Beyond estrogen: targeting gonadotropin hormones in the treatment of Alzheimer's disease.

Abstract

Based on epidemiological and observational studies, estrogen and hormone-replacement therapy were until recently viewed as major factors in the prevention of Alzheimer's disease (AD). However, a recent randomized clinical trial revealed that hormone replacement therapy using estrogen plus progestin may actually exacerbate the incidence of dementia when administered to elderly women. These contradictory reports have cast grave doubt on the role of estrogen in disease pathogenesis and led us to consider an alternate hypothesis that would be consistent with both observations. Specifically, we suspect that hormones of the hypothalamic pituitary gonadal axis such as gonadotropins, that are regulated by estrogen (or in males by testosterone), are involved in the pathogenesis of Alzheimer's disease. One such gonadotropin, luteinizing hormone (LH), is significantly elevated in both the sera and brain tissue of patients with AD and leads to an increased production of amyloid-beta. Importantly, a key role in disease pathogenesis is further supported by the fact that the distribution of neuronal receptors for LH parallels those populations of neurons that degenerate during the course of the disease. That gonadotropins, not estrogen nor testosterone, mediate disease pathogenesis has led to a paradigm shift, not only for the treatment of AD but a wide variety of other age-related diseases. Therefore, the effects of agents that abolish LH, such as leuprolide acetate, which are currently being evaluated in Phase II clinical trials for the treatment of AD, are eagerly anticipated.

• Authors: Gemma Casadesus, Xiongwei Zhu, Craig S Atwood, Kate M Webber, George Perry, Richard L Bowen, Mark A Smith
• Journal: Current drug targets. CNS and neurological disorders (Curr Drug Targets CNS Neurol Disord) Vol. 3 Issue 4 Pg. 281-5 (Aug 2004) ISSN: 1568-007X [Print] Netherlands
• PMID: 15379604 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Amyloid beta-Peptides
• Estrogens
• Gonadotropins, Pituitary
• Receptors, LH
• Luteinizing Hormone
• Leuprolide

Topics

• Alzheimer Disease (drug therapy, metabolism, physiopathology)
• Amyloid beta-Peptides (biosynthesis)
• Animals
• Estrogens (adverse effects)
• Female
• Gonadotropins, Pituitary (antagonists & inhibitors, metabolism)
• Hormone Replacement Therapy (adverse effects)
• Humans
• Hypothalamo-Hypophyseal System (metabolism, physiopathology)
• Leuprolide (pharmacology, therapeutic use)
• Luteinizing Hormone (antagonists & inhibitors, metabolism)
• Male
• Receptors, LH (metabolism)
• Up-Regulation (drug effects, physiology)