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Molecular-Based Treatment Strategies for Osteoporosis: A Literature Review.

Osteoporosis is an unavoidable public health problem in an aging or aged society. Anti-resorptive agents (calcitonin, estrogen, and selective estrogen-receptor modulators, bisphosphonates, anti-receptor activator of nuclear factor κB ligand antibody along with calcium and vitamin D supplementations) and anabolic agents (parathyroid hormone and related peptide analogs, sclerostin inhibitors) have major roles in current treatment regimens and are used alone or in combination based on the pathological condition. Recent advancements in the molecular understanding of bone metabolism and in bioengin

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… PTH, parathyroid hormone; SERMs, selective estrogen receptor modulators; RANKL, receptor activator of nuclear factor κB ligand; OPG, osteoprotegerin; N/A, not available; BMP, bone morphogenetic protein. … PTH, parathyroid hormone; BMD, bone mineral density; RANKL, receptor activator of nuclear factor κB ligand; SERM, selective estrogen receptor modulator. …

Highly potent and selective degrader targeting ERα to improve the treatment outcomes of breast cancer.

Estrogen receptor alpha (ERα) is overexpressed in approximately 70 % of breast cancer cases; therefore, it is considered a primary therapeutic target for breast cancer. Several therapeutic agents, including selective estrogen receptor modulators, aromatase inhibitors, selective estrogen receptor degraders, and proteolysis-targeting chimeras (PROTACs), have been developed to antagonize and degrade ERα. The representative ERα-targeting PROTAC (ERα-PROTAC) agent ARV-471 has been used to treat locally advanced or metastatic breast cancer in clinical trials. Herein, we designed, synthesized, and ev…

Sex steroids and the GH axis: Implications for the management of hypopituitarism.

Growth hormone (GH) regulates somatic growth, substrate metabolism and body composition. Sex hormones exert profound effect on the secretion and action of GH. Estrogens stimulate the secretion of GH, but inhibit the action of GH on the liver, an effect that occurs when administered orally. Estrogens suppress GH receptor signaling by stimulating the expression proteins that inhibit cytokine receptor signaling. This effect of estrogens is avoided when physiological doses of estrogens are administered via a non-oral route. Estrogen-like compounds, such as selective estrogen receptor modulators, p…

Effects of hormonally active agents on steroid hormone receptor expression and cell proliferation in the myometrium of ovariectomized macaques.

Hormone replacement therapy and selective estrogen receptor modulators have been controversial treatment options for postmenopausal women because of their potential health benefits and/or risks. In this study, we determine the effects of the hormonally active compounds, conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), CEE + MPA, and tamoxifen (TAM) on the myometrium of ovariectomized macaques. Immunoexpression of estrogen receptor-α (ERα), progesterone receptor (PR), and Ki-67 in the myometrium is assessed. We found no significant difference in ERα myometrial expression in…

Regulation of activities of steroid hormone receptors by tibolone and its primary metabolites.

This work was undertaken (i) to study deeply the estrogen, androgen and progestative activities of tibolone and its metabolites (ii) to determine whether tibolone and its metabolites present glucocorticoid or mineralocorticoid activity. For this purpose, we used human cell lines bearing a luciferase gene with a responsive element under the control of human estrogen receptor alpha (ERalpha) or estrogen receptor beta (ERbeta) or androgen receptor (AR) or chimeric Gal4 fusion with progesterone receptor (PR), glucocorticoid receptor (GR) or mineralocorticoid receptor (MR). The major tibolone metab

Identifying and treating sexual dysfunction in postmenopausal women: the role of estrogen.

Sexual dysfunction is a common, but frequently overlooked, problem in postmenopausal women. At menopause, dramatic decreases in circulating … xual function. Emerging treatments, such as ultra-low-dose vaginal estradiol tablets, new selective estrogen receptor modulators (SERMs), and intravaginal dehydroepiandrosterone (DHEA) are other promising options for postmenopausal women with vaginal atrophy and sexual dysfunction.

Advances and challenges of estrogen receptor-targeted agents in breast cancer.

