Nonsteroidal Estrogen Receptor Antagonist Research Articles

Enclomiphene citrate for the treatment of secondary male hypogonadism

ABSTRACTIntroduction: Hypogonadism is a growing concern in an aging male population. Historically treated using exogenous testosterone, concerns about possible adverse effects of testosterone have led physicians to seek alternative treatment approaches.Areas covered: Enclomiphene citrate is the trans isomer of clomiphene citrate, a non-steroidal estrogen receptor antagonist that is FDA-approved for the treatment of ovarian dysfunction in women. Clomiphene citrate has also been used off-label for many years to treat secondary male hypogonadism, particularly in the setting of male infertility. Here we review the literature examining the efficacy and safety of enclomiphene citrate in the setting of androgen deficiency.Expert opinion: Initial results support the conclusion that enclomiphene citrate increases serum testosterone levels by raising luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, without negatively impacting semen parameters. The ability to treat testosterone deficiency in men while maintaining fertility supports a role for enclomiphene citrate in the treatment of men in whom testosterone therapy is not a suitable option.

Simultaneous determination of erlotinib and tamoxifen in rat plasma using UPLC-MS/MS: Application to pharmacokinetic interaction studies.

Tamoxifen (TAM) is a non-steroidal estrogen receptor antagonist that enhances erlotinib (ERL)-induced cytotoxicity in the treatment of NSCLC. ERL and TAM are metabolized by CYP3A4 enzymes. In addition, both drugs have the potential of altering the enzymatic activity through either inhibition (ERL) or induction (TAM). Thus it was expected that pharmacokinetics (PK) drug-drug interactions (DDIs) could be encountered following their co-administration. In this respect, a bioanalytical UPLC-MS/MS method has been developed and validated for the simultaneous determination of ERL and TAM in rat plasma samples, using ondansetron (OND) as an internal standard (IS). Plasma samples were prepared using mixed mode cationic solid phase extraction (SPE) STRATA™ -X-C 33μm cartridges with good extraction recovery of both drugs from rat plasma (Er% from -13.92 to -3.32). The drugs were separated on a Waters BEH™ C18 column with an isocratic elution using a mobile phase composed of a mixture of acetonitrile and water, each with 0.15% formic acid, in the ratio of 80: 20, v/v. Quantitation was carried out using the positive ionization mode with multiple reaction monitoring (MRM) at m/z 394.20>278.04 (ERL), m/z 372.25>72.01 (TAM), and m/z 294.18>170.16 (OND). The method was fully validated as per the FDA guidelines over the concentration range of 0.2-50ng/mL with very low lower limit of quantification (LLOQ) of 0.2ng/mL for both ERL and TAM. The intra- and inter-day assay precision (in terms of relative standard deviation, RSD) and accuracy (in terms of percentage relative error, % Er) were evaluated for both drugs and the calculated values evaluated at four different concentration levels were within the acceptable limits (<15%) for concentrations other than LLOQ and 20% for LLOQ. The method was successfully applied to the study of possible PK-DDI following the oral administration of ERL and TAM in a combination, compared to their single administration.

Estrogen mediates metabolic syndrome-induced erectile dysfunction: a study in the rabbit.

