Effects of raloxifene combined with low-dose conjugated estrogen on the endometrium in menopausal women at high risk for breast cancer

OBJECTIVES: To compare the effects of low-dose conjugated estrogen (CE), raloxifene, and the combination thereof on the endometrium of postmenopausal women. METHODS: Postmenopausal women between 45 and 60 years of age, with Gail score≥1.67 and no endometrial disorders, were randomly assigned to receive low-dose CE (0.3 mg), raloxifene (60 mg), or combined therapy for 1 year. Transvaginal ultrasound was performed at baseline and every 3 months; the Kupperman Index was assessed at baseline and every 6 months. Endometrial biopsies were performed if endometrial thickness (ET) was ≥5 mm or if vaginal bleeding occurred. The primary outcome was the occurrence of ET≥5 mm over the one-year period. RESULTS: Seventy-three women were randomly assigned and analyzed on an intent-to-treat basis. Eight, three, and four women in the CE, raloxifene, and combination groups, respectively, exhibited ET≥5 mm. No genital bleeding was reported in the combination group. Endometrial biopsy revealed atrophy or polyps in all groups, with one patient in the CE group exhibiting a proliferative endometrium without atypia. At 6 months, there was a progressive increase in mean ET in the CE group, but not in the other two groups, with statistically significant differences at 6, 9, and 12 months. Mean scores for vasomotor symptoms and Kupperman Index favored the CE and combination groups over raloxifene. CONCLUSION: Combined raloxifene and low-dose CE decreased the severity of menopausal symptoms to a similar extent as CE alone and had similar effects as raloxifene alone on the endometrium.

Quimioprevención del cáncer de mama / Chemoprevention in breast cancer

El conocimiento actual del mecanismo de carcinogénesis ha impulsado el estudio de diferentes fármacos que podrían influir en el desarrollo del cáncer de mama. Se ha observado beneficio con la inhibición de la actividad estrogénica sobre el tejido mamario en pacientes con riesgo aumentado. Esto constituye una estrategia de prevención primaria, por lo que se ha denominado quimioprevención. La categorización del riesgo se basa en el análisis de factores de riesgo, el estudio de síndromes de cánceres hereditarios y la presencia de lesiones proliferativas con atipía de la mama. Existen modelos matemáticos para estimar el riesgo, pero todavía no han sido validados en nuestra población. Los fármacos aprobados para quimioprevención son dos serms: el tamoxifeno y el raloxifeno. En cuanto a los Inhibidores de la Aromatasa, si bien han demostrado beneficio, aún no han sido aprobados. Lo que se recomienda es establecer medidas de quimioprevención en pacientes con score de alto riesgo según índices matemáticos (en aquellas poblaciones en que han sido validados), en pacientes con lesiones proliferativas con atipía (Carcinoma lobulillar in situ, Hiperplasia ductal atípica, Hiperplasia lobulillar atípica). Hasta la actualidad, existe controversia en cuanto a su empleo en pacientes con antecedentes de cánceres hereditarios, debido a la alta frecuencia de receptores negativos que presentan estos tumores. A pesar de dichas recomendaciones, la indicación y adherencia a la quimioprevención continua siendo baja.

Current knowledge of the mechanism of carcinogenesis has launched the study of different drugs that could influence the development of breast cancer. Benefit has been observed with the inhibition of estrogenic activity on tissue in high risk patients. This constitutes a strategy of primary prevention; so it has been denominated chemoprevention. Risk categorization is based on the analysis of risk factors, the study of risk syndromes hereditary cancers and the presence of proliferative lesions with breast atypia. There are mathematical models for estimating risk, but they have not been yet validated in our population. Approved drugs for chemoprevention are serms: tamoxifen and raloxifene. Although the benefit of Aromatase Inhibitors have been demonstrated, so far they have not been approved. Therefore it is recommended to establish chemoprevention in patients with high risk score according to mathematical indexes (in population that has been validated), in patients with proliferative lesions with atypia (Lobular carcinoma in situ, Atypical ductal hyperplasia, Lobular hyperplasia atypical). Still remains controversy in patients with hereditary cancer, due to the high frequency of negative receptors that present these tumors. Despite of these recommendations, the indication and adherence to chemoprevention continues being low.