Estrogen receptors (ERs) are expressed in approximately 70% of breast cancer patients and serve as pivotal therapeutic targets. ER-targeting agents like selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) have harvested encouraging clinical outcomes. However, the expansion of their clinical utility remains limited by adverse effects, acquired resistance, and suboptimal pharmacokinetic properties. Recent advancements in ER biology have driven the development of novel ER-targeted agents, including third-generation SERMs, oral SERDs, complete ER antago…

Sex Hormone Receptor Signaling in Bladder Cancer: A Potential Target for Enhancing the Efficacy of Conventional Non-Surgical Therapy.

There have been critical problems in the non-surgical treatment for bladder cancer, especially residence to intravesical pharmacotherapy, including BCG immunotherapy, cisplatin-based chemotherapy, and radiotherapy. Recent preclinical and clinical evidence has suggested a vital role of sex steroid hormone-mediated signaling in the progression of urothelial cancer. Moreover, activation of the androgen receptor and estrogen receptor pathways has been implicated in modulating sensitivity to conventional non-surgical therapy for bladder cancer. This may indicate the possibility of anti-androgenic a

Tissue selectivity of ospemifene: pharmacologic profile and clinical implications.

The multifactorial consequences of menopausal estrogen deficiency affect numerous tissues throughout the body. Supplemental hormonal therapies carry the burden of a risk/benefit ratio that must be highly individualized. Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) agonist/antagonists designed to induce benefits comparable with estrogen while minimizing adverse effects. Here, we review the estrogen agonist/antagonist profile of ospemifene, a novel triphenylethylene derivative recently approved to treat dyspareunia, a symptom of vulvar and vaginal atrophy (VVA) due t…

Raloxifene modulates estrogen-mediated B cell autoreactivity in NZB/W F1 mice.

OBJECTIVE: Estrogen has been found to exacerbate disease activity in murine lupus and to induce a lupus-like syndrome in nonspontaneously autoimmune mice. This has led to the consideration that estrogen may be a risk factor for the development of systemic lupus erythematosus (SLE), and selective estrogen receptor modulators (SERM) may serve to ameliorate lupus activity. We evaluated the effects and mechanism of action of the SERM raloxifene in murine lupus. METHODS: Effects of raloxifene on the development of lupus in NZB/W F1 mice were evaluated in the presence and absence of estrogen by ass…

Role of Estrogen and Estrogen Receptor in GH-Secreting Adenomas.

Acromegaly is a rare disease with several systemic complications that may lead to increased overall morbidity and mortality. Despite several available treatments, ranging from transsphenoidal resection of GH-producing adenomas to different medical therapies, complete hormonal control is not achieved in some cases. Some decades ago, estrogens were first used to treat acromegaly, resulting in a significant decrease in IGF1 levels. However, due to the consequent side effects of the high dose utilized, this treatment was later abandoned. The evidence that estrogens are able to blunt GH activity al

Immediate and residual effects of tamoxifen and ethynylestradiol in the female rat hypothalamus.

Very little is known about the impact of selective estrogen receptor modulators (SERMs) on the brain. We examined the effects of tamoxifen (TAMOX) and the synthetic estrogen 17alpha-ethynylestradiol (EE) on estrogen-dependent gene expression and receptor binding in the female rat brain. Both immediate and residual effects were examined in both the presence and absence of 17beta-estradiol. Two groups of adult, ovariectomized, female rats (n=30 per group) were injected with TAMOX (5 mg/kg), EE (0.1 mg/kg), or sesame oil daily for 14 days. Animals from the first group were implanted with blank or…

Endocrine therapy of breast cancer.

Breast cancer remains one of the first leading causes of death in women, and currently endocrine treatment is of major therapeutic value in patients with estrogen-receptor positive tumors. Selective estrogen-receptor modulators (SERMs), such as tamoxifen and raloxifene, aromatase inhibitors, and GnRH agonists are the drugs of choice. Tamoxifen, a partial nonsteroidal estrogen agonist, is a type II competitive inhibitor of estradiol at its receptor, and the prototype of SERMs. Aromatase inhibitors significantly lower serum estradiol concentration in postmenopausal patients, having no detectable

The intersection of the HER2-low subtype with endocrine resistance: the role of interconnected signaling pathways.

