Effects of estrogen receptor modulators on cytoskeletal proteins in the central nervous system

Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer treatment and osteoporosis in postmenopausal women, as well as for the treatment of climacteric symptoms. Similar to estrogens, neuroprotective effects of estrogen receptor modulators have been described in different models. However, the mechanisms of action of these compounds in the central nervous system have not been fully described. We conducted a systematic search to investigate the effects of estrogen receptor modulators in the central nervous system, focusing on the modulation of cytoskeletal proteins. We found that raloxifene, tamoxifen, and tibolone modulate some cytoskeletal proteins such as tau, microtuble-associated protein 1（MAP1）, MAP2, neurofilament 38（NF38） by different mechanisms of action and at different levels： neuronal microfilaments, intermediate filaments, and microtubule-associated proteins. Finally, we emphasize the importance of the study of these compounds in the treatment of neurodegenerative diseases since they present the benefits of estrogens without their side effects.

Design, Synthesis and Biological Evaluation of 2-Aroyl-3-aryl-6,7-dihydro-5H-furo[3,2-g]chromen Derivatives as a Novel Series of Estrogen Receptor Modulators

Based on the principles of the bioisosterism, combination of the active substructures of selective estrogen receptor modulators which are currently therapeutic agents available for the prevention and treatment of various estrogen dependent diseases, and structural optimization, a novel series of 2-aroyl-3-aryl-6,7-dihydro-5H-furo[3,2-g]- chromen derivatives was designed as potent selective estrogen receptor modulators via molecular docking. The target compounds have been synthesized, and characterized by 1R, proton NMR, ESI-MS, elemental analysis and evaluated for their antitumor activity against human osteosarcoma U2OS-EGFP-4FI2G cell line. Some target compounds showed good inhibition effects on U2OS-EGFP-4F12G cell line and the preliminary structure-activity relationships were discussed.

Selective Estrogen Receptor Modulator: Raloxifene

Selective estrogen receptor modulators （SERMs） are structurally different com- pounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists and antagonists. Raloxifene is the only SERM approved worldwide for the prevention and treatment of postmenopausal osteoporosis. Raloxifene, which has estrogen-like actions on bone, lipids and the coagulation system, and estrogen antagonist effects on the breast and uterus, has undergone very extensive prospective, placebo-controlled, randomized trial evaluation.

Tamoxifen:an FDA approved drug with neuroprotective effects for spinal cord injury recovery

Spinal cord injury（SCI） is a condition without a cure,affecting sensory and/or motor functions.The physical trauma to the spinal cord initiates a cascade of molecular and cellular events that generates a non-permissive environment for cell survival and axonal regeneration.Among these complex set of events are damage of the blood-brain barrier,edema formation,inflammation,oxidative stress,demyelination,reactive gliosis and apoptosis.The multiple events activated after SCI require a multi-active drug that could target most of these events and produce a permissive environment for cell survival,regeneration,vascular reorganization and synaptic formation.Tamoxifen,a selective estrogen receptor modulator,is an FDA approved drug with several neuroprotective properties that should be considered for the treatment of this devastating condition.Various investigators using different animal models and injury parameters have demonstrated the beneficial effects of this drug to improve functional locomotor recovery after SCI.Results suggest that the mechanism of action of Tamoxifen administration is to modulate anti-oxidant,anti-inflammatory and anti-gliotic responses.A gap of knowledge exists regarding the sex differences in response to Tamoxifen and the therapeutic window available to administer this treatment.In addition,the effects of Tamoxifen in axonal outgrowth or synapse formation needs to be investigated.This review will address some of the mechanisms activated by Tamoxifen after SCI and the results recently published by investigators in the field.

Treatment of hypogonadotropic male hypogonadism: Case-based scenarios

The aim of this study is to review four case-based scenarios regarding the treatment of symptomatic hypogonadism in men. The article is designed as a review of published literature. We conducted a PubMed literature search for the time period of 1989-2014, concentrating on 26 studies investigating the effcacy of various therapeutic options on semen analysis, pregnancy outcomes, time to recovery of spermatogenesis, as well as serum and intratesticular testosterone levels. Our results demonstrated thatexogenous testosterone suppresses intratesticular testosterone production, which is an absolute prerequisite for normal spermatogenesis. Cessation of exogenous testosterone should be recommended for men desiring to maintain their fertility. Therapies that protect the testis involve human chorionic gonadotropin （hCG） therapy or selective estrogen receptor modulators （SERMs）, but may also include low dose hCG with exogenous testosterone. Off-label use of SERMs, such as clomiphene citrate, are effective for maintaining testosterone production long-term and offer the convenience of representing a safe, oral therapy. At present, routine use of aromatase inhibitors is not recommended based on a lack of long-term data. We concluded that exogenous testosterone supplementation decreases sperm production. It was determined that clomiphene citrate is a safe and effective therapy for men who desire to maintain fertility. Although less frequently used in the general population, hCG therapy with or without testosterone supplementation represents an alternative treatment.

Preserving fertility in the hypogonadal patient： an update

An increasing number of young and middle-aged men are seeking treatment for symptoms related to deficient levels of androgens （hypogonadism） including depression, loss of libido, erectile dysfunction, and fatigue. The increase in prevalence of testosterone supplementation in general and anabolic steroid-induced hypogonadism specifically among younger athletes is creating a population of young men who are uniquely impacted by the testicular end-organ negative consequences of exogenous steroid use. Exogenous testosterone therapy can alter the natural regulation of the hypothalamic-pituitary-gonadal axis leading to impaired spermatoganesis with azoospermia being a serious possible result, thus rendering the individual infertile. For men of reproductive age who suffer from hypogonadal symptoms, preservation of fertility is an important aspect of their treatment paradigm. Treatment with human chorionic gonadotropin （hCG） has shown the ability not only to reverse azoospermia brought on by testosterone supplementation therapy but also to help maintain elevated intratesticular testosterone levels. In addition, selective estrogen receptor modulators, often used with hCG have been shown both to elevate total testosterone levels and to maintain spermatogenesis in hypogonadal men.