Estrogen receptor (ER) α is critical in mediating the harmful effects of hyperestrogenism in fetal or neonatal life on the developing penis. In contrast, little is known on the impact of an excess of estrogens on penile function in adulthood. To investigate the effect of estrogens on metabolic syndrome (MetS)-associated erectile dysfunction (ED). We employed a recently established animal model of high fat diet (HFD)-induced MetS. Subgroups of MetS rabbits were dosed with either testosterone (T) or tamoxifen. We evaluated penile responsiveness to acetylcholine (Ach) as well as the expression of genes related to penile smooth muscle relaxation and contractility. Associations between MetS-induced penile alterations and sex steroids were investigated in an animal model of HFD-induced MetS. To understand the role of either androgen deficiency or estrogen excess on ED, we treated subgroups of MetS rabbits with either T or tamoxifen, a classical ER antagonist. Feeding an HFD-induced MetS was associated to elevated estradiol (E2) and low T levels. E2, but not T, was independently and negatively associated with genes able to affect penile erection. Smooth muscle-related markers decreased as a function of E2 and were positively associated with all the variables investigated. Increasing concentrations of circulating E2 were negatively associated with Ach-induced relaxation. In HFD rabbits, in vivo T dosing significantly improved MetS and completely normalized circulating E2. Conversely, in vivo tamoxifen dosing reduced visceral adiposity and partially restored T level. Ach-induced relaxation was severely impaired by HFD and significantly restored, up to the control level, by both tamoxifen and T dosing. In rabbit smooth muscle cells cultures 17β-E2 (1 nM) significantly reduced the expression of α-smooth muscle actin, transgelin, and phosphodiesterase type 5. The effects of 17β-E2 were completely reverted by tamoxifen (100 nM). This study demonstrates, for the first time, that HFD-induced ED is more associated with a high E2, rather than to a low T, milieu. HFD-induced ED is partially restored by in vivo treatment not only with T but also with the nonsteroidal ER antagonist, tamoxifen.

Synthesis of Non-Steroidal Estrogen Receptor Antagonists R1128 A, B, C, and D via an Oxazoline-Promoted Iterative ortho-Lithiation Strategy

Abstract A concise total synthesis of non-steroidal estrogen receptor antagonists R1128 A–D (1a–1d) has been achieved using iterative ortho-lithiation of 2-(4-methoxyphenyl)-4,4-dimethyloxazoline (3) as the key reaction.

Cloning, Nucleotide Sequence, and Heterologous Expression of the Biosynthetic Gene Cluster for R1128, a Non-steroidal Estrogen Receptor Antagonist: INSIGHTS INTO AN UNUSUAL PRIMING MECHANISM

R1128 substances are anthraquinone natural products that were previously reported as non-steroidal estrogen receptor antagonists with in vitro and in vivo potency approaching that of tamoxifen. From a biosynthetic viewpoint, these polyketides possess structurally interesting features such as an unusual primer unit that are absent in the well studied anthracyclic and tetracyclic natural products. The entire R1128 gene cluster was cloned and expressed in Streptomyces lividans, a genetically well developed heterologous host. In addition to R1128C, a novel optically active natural product, designated HU235, was isolated. Nucleotide sequence analysis of the biosynthetic gene cluster revealed genes encoding two ketosynthases, a chain length factor, an acyl transferase, three acetyl-CoA carboxylase subunits, two cyclases, two oxygenases, an amidase, and remarkably, two acyl carrier proteins. Feeding studies indicate that the unusual 4-methylvaleryl side chain of R1128C is derived from valine. Together with the absence of a dedicated ketoreductase, dehydratase, or enoylreductase within the R1128 gene cluster, this suggests a functional link between fatty acid biosynthesis and R1128 biosynthesis in the engineered host. Specifically, we propose that the R1128 synthase recruits four subunits from the endogenous fatty acid synthase during the biosynthesis of this family of pharmacologically significant natural products.

R1128 substances, novel non-steroidal estrogen-receptor antagonists produced by a Streptomyces. I. Taxonomy, fermentation, isolation and biological properties.

New non-steroidal estrogen-receptor antagonists, R1128 A, B, C and D, were isolated from the cultured broth of Streptomyces sp. No. 1128 by solvent extraction, silica gel chromatography, reverse phase chromatography and preparative HPLC. These compounds inhibited estrogen binding to its receptor. The IC50 values of R1128 A, B, C and D for partially purified rat uterine cytosol receptor were 1.1 x 10(-7) M, 1.2 x 10(-7) M, 2.6 x 10(-7) M and 2.7 x 10(-7) M, respectively.