Since its introduction in the 1970s, endocrine therapy that targets the estrogen receptor alpha (ERα) signaling pathway has had tremendous s … to complete resistance to all current endocrine therapies including aromatase inhibitors, selective estrogen receptor modulators, and selective estrogen receptor degraders, as well as cross-resistance to CDK4/6 inhibitors (CDK4/6is). Emerging evidence points to an intriguing connection between endocrine-resistant tumors and the HER2-low subtype. Specifically, recent studies a …

Allopregnanolone and mood disorders.

UNLABELLED: Certain women experience negative mood symptoms during the menstrual cycle and progesterone addition in estrogen treatments. In women with PMDD increased negative mood symptoms related to allopregnanolone increase during the luteal phase of ovulatory menstrual cycles. In anovulatory cycles no symptom or sex steroid increase occurs. This is unexpected as positive modulators of the GABA-A receptor are generally increasing mood. This paradoxical effect has brought forward a hypothesis that the symptoms are provoked by allopregnanolone the GABA-A receptor system. GABA-A is the major in

Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling.

Antiestrogens include agents such as tamoxifen, toremifene, raloxifene, and fulvestrant. Currently, tamoxifen is the only drug approved for use in breast cancer chemoprevention, and it remains the treatment of choice for most women with hormone receptor positive, invasive breast carcinoma. While antiestrogens have been available since the early 1970s, we still do not fully understand their mechanisms of action and resistance. Essentially, two forms of antiestrogen resistance occur: de novo resistance and acquired resistance. Absence of estrogen receptor (ER) expression is the most common de no

Endocrine manipulation in advanced breast cancer: recent advances with SERM therapies.

Tamoxifen is one of the most effective treatments for breast cancer through its ability to antagonize estrogen-dependent growth by binding estrogen receptors (ERs) and inhibiting breast epithelial cell proliferation. However, tamoxifen has estrogenic agonist effects in other tissues such as bone and endometrium because of liganded ER-activating target genes in these different cell types. Several novel antiestrogen compounds have been developed that are also selective ER modulators (SERMs) but that have a reduced agonist profile on breast and gynecological tissues. These SERMs offer the potenti

Sequence to structure approach of estrogen receptor alpha and ligand interactions.

Estrogen receptors (ERs) are steroid receptors located in the cytoplasm and on the nuclear membrane. The sequence similarities of human ERα, … stradiol>moxestrol>estriol (E3)>4-OH estradiol>estrone-3-sulfate. Estrogen mimetic drugs, selective estrogen receptor modulators (SERMs), have been used as hormonal therapy for ER positive breast cancer and postmenopausal osteoporosis. In the postgenomic era, in silico models have become effective tools for modern drug discovery. These provide three dimensional structures of …

New developments in the management of vulvovaginal atrophy: a comprehensive overview.

INTRODUCTION: Proper recognition and individualized therapy of vulvovaginal atrophy (VVA) is paramount. AREAS COVERED: Assessment of VVA sh … monal treatment, when non-hormonal treatments fail. New estrogens, androgens, and several Selective Estrogen Receptor Modulators (SERMs) are being developed and tested. Intravaginal Hyaluronic Acid (HA) or Vit D can help women who can't or don't want to use hormones. EXPERT OPINION: Proper treatment is not possible without a correct and full diagnosis, including microscopy o …

Stimulation of Leydig and Sertoli Cellular Secretory Function by Anti-Oestrogens: Tamoxifen.

Tamoxifen is a selective oestrogen receptor modulator (SERM). SERMs act on oestrogen receptors to inhibit oestradiol mediated negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis, thereby upregulating gonadotrophin secretion and release from the pituitary. Hence, Tamoxifen is used to upregulate activation of the HPG axis in the treatment of male-factor infertility. However, due to a lack of robust evidence, Tamoxifen has not been FDA approved for use in male-factor infertility and so its use is currently off-label. In this study, we performed a literature search of the OVID medli