Correspondence

Estrogen-Receptor Polymorphism and Hormone-Replacement Therapy

N Engl J Med 2002; 347:762-763September 5, 2002

Article

To the Editor:

Often, it is forgotten that the postmenopausal reduction in estrogen levels increases the levels of low-density lipoprotein (LDL) cholesterol and Lp(a) lipoprotein. Sometimes this effect is more important than and precedes the reduction in high-density lipoprotein (HDL) cholesterol levels. Postmenopausal hormonal changes cause a decrease in LDL-receptor activity, with a decrease in the apolipoprotein B–LDL catabolic rate.1

This potential effect of estrogens on LDL cholesterol levels is another explanation for the increased rates of heart disease among postmenopausal women. Probably the best explanation is represented by the ratio of LDL to HDL cholesterol or the ratio of total cholesterol to HDL cholesterol.

In their article about estrogen-receptor polymorphisms and the effects of estrogen replacement on HDL cholesterol in women with coronary disease, Herrington et al. (March 28 issue)2 state, “The numerically greater reductions in levels of LDL cholesterol and apolipoprotein B among women with the IVS1–401 C/C genotype were not sufficiently large to support an inference of interaction,” yet they do not provide any information about the ratio of LDL to HDL cholesterol. Would this ratio have supported the inferences of the interaction, if it had been used? And what about the Lp(a) lipoprotein levels?

Juan Antonio Garrido, M.D.
Hospital A. Marcide–Novoa Santos, 15405 Ferrol, Spain
ja_garrido@terra.es

2 References

1. 1

   Arca M, Vega GL, Grundy SM. Hypercholesterolemia in postmenopausal women: metabolic defects and response to low-dose lovastatin. JAMA 1994;271:453-459
   CrossRef | Web of Science | Medline

2. 2

   Herrington DM, Howard TD, Hawkins GA, et al. Estrogen-receptor polymorphisms and effects of estrogen replacement on high-density lipoprotein cholesterol in women with coronary disease. N Engl J Med 2002;346:967-974
   Full Text | Web of Science | Medline

To the Editor:

In his editorial accompanying the article by Herrington et al., Krauss discusses the cardiovascular effects of hormone-replacement therapy.1 I find the claim that thrombogenic hormones provide a cardiovascular benefit somewhat surprising. I noted elsewhere that more than 60 formulations of 7 progestins and 2 estrogens that could be correlated with clinical side effects had been reported as causing changes in endometrial blood vessels.2 Arteriolar-wall thickening was reported in women who were receiving such medications and in whom headaches, migraines, hypertension, strokes, or myocardial infarction developed.2 I would suggest that flawed observational epidemiologic studies with a short median period of hormone use, together with divergent effects of such hormones on lipid metabolism, may have confounded estimates of risk.

Ellen C.G. Grant, M.B., Ch.B.
20 Coombe Ridings, Kingston-upon-Thames KT2 7JU, United Kingdom
ellencggrant@onetel.net.uk

2 References

1. 1

   Krauss RM. Individualized hormone-replacement therapy? N Engl J Med 2002;346:1017-1018
   Full Text | Web of Science | Medline

2. 2

   Grant ECG. The Pill, hormone replacement therapy, vascular and mood over-reactivity, and mineral imbalance. J Nutr Environ Med 1998;8:105-116
   CrossRef

Author/Editor Response

The authors reply:

To the Editor: We agree with Dr. Garrido that reductions in the ratio of LDL to HDL cholesterol and levels of Lp(a) lipoprotein are also potentially important effects of hormone therapy. In the Estrogen Replacement and Atherosclerosis trial, we found that among women with the estrogen receptor-α (ER-α) IVS1–401 C/C genotype (i.e., C on both chromosomes in intervening sequence 1 at position 401) who were treated with hormone therapy, there was a nonsignificant trend toward a greater reduction in the ratio of LDL to HDL cholesterol than among women with the C/T or T/T genotype (Figure 1Figure 1Base-Line and Follow-up Ratios of Low-Density Lipoprotein (LDL) Cholesterol to High-Density Lipoprotein (HDL) Cholesterol among Women Who Received Hormone-Replacement Therapy (HRT) or Placebo, According to the Estrogen Receptor α IVS1–401 Genotype (C/C vs. C/T or T/T).).

The reduction in the mean Lp(a) lipoprotein level was also greater in the women with the ER-α IVS1–401 C/C genotype (6.3 percent) than in those with the C/T or T/T genotype (0.5 percent). However, in this case the smaller treatment effects and the wide standard errors do not support a clear differential effect according to the genotype.

On the other hand, we recently reported significantly greater treatment-associated reductions in levels of E-selectin in women with the ER-α IVS1–401 C/C genotype,1 adding further support for a true drug–gene interaction with respect to several estrogen-sensitive intermediate end points. The effect of this common variant of the gene for ER-α on clinical outcomes is not yet known.

David M. Herrington, M.D., M.H.S.
David M. Reboussin, Ph.D.
Wake Forest University School of Medicine, Winston-Salem, NC 27157-1045

1 References

1. 1

   Herrington DM, Howard TD, Brosnihan KB, et al. Common estrogen receptor polymorphism augments effects of hormone replacement therapy on E-selectin but not C-reactive protein. Circulation 2002;105:1879-1882
   CrossRef | Web of Science | Medline