Bidirectional regulation of angiogenesis by phytoestrogens through estrogen receptor-mediated signaling networks / 中国天然药物

Sex hormone estrogen is one of the most active intrinsic angiogenesis regulators; its therapeutic use has been limited due to its carcinogenic potential. Plant-derived phytoestrogens are attractive alternatives, but reports on their angiogenic activities often lack in-depth analysis and sometimes are controversial. Herein, we report a data-mining study with the existing literature, using IPA system to classify and characterize phytoestrogens based on their angiogenic properties and pharmacological consequences. We found that pro-angiogenic phytoestrogens functioned predominantly as cardiovascular protectors whereas anti-angiogenic phytoestrogens played a role in cancer prevention and therapy. This bidirectional regulation were shown to be target-selective and, for the most part, estrogen-receptor-dependent. The transactivation properties of ERα and ERβ by phytoestrogens were examined in the context of angiogenesis-related gene transcription. ERα and ERβ were shown to signal in opposite ways when complexed with the phytoestrogen for bidirectional regulation of angiogenesis. With ERα, phytoestrogen activated or inhibited transcription of some angiogenesis-related genes, resulting in the promotion of angiogenesis, whereas, with ERβ, phytoestrogen regulated transcription of angiogenesis-related genes, resulting in inhibition of angiogenesis. Therefore, the selectivity of phytoestrogen to ERα and ERβ may be critical in the balance of pro- or anti-angiogenesis process.

Perception of severe osteoporosis amongst medical doctors in South Korea: Awareness, impact, and treatment

OBJECTIVES: Little is currently known about the issues surrounding management and treatment of severe osteoporosis in South Korea. Our objective was to assess doctors' views on the perception, diagnosis, and treatment of severe osteoporosis. METHODS: Face-to-face interviews were conducted (16 February-13 March 2015) with 100 doctors (specialists in orthopedic surgery, endocrinology, neurosurgery, family medicine, or rheumatology) who treated ≥5 severe osteoporosis (T-score ≤ -2.5, plus fracture) patients per month. Respondent demographic characteristics, their perception of severe osteoporosis, its impact and treatment, and their views on current practice and unmet needs were assessed. RESULTS: Of 416 doctors approached, 100 completed the survey (24% response rate). Most doctors (90%) specialized in orthopedic surgery, endocrinology, or neurosurgery. When diagnosing severe osteoporosis, most doctors (79%) considered both bone mineral density and fracture. Almost all doctors (≥91%) ranked disease impact and seriousness highly, but much fewer (≤25%) doctors thought society agreed. Most doctors (89%) had concerns with current treatments, switching treatments because of the efficacy and safety of bisphosphonates (>89%), the efficacy of selective estrogen receptor modulators (>71%), and the high cost of parathyroid hormone (>73%). Parathyroid hormone was ranked highest for efficacy and was preferentially prescribed to severe osteoporosis patients (mean 32.2% of prescriptions) compared with osteoporosis patients overall (3.7%). "Limitations with reimbursement" was the most commonly cited (76%) unmet need. CONCLUSIONS: There are concerns with the safety, efficacy, and affordability of current treatments for severe osteoporosis in South Korea, as well as a perceived lack of disease awareness amongst patients and doctors.

Alternatives to Hormone Replacement Therapy in Postmenopausal Women.

Substantial number of postmenopausal women suffers in silence. They experience vasomotor symptoms, sleep disturbances, atrophic changes in the genital and urinary systems and lack of sexual desire. The fear, side effects and contra indications of oestrogen discourage hormone replacement therapy. Life style modification with change in dietary habit, regular exercise, cessation of alcohol and smoking can help them immensely. Tibolone, Selective oestrogen receptor modulators (SERMs), Antidepressants like Venlafaxine, th Alpha 2 agonists like clonidine, carbapentine and various supplements are frequently prescribed. Available alternatives and their merits are discussed.

Osteoporosis: Current Management Guidelines.