R1128 substances, novel non-steroidal estrogen-receptor antagonists produced by a Streptomyces. II. Physico-chemical properties and structure determination.

R1128 A, B, C and D, new non-steroidal estrogen-receptor antagonists, were isolated from the cultured broth of Streptomyces sp. No. 1128. Their structures were elucidated to be 1,3,6-trihydroxy-8-alkylanthraquinones on the basis of their physico-chemical properties and spectroscopic data.

R1128 substances, novel non-steroidal estrogen-receptor antagonists produced by a Streptomyces. III. Pharmacological properties and antitumor activities.

R1128 B (1,3,6-trihydroxy-8-n-butylanthraquinone), a new antibiotic produced by Streptomyces sp. No. 1128, inhibited estrogen binding to its receptor. The IC50 value of R1128 B for partially purified rat uterine cytosol receptor was 1.2 x 10(-7) M. However, the IC50 value of R1128 B against androgen-receptor binding was about 50-fold greater than that against estrogen-receptor binding. R1128 B was a competitive inhibitor against estrogen-receptor binding. R1128 B inhibited the growth of estrogen-responsive human mammary adenocarcinoma MCF-7 cells in soft agar. This inhibition, however, was reversed when estradiol was added to the culture medium. R1128 B showed antitumor activities against MCF-7 both xenografted to nude mice and implanted in subrenal capsule of mice (SRC assay). The potency of R1128 B was about 8-fold lower than that of tamoxifen both in vitro and in vivo.

Napyradiomycins A and B1: non-steroidal estrogen-receptor antagonists produced by a Streptomyces.

Napyradiomycins A and B1: non-steroidal estrogen-receptor antagonists produced by a Streptomyces.

The influence of gonadal steroids on the dopamine inhibitory effect on gonadotropin release in men

The aim of this study was to ascertain whether an interrelationship exists between gonadal steroids and the inhibition of gonadotropin secretion by dopamine. The effect of dopamine infusion (4 micrograms/kg/minute intravenously) on gonadotropin plasma levels in four castrated men (18 to 23 years of age) and in four age-matched normal men was studied. Normal subjects were studied before and after treatment with a specific nonsteroidal estrogen receptor antagonist, CC. LH plasma levels in normal subjects receiving CC had a maximum decrease percentage and a net decrease significantly greater (P less than 0.005 and P less than 0.012, respectively) than those before CC treatment. In castrated subjects the maximum decrease percentage was significantly greater (P less than 0.005) than in control subjects, but it did not show any difference from that of normal subjects receiving CC. In none of the group were significant changes in FSH concentration observed. The findings suggest that whenever there is a gonadal steroid deficiency, dopamine infusion causes an increased sensitivity to LH inhibition. This may be due to a lower endogenous dopaminergic influence on LH secretion.

Gonadal steroids and opioid control of gonadotropin secretion in man

The aim of this study was to ascertain whether there was an interrelationship between gonadal steroids and endogenous opioid peptides. The effects of naloxone (20 mg, intravenously) and of a met-enkephalin analog (DAMME) (250 micrograms, intravenously) on gonadotropin secretion in three castrated men (18 to 23 years of age) and in five age-matched normal men were studied. Normal subjects were studied before and after treatment with a specific nonsteroidal estrogen receptor antagonist, clomiphene. Naloxone caused a significant increase in luteinizing hormone (LH) (P less than 0.05); in these subjects, clomiphene treatment significantly increased LH and follicle-stimulating hormone plasma levels but totally suppressed the naloxone-induced rise in LH. In castrated men, naloxone failed to increase plasma LH levels. However, DAMME significantly reduced plasma LH levels in normal, in castrated, and in clomiphene-treated normal subjects. The results demonstrate that in castrated subjects who lack gonadal steroids and in normal subjects with blocked estrogen receptors there is a reduced opioid inhibitory tone on gonadotropin secretion. The effect of DAMME on gonadotropin secretion, however, is not influenced by the gonadal steroid environment.