Genetics of menopause-associated diseases

Menopause is the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. It is estimated that perhaps 50 million women worldwide will go into menopause annually. Atherosclerotic cardiovascular disease, osteoporotic fractures and Alzheimer's dementia are common chronic disorders after menopause, representing major health problems in most developed countries. Apart from being influenced by environmental factors, these chronic disorders recognize a strong genetic component, and there are now considerable clinic evidences that these disorders are related to low hormonal milieu of postmenopausal women. Here, we review up-to-date available data suggesting that genetic variation may contribute to higher susceptibility to four sporadic chronic syndromes such as osteoporosis (OP), osteoarthritis (OA), Alzheimer's disease (AD) and coronary artery disease (CAD). For these four syndromes candidate genes that today appear as major loci in genetic susceptibility encode for proteins specific of a given system, as the vitamin D receptor (VDR) gene for the skeleton and, therefore, OP or angiotensin converting enzyme (ACE) for the cardiovascular system and, therefore, CAD. The investigation of gene polymorphisms in various pathological conditions typical of postmenopause offer an explanation not only of their genetic inheritance but also of their co-segregation in given individuals. In this view, it may be possible to identify a common set of genes whose variants contribute to a common genetic background for these different disorders. Ideal candidates appear genes of the estrogen response cascade [i.e. estrogen receptor (ERs), enzymes involved in estrogen metabolism or co-activators and co-inhibitors]. All together this information may represent the basis both for future recognition of individuals at risk and for the pharmacogenetic driving of drug responsiveness.