Osteoporosis is a multifactorial progressive skeletal disorder characterized by reduced bone mass and deterioration of bone microarchitecture. Fragility fractures, the consequence of osteoporosis, are responsible for excess mortality, morbidity, chronic pain, admission to hospitals and economic costs. Approximately 1.6 million hip fractures occur each year worldwide and the incidence is set to increase to 6.3 million by 2050. Preventive measures should be started at an early age and should include smoking cessation and weight-bearing exercises. Pharmacologic prevention methods include calcium supplementation and administration of raloxifene or bisphosphonates. No treatment can completely reverse established osteoporosis. Early intervention can prevent osteoporosis in most people. For patients with established osteoporosis, medical intervention can halt its progression. Currently available therapies include bisphosphonates, selective estrogen receptor modulators (SERMs), hormone replacement therapy (HRT), denosumab, teriparatide, calcitonin and strontium ranelate. Cathepsin K inhibitors (balicatib and odanacatib) are among recent drugs under development. Saracatinib, a novel orally available competitive inhibitor of Src kinase has been shown to inhibit bone resorption in vitro. Lasofoxifene, bazedoxifene and arzoxifene are new SERMs in late-stage treatment trials. Nonpharmacological measures are required when patients experience adverse effects because of drug therapy, when symptoms are not controlled by drug therapy alone or when patient is not willing to take drugs for a prolonged duration.

Molecular mapping of heterocyclic diazene derivatives for estrogen receptor modulation.

Selective estrogen receptor modulators (SERMs) are effectively used in hormone replacement therapy (HRT) by reducing post-menopausal symptoms, including hormone-responsive breast cancer and osteoporosis. The present study explored the pharmacophore features of diazene derivatives for selective estrogen receptor (ER) modulation using quantitative structure activity relationship (QSAR) and space modeling approaches. The 2D-QSAR models (R2α = 0.907, Q2α = 0.700, R2pred-α = 0.735; R2β = 0.913, Q2β = 0.756, R2pred-β = 0.745) showed the importance of orbital energies, hydrophobicity, refractivity and atomic charges for selective binding affinity to ER. In 3D-QSAR, molecular field (CoMFA, R2α = 0.948, Q2 = 0.720, R2pred-α = 0.708; R2β = 0.994, Q2β = 0.541, R2pred-β = 0.721) and similarity models (CoMSIA, R2α = 0.984, Q2α = 0.793, R2pred-α = 0.738; R2β = 0.996, Q2β = 0.681, R2pred-β = 0.725) indicated that steric and hydrophobic properties were important for binding selectivity. Space modeling study (R2α = 0.885, Q2α = 0.855, R2pred-α = 0.666; R2β = 0.872, Q2β = 0.883, R2pred-β = 0.814) revealed that hydrophobic and aromatic ring features were important for both subtypes, whereas hydrogen bond (HB) acceptor and donor were crucial for β- and α-subtypes, respectively. Interactions observed between ligand and catalytic residues at the active site in docking study substantiated the developed model which may be successfully used in high throughput screening (HTS) to obtain promising lead molecules for selective estrogen therapy.

Papel de los estrógenos en el sistema nervioso central y su implicancia en los trastornos psiquiátricos: segunda parte / Role of estrogens in the central nervous system and their Implication for psychiatric disorders: second part

En esta segunda parte del trabajo se focaliza en cómo los estrógenos, con sus diferentes concentraciones a lo largo de las distintas etapas de la vida, por su presencia o ausencia, vulnerabilizan a padecer determinadas patologías neuropsiquiátricas, así como también protegen de algunas otras. En este sentido, se considera que la patología de la mujer debería incluir profundos conocimientos sobre la implicancia que las hormonas sexuales tienen en el desarrollo de determinadas enfermedades neuropsiquiátricas. Se relevan también otros estudios sobre la administración de terapia hormonal de reemplazo, ya que son los procesos neurodegenerativos, como la enfermedad de Alzheimer, los que mayor lugar han tenido entre las investigaciones de las últimas décadas. Allí los resultados se vislumbran promisorios, pues la administración de estrógenos inmediatamente después de la menopausia revela tener efecto en la prevención del desarrollo de estos procesos, lo que no ocurre una vez iniciados los procesos neurodegenerativos. Se incluyen, a su vez, otros trabajos en otras patologías psiquiátricas, en donde se ha evaluado la eficacia de la prescripción de estrógenos, como ser en determinadas formas de depresión mayor (como coadyuvante), con buenos resultados. A pesar de los avances en el campo de la neurociencia y la influencia que ésta ha tenido en el conocimiento de las enfermedades psiquiátricas, es necesario proseguir con las investigaciones en donde se incluyan nuevos fármacos, como ser hormonas sexuales y SERMs, que seguramente traerán aportes promisorios en determinadas patologías neuropsiquiátricas.

