Menopause Research

Estrogen deficiency in the postmenopausal woman usually first manifests as vasomotor symptoms. The hot flushes can be disruptive and disturb sleep patterns, outcomes resulting in fatigue, depression, insomnia, and irritability. Absence of estrogen action occurs at other target sites such as bone, heart, and brain, although clinical manifestations may not become apparent until years later. The effect of estrogen on the preservation of bone is well documented, and bone loss begins with a decrease in estrogen levels during the perimenopausal period. The possible resultant fractures can lead to severe disability with pulmonary, gastrointestinal, or bladder symptoms and loss of independence due to compression fractures of the spine and hip fractures. Observational studies have indicated an increased risk of cardiovascular disease in estrogen-deficient women. In Western society, cardiovascular disease is the most common cause of death in women older than 50 years. Studies of cognition have also implicated a positive influence of estrogen.

Because life expectancy is age 80 years for women in Western countries and the average age of menopause is close to age 50 years, approximately 30 years can be associated with an “estrogen-deficiency” state. Use of estrogen in the postmenopausal woman clearly has health benefits but, as with many pharmacological interventions, also has attendant risks. Unopposed estrogen therapy in standard doses is associated with an increased risk of endometrial hyperplasia and cancer, which can be attenuated by concurrent administration of a progestin.

Recently, a meta analysis was published in Lancet (Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidenceCollaborative Group on Hormonal Factors in Breast Cancer* Lancet 2019; 394: 1159–68). Researchers found that compared with women who never used MHT (menopausal hormone therapy), women who did had a significantly higher risk of developing invasive breast cancer. They estimated that 6.3% of women who never used MHT developed breast cancer, compared to 8.3% of women who used the combination drug continually for five years. That’s roughly one extra cancer diagnosis for every 50 users.

The longer women used MHT, the greater their risk of breast cancer. Women who were no longer using MHT had a lower relative risk than women who were currently using it — but they remained at an elevated risk for more than a decade after they stopped taking the drug. The level of risk was dependent on how long a woman took MHT. The study also found that women who took the combination drug were more likely to develop cancer than women who took the estrogen-only drug

The two isoforms of estrogen receptor (ER) alpha and beta play opposite roles in regulating proliferation and differentiation of breast cancers, with ER-alpha mediating mitogenic effects and ER-beta acting as a tumor suppressor.

ER alpha mediates cancer-promoting effects of estrogen and has been shown to be an effective therapeutic target for decades. In contrast, ER beta has a well known growth and invasion inhibitory activity in ERα-positive breast cancer cells, at least in part due to ER beta’s inhibition of ER alpha selective target gene expression, and can be considered as an endogenous partial dominant negative receptor.

Besides this function, Estrogen receptor beta plays a key role in skin and in the cardiovascular system to reduce oxidative stress but also inflammation.

Thus, there is a huge demand for estrogen replacement therapeutics acting on beta estradiol receptors but not activating alpha estrogen receptors and thus increasing the risk to develop cancer. Plant derived therapeutics might be such desirable therapeutic since usually they do have a broad range of activities, which could be used for the various symptoms occurring with menopause.

Phytoestrogens have long had a role in the treatment of various disorders. Hippocrates used Queen Anne’s lace, a plant phytoestrogen, to enhance contraception. The estrogenic effect of phytoestrogens was first recognized as a reproductive disorder in sheep after the sheep ingested a specific type of clover. Many phytoestrogens with mixed estrogen agonist and antagonist properties have been identified. In general, phytoestrogens are more soluble than estrogens but also are capable of exerting systemic effects. A wide variety of commonly consumed foods contain appreciable amounts of different phytoestrogens. Phytoestrogens consist of at least 20 compounds from 300 plants and are found in such common foods as parsley, garlic, soybeans, wheat, rice, dates, pomegranates, cherries, and coffee. In general, they are weaker than natural estrogens, easily broken down, and not stored in tissue. Accumulating evidence from molecular and cellular experiments and animal studies may confirm health benefits of phytoestrogens in relation to cardiovascular diseases, cancer, osteoporosis, and menopausal symptoms.

We therefor designed a platform to study the effects of products on menopause symptoms including various models and parameters shown to be involved in the symptoms accompanied with menopause.