Human embryonic stem cell-derived neurons as a model to discover safer estrogens for hot flashes
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.
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.