To the Editor: Dr Zandi and colleagues1 found that postmenopausal estrogen replacement therapy (ERT) reduced the risk of Alzheimer disease (AD), but only among long-term users of ERT. It is possible, however, that some of this trend may be mediated by indirect effects of estrogen. In particular, serum concentrations of gonadotropins, luteinizing hormone, and follicle-stimulating hormone are sensitive to changes in estrogen, since gonadotropins are the primary regulator of estrogen production. In postmenopausal women, the loss of estrogen results in a significant increase in circulating gonadotropin concentrations.2 Conversely, when women take ERT, gonadotropin concentrations are suppressed due to the inhibitory feedback of estrogen on the hypothalamic-pituitary-gonadal axis.3 Thus, the effects of ERT may be related to hormones other than estrogen.

In their accompanying Editorial, Drs Resnick and Henderson4 suggest the idea of a "critical period" for the timing of ERT. Such a temporal effect might be better explained by changes in the concentrations of gonadotropins during the postmenopausal period. In the early postmenopausal years, serum gonadotropins are extremely elevated but subsequently decline,2 and therefore early estrogen replacement might be more protective against the potentially detrimental effects of the gonadotropins at this time. Additional support for this idea is evidenced by the greater incidence of AD among women; by contrast, in elderly men, gonadotropins are suppressed by continued production of testosterone. Similarly, we have recently reported that serum gonadotropin concentrations are higher in women with AD5 and that gonadotropin concentrations are markedly increased in neurons vulnerable to AD pathology.6

Financial Disclosure: Dr Bowen is an employee and a major shareholder of Voyager Pharmaceutical Corp, and the other authors are all paid consultants of Voyager. In addition, Dr Perry is chair of the Scientific Advisory Board and has options for Voyager stock.

Mark A. Smith, PhD; George Perry, PhD; Craig S. Atwood, PhD
Department of Pathology
Case Western Reserve University
Cleveland, Ohio

Richard L. Bowen, MD
Voyager Pharmaceutical Corp
Raleigh, NC

1. Zandi PP, Carlson MC, Plassman BL, et al for the Cache County Memory Study Investigators. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA. 2002;288:2123-2129. ABSTRACT/FULL TEXT
2. Wide L, Nillius SJ, Gemzell C, Roos P. Radioimmunosorbent assay of follicle-stimulating hormone and luteinizing hormone in serum and urine from men and women. Acta Endocrinol Suppl (Copenh). 1973;174:3-58.
3. Abdel-sayed WS, Toppozada HK, Said SA, El-sayed OK. Some metabolic and hormonal changes in women using long acting injectable contraceptives. Alex J Pharm Sci. 1989;3:29-32. MEDLINE
4. Resnick SM, Henderson VW. Hormone therapy and risk of Alzheimer disease: a critical time. JAMA. 2002;288:2170-2172. FULL TEXT
5. Bowen RL, Isley JP, Atkinson RL. An association of elevated serum gonadotropin concentrations and Alzheimer disease? J Neuroendocrinol. 2000;12:351-354. CrossRef | ISI | MEDLINE
6. Bowen RL, Smith MA, Harris PL, et al. Elevated luteinizing hormone expression colocalizes with neurons vulnerable to Alzheimer's disease pathology. J Neurosci Res. 2002;70:514-518. CrossRef | ISI | MEDLINE

Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.

JAMA. 2003;289:1100.