Hao J, Rapp PR, Janssen WG, Lou W, Lasley BL, Hof PR, Morrison JH.
Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex.
Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11465-70.
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To Succeed, HRT Must Mimic Normal Hormone Physiology More Closely
Hormone replacement therapy (HRT) in humans has long been a rather crude enterprise, with, historically, the most common form of administration being a highly complex, partially purified fraction of the urine of pregnant horses. Typical treatment was continuous, rather than cyclical, and entirely estrogenic, with no accounting for the progestational arm of the cycle. Scientists studying the molecular basis of hormone action would not be surprised to learn that traditional continuous therapy with a poorly defined mixture of conjugated estrogens is not the optimal mimic of the human menstrual cycle.
Both estrogen and testosterone are reported to have a number of salutary neuroactive properties. Both are anti-amyloidogenic, as shown by Xu et al. in 1998, and, most recently, Rosario and Pike (2006). Segarra and McEwen demonstrated in 1991 that estrogen regulated dendritic spine density in rats. In this paper (Hao et al., 2007), Patrick Hof, John Morrison, and their colleagues demonstrated the importance of both aging and cyclicity in estrogen-dependent remodeling of dendritic spine morphology in the nonhuman primate. One assumes that this is the case in humans as well.
What are the implications for human HRT? Certainly the role of HRT in modifying the risk for dementia remains a highly challenging and controversial area. Recent evidence that perimenopausal initiation of HRT might well delay onset of dementia dovetails well with the well-known cross-sectional evidence in support of the cognitive protective benefit of HRT. Further trials in this area, if they are to resolve the issue definitively, will be large, long, expensive, and difficult, especially given the negative experience in treating dementia and in the late (after 65 yrs.) initiation of HRT. KEEPS (the Kronos Early Estrogen Protection Study) may offer new, additional hints when results emerge from its 5-year prospective study of early replacement in a cohort of over 700 subjects. Regardless of the outcome of KEEPS, one can safely predict that, if normal physiology is the key to HRT, then we will still need to come a long way in refining our hormone preparations and the regimens with which they are administered.
References:Rosario ER, Carroll JC, Oddo S, LaFerla FM, Pike CJ. Androgens regulate the development of neuropathology in a triple transgenic mouse model of Alzheimer's disease. J Neurosci. 2006 Dec 20;26(51):13384-9. Abstract
Segarra AC, McEwen BS. Estrogen increases spine density in ventromedial hypothalamic neurons of peripubertal rats. Neuroendocrinology. 1991 Oct;54(4):365-72. Abstract
Xu H, Gouras GK, Greenfield JP, Vincent B, Naslund J, Mazzarelli L, Fried G, Jovanovic JN, Seeger M, Relkin NR, Liao F, Checler F, Buxbaum JD, Chait BT, Thinakaran G, Sisodia SS, Wang R, Greengard P, Gandy S. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med. 1998 Apr;4(4):447-51. Abstract