapy reduced the risk of having any coronary event 27%, and reduced all-cause mortality by 30%.

Atorvastatin, a newly released synthetic lipid lowering agent

Atorvastatin is a newly released member of the "Statin" family of drugs, a family which includes Mevacor, Zocor, Pravachol, and Lescol. In this family, Zocor and Pravachol have been shown to reduce the risk of heart attack and stroke in patients who have had previous heart attack or stroke, and, for Pravachol, to have the same protective effect in patients who had not had previous heart attack or stroke.

Like the other statins, Atorvastatin works in the liver, reducing synthesis of LDL cholesterol in the liver, and forcing the liver to chop up (catabolize) LDL cholesterol (which is what we want it to do).

ATORVASTATIN-DOSE RESPONSE, % CHANGE Comment: A potent LDL lowering drug with excellent triglyceride lowering effects, which should have a wide range of clinical utility .

 

ATORVASTATIN VS OTHER STATINS, % CHANGE (A = Atorvastin, L = Lovastatin, P = Pravastatin, S = Simvastatin)
 

Side Effects:

A small percentage (0.2%, 0.6%, 0.6%, and 2.3%) of patients on 10, 20, 40, and 80 mg/day get changes in liver function tests > 3 times the upper normal limit, requiring that the Atorvastatin be stopped. When the drug is stopped, then the liver tests come back to normal.

Very rarely, patients can develop muscle aches, cramps, or tenderness on Atorvastatin. If this happens, stop the drug and call us (513-585-7800).

Pregnancy:

The Atorvastatin might be toxic to the fetus. If Atorvastatin is taken by patients who have the capability of becoming pregnant, then they need bomb-proof contraception to avoid pregnancy while taking the drug.

Drug-Drug Interactions: Atorvastatin is metabolized by cytochrome P450 3A4, which means that it should never be taken with the antibiotic Erythromycin, the antidepressant Serzone, or the Ketoconazole drugs for fungus, three drugs which are metabolized by the same cytochrome system.

Prevention of Heart Attack and Stroke:

Because this is a newly released drug, to date there are no published controlled clinical trials which shown that Atorvastatin, when compared to placebo, reduces the risk of heart attack or stroke. For the "older" statin drugs, such data has been published for Mevacor, Pravachol, and Zocor. The best current evidence suggests that when LDL cholesterol is lowered, optimally below 130 mg/dl in patients without atherosclerotic vascular disease (ASCVD), or below 100 mg/dl in those with ASCVD, risk of heart attack and stroke is reduced 30 to 60% and all cause mortality (everything which kills people) is reduced 22 to 34%. It is a reasonable assumption that Atorvastatin will have the same beneficial effects, but it will take time for the ongoing studies to be completed.

 

Severe hypertriglyceridemia and pancreatitis. Estrogen induced hypertriglyceridemia when exogenous estrogens or pregnancy are superimposed on pre-existing familial hypertriglyceridemia.

Charles J. Glueck MD. Cholesterol Center, Jewish Hospital, 3200 Burnet Ave, Cincinnati Ohio, 45229. Phone 513-585-7800, Fax 513-585-7950, email glueckch@healthall.com, website http://www.uc.edu/~gartsips.

References

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.

 

Estrogen increases risk of venous thrombosis and osteonecrosis in women heterozygous for the mutant Factor V Leiden gene.

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, In Press, 3/12/98.

3. Levesque H et al. Estrogen therapy and venous thromboembolic disease. Reve Med Interne 1997;18 (suppl 6): 620S-625S.

4. Weitz IC et al. Tamoxifen-associated venous thrombosis and activated protein C resistance due to factor V Leiden. Cancer 1997;79:2024-2027.

5. Hennekens CM et al. Sensitivity to activated protein C; influence of oral contraceptives and sex. Thromb Haemost 1996;73:402-404.

6. Caine YG, Bauer KA, Barzegar S, et al. Coagulation activation following estrogen administration to postmenopausal women. Thrombosis and Haemostasis 1992;68:392-395.

7. 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.

 

HERS STUDY- JAMA 1998;280:605-613

Introduction and background:

Because cross-sectional studies had suggested that estrogen-progestin supplementation in postmenopausal women would prevent the development of coronary heart disease, the HERS study was set up to examine this crucial question in a blinded, prospective, placebo-controlled trial.

1. 2763 WOMEN WITH CORONARY DISEASE

2. < AGE 80, POSTMENOPAUSAL, INTACT UTERUS

3. 625 PREMARIN + 2.5 MG MEDROXYPROGESTERONE

(N=1380), VS PLACEBO (N=1383), 4.1 YEAR FOLLOW-UP

4. PRIMARY OUTCOME: NON-FATAL MI, CHD DEATH

5. SECONDARY OUTCOME: CABG, ANGINA, CHF, CARDIAC

ARREST, STROKE, TIA, PVD, ALL CAUSE MORTALITY.

OUTCOMES: 

1: NO SIGNIFICANT DIFFERENCES BETWEEN GROUPS IN THE PRIMARY OUTCOME OR SECONDARY CARDIOVASCULAR OUTCOMES.

2: MORE CHD IN PLACEBO IN YEAR 1, FEWER IN YEARS 4,5

3: 289% INCREASE IN THROMBOEMBOLISM, 38% INCREASE IN GALL BLADDER DISEASE.

4: NO DIFFERENCE IN ALL-CAUSE MORTALITY

Comment and CONCLUSIONS:

Placebo-controlled clinical trials are crucial in optimizing therapeutic decisions. The failure of the HERS trial to reveal any benefit in reducing CHD in secondary prevention, and the increase in thromboembolism and gall bladder disease is very important data. The difference between the placebo-controlled trial and the epidemiological observational studies is understandable, since the observational studies all had a major self-referral bias such that the estrogen users had characteristics which made it much less likely that they would develop CHD.

GIVEN INCREASED RATE OF THROMBOEMBOLIC EVENTS, GALLBLADDER DISEASE, AND INCREASED CHD EVENTS IN YEAR 1, PLUS NO CHANGE IN OVERALL CARDIOVASCULAR EVENTS, DO NOT USE E/P FOR SECONDARY PREVENTION OF CHD!

E/P, TRIGLYCERIDES, THROMBOEMBOLISM

1. NEVER GIVE E/P UNLESS FASTING PLASMA TRIGLYCERIDES HAVE FIRST BEEN MEASURED. IF TRIGLYCERIDE >300 AND <500 MG/DL, THEN E/P RELATIVELY CONTRAINDICATED, IF >500, ABSOLUTELY CONTRAINDICATED DUE TO AUGMENTATION OF HYPERTRIGLYCERIDEMIA, PANCREATITIS, ACUTE MYOCARDIAL INFARCTION, STROKE.

2. BEFORE GIVING POST MENOPAUSAL ESTROGENS OR ESTROGEN-CONTAINING ORAL CONTRACEPTIVES, DO PCR DNA ASSAY FOR MUTANT FACTOR V LEIDEN TRAIT (PRESENT IN 6% OF CAUCASIAN WOMEN). EIGHTY FOLD INCREASED RISK OF VENOUS (AND PROBABLY) ARTERIAL THROMBOSIS WHEN E/P INDUCED RESISTANCE TO ACTIVATED PROTEIN C SUPERIMPOSED ON THROMBOPHILIC V LEIDEN TRAIT.

E-mail: glueckch@healthall.com
or cglueck@fuse.net
Fax: 513-585-7950