Because of longer lifespans, health problems affecting menopausal women are becoming increasingly common. Hot flashes, sleep issues, and mood swings are typical short-term symptoms that can have a negative impact on quality of life and productivity at work. An increased incidence of chronic disorders such as osteoporosis, obesity, diabetes, metabolic syndrome, and cardiovascular disease is linked to long-term estrogen insufficiency following menopause. Menopausal hormone therapy (MHT) is effective at reducing menopausal symptoms and preventing some chronic diseases, but according to the Women's Health Initiative (WHI), long-term therapy has more risks than benefits. The use of MHT among menopausal women has sharply dropped since the publication of the WHI data. MHT is currently recommended for a 5-year short-term treatment of hot flashes and vaginal symptoms. MHT is no longer recommended for the primary prevention of chronic diseases. Countless menopausal women continue to wait anxiously for a safer long-term MHT to improve their quality of life and health. In the meantime, many women opt for unproven supplements to relieve menopausal symptoms. There is a significant unmet need for developing new MHT formulations that can be utilized for long-term therapy because many women suffer from menopausal symptoms for more than five years and chronic diseases increase throughout menopause. Almost 80 years after MHT was approved, there is still no MHT formula safe for long- term therapy. Our objective is to develop a safer MHT formula that can be used long-term to treat protracted menopausal symptoms and prevent chronic diseases, such as osteoporosis, diabetes, obesity, and metabolic syndrome. We discovered a class of compounds that we termed estrogen receptor (ER) reprogramming ligands. We found that when a reprogramming ligand is combined with estradiol (E2), a new set of genes are regulated that are not regulated by the reprogramming ligand or E2 alone. The reprogramming ligand blocked the proliferation of human breast cancer cells and the growth of the mouse uterus in response to E2. Our goal is to create an E2/reprogramming ligand combination by replacing the progestin component of MHT with a reprogramming ligand and adding it to the estrogen-alone formulation. Our hypothesis is that the E2/reprogramming ligand combination will be safer than the single estrogen and estrogen/progestin MHT preparations currently on the market so that they can be used as a long-term therapy to prevent protracted menopausal symptoms and chronic diseases. Our original reprogramming ligand was a natural compound. To improve its pharmacological properties and strengthen its patent protection, we prepared and identified several synthetic analogs that behave similarly to the natural reprogramming ligand in cell-based assays. As the next step in the clinical development pathway, we will test the synthetic analogs in animal models to select the lead analog that is the most effective and safe for future clinical trials.
Public Health Relevance Statement: Project Narrative Menopausal hormone treatment (MHT), which contains estrogen, can relieve hot flashes and help menopausal women avoid some chronic illnesses like osteoporosis. The current MHT regimens are not recommended for long-term use due to the potential for serious adverse effects. Our goal is to develop a long-term MHT regimen that is less harmful and can be used to treat persistent menopausal symptoms and prevent chronic diseases associated with menopause.
Project Terms: Affect; Allosteric Site; Award; Biological Assay; Assay; Bioassay; Biologic Assays; Blood coagulation; Blood Clotting; bone; Bone Density; Bone Mineral Density; Breast; malignant breast neoplasm; Breast Cancer; malignant breast tumor; Cardiovascular Diseases; cardiovascular disorder; Cells; Cell Body; Chronic Disease; Chronic Illness; chronic disorder; Clinical Trials; Diabetes Mellitus; diabetes; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Estradiol; Aquadiol; Dimenformon; Diogyn; Diogynets; Estrace; Estradiol-17 beta; Estradiol-17beta; Estraldine; Ovocyclin; Ovocylin; Progynon; Therapeutic Estradiol; Estrogens; Therapeutic Estrogen; Fatty acid glycerol esters; Fats; Fright; Fear; Future; Gene Expression; Genes; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; Health; Human; Modern Man; Incidence; Lead; Pb element; heavy metal Pb; heavy metal lead; Ligands; Longevity; Length of Life; life span; lifespan; Marketing; Menopause; Metabolism; Intermediary Metabolism; Metabolic Processes; Molecular Conformation; Molecular Configuration; Molecular Stereochemistry; conformation; conformational; conformational state; conformationally; conformations; Moods; Morbidity - disease rate; Morbidity; mortality; Mus; Mice; Mice Mammals; Murine; Night Sweating; Obesity; adiposity; corpulence; Osteoporosis; Ovariectomy; Oophorectomy; female gonadectomy; Legal patent; Patents; Primary Prevention; Productivity; Progestins; Corlutina; Corluvite; Cyclogest; Gestagenic Agents; Gestagens; Gestiron; Gestone; Lipo-Lutin; Luteohormone; Lutocyclin; Lutocylin M; Lutogyl; Lutromone; Progestagenic Agents; Progestasert; Progestational Agents; Progestational Compounds; Progestational Hormones; Progesterone Agents; Progestogel; Progestogens; Progestol; Progeston; Prolidon; Proluton; Syngesterone; Therapeutic Progestin; Utrogestan; Progesterone; Corpus Luteum Hormone; Delta4-pregnene-3,20-dione; Pregn-4-ene-3,20-dione; Pregnenedione; Therapeutic Progesterone; Publications; Scientific Publication; Quality of life; QOL; Estrogen Receptors; Recommendation; Risk; Safety; Skin Temperature; Sleep; Tail; Testing; Time; Genitourinary system; Genitourinary; Urogenital; Urogenital System; Uterus; womb; Vagina; Vaginal; Woman; Work; Measures; Women's Health; Female Health; Health Costs; Healthcare Costs; Health Care Costs; Mediating; Organ; improved; Chronic; Clinical; Phase; Post-Menopause; Post-menopausal Period; Postmenopausal Period; after menopause; following menopause; past menopause; post-menopausal; postmenopausal; postmenopausal status; Postmenopause; Link; Blood Serum; Serum; Menopausal Symptom; analog; Chemosensitization/Potentiation; Potentiation; Chemosensitization; Atrophic; Atrophy; Prediabetes syndrome; Prediabetes; Prediabetic State; pre-diabetes; pre-diabetic; prediabetic; Complex; Xenograft procedure; Heterograft; Heterologous Transplantation; Xenograft; Xenotransplantation; xeno-transplant; xeno-transplantation; experience; MCF7 cell; MCF-7; MCF-7 Cell; MCF-7DR; MCF-7WT; MCF7; neoplastic cell; Tumor Cell; Animal Model; Animal Models and Related Studies; model of animal; Hot flushes; hot flash; Toxic effect; Toxicities; Estrogen Receptor alpha; ERalpha; ERα; Estradiol Receptor alpha; Estradiol Receptor α; Estrogen Receptor α; Prevention; Benefits and Risks; Selective Estrogen Receptor Modulators; SERMs; Modeling; Property; response; Adverse effects; Metabolic syndrome; Drops; Molecular Interaction; Binding; Therapeutic Uses; Effectiveness; preventing; prevent; Dose; Symptoms; Breast Cancer Risk Factor; breast cancer risk; Data; Breast Cancer Cell; breast tumor cell; Proliferating; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Preparation; preparations; Development; developmental; Pathway interactions; pathway; bone turnover; murine model; mouse model; tumor; bio-markers; biologic marker; biomarker; Biological Markers; drug candidate; Regimen; anxious; Formulation; gene product; High Fat Diet; experiment; experimental research; experiments; experimental study; clinical development; lead candidate; side effect; pharmacologic; Natural Compound; naturally occurring compound; Estrogen deficiency; deficiency in estrogen; new chemical entity; menopausal hormone therapy; menopausal hormone treatment