The second part of the article focuses on estrogens, with their varying concentrations, throughout the different stages of life, which, whether by their presence or absence, predispose to suffering from certain neuropsychiatric diseases, just as they protect the individual from some others. In this sense, it is considered that female pathology should involve a deep knowledge on the impact that sexual hormones have on the development of certain neuropsychiatric diseases. The article also includes other studies on the administration of hormone replacement therapy, since it is neurodegenerative processes, such as Alzheimer's Disease, which occupied a leading place in investigations during the past decades. In such investigations, outcomes seem to be promising, since the administration of estrogens right after menopause demonstrates to have an impact on preventing the development of these processes, which does not occur once neurodegenerative processes have started. Also included are other investigations conducted on other psychiatric pathologies, in which the efficacy of prescribing estrogens, such as for certain forms of major depression (as adjunctive therapy) are evaluated, with positive results. Despite the advances in neuroscience and its influence on the knowledge of psychiatric diseases, it is necessary to continue preforming investigations that include new pharmacological drugs, such as sexual hormones and SERMs, which will possibly bring about promissory contributions to certain neuropsychiatric diseases.

Papel de los estrógenos en el sistema nervioso central y su implicancia en los tratornos psiquiátricos: primera parte / Role of estrogens in the central nervous system and their Implication for psychiatric disorders: first part

El Sistema Nervioso Central (SNC) muestra en su morfología, estructura, funcionamiento y organización, la influencia de varios factores: genéticos, ambientales, sexuales y su respectiva interacción. El momento en que estos factores ejercen sus efectos sobre el SNC (períodos críticos) es también de suma importancia. Desde hace varios años, entre estos factores se estudia las hormonas sexuales y sus efectos sobre el SNC. Se han podido conocer y entender las interacciones que existen entre las hormonas sexuales y los demás sistemas de neurotransmisión, así como, la relación con los diferentes ejes neuroendócrinos. Es también conocida la influencia que las hormonas sexuales ejercen en el establecimiento del dimorfismo del cerebro, no sólo estableciendo diferencias morfológicas, estructurales, funcionales y de conductas sexuales, sino además en el desempeño de determinadas habilidades neurocognitivas entre ambos sexos. En este trabajo se estudió e investigó particularmente los estrógenos, de gran influencia sobre varios procesos que involucran a las neuronas. A su vez, estas hormonas sexuales son de gran interés por los efectos que tienen sobre el neurodesarrollo, la sinaptogénesis, la supervivencia neuronal y la respuesta fisiológica al estrés; pero también por la vulnerabilidad a presentar mayor incidencia de determinadas patologías inmunológicas, hormonales, psiquiátricas y neurológicas.En esta primera parte, se desarrollan los aspectos neurobiológico de los estrógenos, los receptores estrogénicos y la relación con los demás sistemas de neurotransmisión. En la segunda parte, se focalizará en las implicancias que los estrógenos por ausencia o disminución, exceso o normalidad, presentan a lo largo de las distintas etapas de la vida, en las diferentes patologías psiquiátricas.

The Central Nervous System (CNS) displays, in its morphology, structure, functioning and organizations, the influence of several factors: genetic, environmental, sexual and the corresponding interaction between them. The moment when those factors produce their effects on the CNS (critical periods) is also of great significance. For many years, among those factores, sexual hormones and their effects on the CNS have been studied. It has been possible to know about the interactions existing between secual hormones and the rest of the neurotransmission systems, as well as the relationshipo with the different neuroendocrine axes. Also known is the influence of sexual hormones on the establishment of brain dimorphism, not only establishing morphological, structural, functional differences and differences of sexual behaviours, but also in the performance of certain neurocognitive abilities between both genders. This work focused mainly on the study and reserch of estrogens, which have a great influence on several processes involving neurons. These sexual hormones are in turn of great significance due to the effects they have on neurodevelopment, synaptogenesis, dence of immunological, hormonal, psychiatric and neurological pathologies. In this first part, the neurobiological aspects of estrogens, estrogenic receptors and the relation with the rest of the neurotransmission system are described. The second part will centre on the implications that estrogens, whether due to their absence, decrease, excess or normality, present throughout the different stages of life, in the different psychiatric pathologies.