Menopause begins in women one year after the last menstrual period. The average age of menopause is 51 years. Because the average life-expectancy in the US is 80 years, most women will spend at least one-third of their life after menopause. Menopause is associated with a large drop in the levels of estrogens in the blood. The drop in estrogens during the menopausal transition leads to onset of hot flashes, night sweats, mood changes, and vagina dryness. Hot flashes are prevalent and extremely bothersome to many postmenopausal women. For over 50 years, women have been taking estrogens to prevent hot flashes, because their quality of life deteriorates due to lack of sleep, heat sensation and sweating. Recently many women have abandoned hormone therapy (HT) due to concerns about potential adverse effects, including breast cancer, strokes and blood clots. Currently, all the estrogenic drugs that are effective at treating menopausal symptoms are known to promote cancer. Because of the safety concerns, many clinicians prescribe non-estrogenic drugs, such as those you to treat depression and anxiety. These drugs are not as effective as estrogens for menopausal symptoms. They also produce adverse side-effects and do not have the beneficial effects of estrogens on preventing osteoporosis. Many postmenopausal women are anxiously waiting for new drugs that relieve menopausal symptoms, but do not promote cancer or other serious side-effects. A major problem that exists to discover safer drugs for menopausal symptoms is the lack of appropriate biological systems to screen estrogens for activity. For example, the cells used to test drugs are not involved in the generation of hot flashes and there is no good animal model to study hot flashes. The best system to study the effects of estrogens are neurons, which are involved in the generation of hot flashes. However, it has not been possible to obtain human neurons in sufficient amounts to test new drugs. The use of embryonic stem cells now makes it possible to generate enough human neurons to study. In this proposal, we will use human embryonic stem (hES) cells as a source for neurons that can be used as a model to identify estrogenic genes that could serve as markers to discover drugs for hot flash prevention.
Statement of Benefit to California:
There are approximately 5 million postmenopausal women in California. Approximately, 80% of these women will experience hot flashes. During menopause the levels of the female hormone, estrogen, drop dramatically. This drop causes hot flashes to occur, which are most common during perimenopause, and usually last for one to five years after menopause. In some women hot flashes can extend extend through the 70s and beyond. A hot flash is a sudden feeling of warmth that is often associated with sweating, palpitations from an elevated heart rate, chills, and a sensation of anxiety. Although variable, hot flashes generally last for seconds or a few minutes and occur every 2-4 hours. Hot flashes are extremely debilitating to many women, because they often awaken many times during with night sweats. The daily and nightly hot flashes often cause women to be extremely tired and irritable and makes it more difficult to concentrate on daily tasks. In some cases job performance suffers. A desire to prevent hot flashes is the main reason women begin hormone therapy. Unfortunately, clinical trials have found that estrogens in hormone therapy can cause breast cancer, strokes and blood clots. The huge, potential beneficial impact of new drugs for treating hot flashes and menopausal symptoms is exemplified by the fact that hormone therapy was the most prescribed drug prior to recent clinical trials. The results of the clinical trials have created a huge need for millions of postmenopausal women in California who are anxiously waiting for safer estrogens for hot flashes and other menopausal symptoms. The goal of this proposal is use neurons that are derived from embryonic stems cells to discover safer estrogens to treat postmenopausal women who seek treatment for hot flashes.
SYNOPSIS: The PI proposes to use hESC-derived neurons to investigate safer drugs to treat menopause. SIGNIFICANCE AND INNOVATION: One reviewer thought the application neither innovative nor original. Another thought it a highly original project to use hESCs as models for drug development. The goal is to use hESC-derived (HSF-6 and H9) neurons to study possible treatments for hot flashes in menopausal women. Two aims are listed: Aim 1 is to optimize laboratory conditions to derive neurons from human ESCs; Aim 2 will identify estrogen receptor-regulated gene markers in hESC-derived neurons. These types of studies are new. STRENGTHS: The PI is an expert in estrogen receptor biology and is dedicated to understanding menopausal symptoms. The experiments are well-designed, well-described and will provide valuable information about the use of hESC-derived neuronal stem cells to measure responses to estrogens and anti-estrogenic compounds. The use of hESCs to evaluate drugs is important. The applicant provides some preliminary data indicating that they have successfully done RT-PCR on the cells and have differentiated ESCs to neurons. They are using a well-established microarray technology (Affymetrix) and should be able to obtain the data. WEAKNESSES: While there is no question that hESC lines have attracted a great deal of attention as a source of human cells for drug testing, it is not clear that this proposal will add new ideas or techniques that are not already being used in the field. The use of human neurons derived from hESCs is not an original idea and is already being used to screen drugs in industry. It is not clear that the investigator is proposing anything that is not already being done and that the investigator is best suited for developing a model system for doing this. The investigators may underestimate the differences between culturing mouse ESCs and hESCs. It is also not clear that the proposed experiments will yield new drugs or reduce the necessity for animal or human testing of the drugs. Although menopausal symptoms affect millions of women, it is not a life-threatening disease for which there is currently no cure. DISCUSSION: There was no further discussion following reviewers' comments