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PubMed1986

The cyclic AMP second messenger system in man: the effects of heredity, hormones, drugs, aluminum, age and disease on signal amplification.

The intracellular effects of a number of hormonal signals are mediated by the cyclic AMP second messenger system in man and the ubiquitous distribution of hormone-stimulated adenylate cyclase suggests the importance of this enzyme complex in normal aging and pathophysiological states. Various vectors including heredity, endogenous catecholamines, steroid hormones, and drugs affect the activity of hormone-stimulated adenylate cyclase in man. The effect of heredity was studied using lymphocytes obtained from monozygotic twin pairs and age and sex-matched sib pairs. Only for forskolin-stimulated activity is a significant proportion of individual variance attributable to heredity, suggesting the relative stability of the catalytic subunit. Beta-adrenergic and prostaglandin E-1 activity are "state" characteristics and their activities are controlled by environmental parameters. A significant reduction in isoproterenol-stimulated cyclic AMP accumulation between the menses and luteal phase of the menstrual cycle is observed in lymphocytes obtained from 11 female subjects. The lowest level of beta-adrenergic receptor activity is associated with the highest levels of progesterone and estradiol hormone levels in blood. Lithium at therapeutic concentrations markedly inhibits adenylate cyclase activity in platelet membranes. Moreover, marked individual differences are observed in sensitivity to lithium as determined by Dixon plot derived Ki values for 9 normal, healthy subjects. Human adenylate cyclase obtained from platelets and lymphocytes is activated by micromolar amounts of aluminum in the presence of NaF. Irreversible activation of adenylate cyclase by aluminum is suggested as a possible mechanism of this metal's neurotoxicity. The biochemical basis for the age-associated decline in beta-adrenergic responsiveness in man is discussed. Several investigations suggest a deficit at two levels in the adenylate cyclase complex: an impaired coupling of the receptor/N protein subunits and an additional lesion distal to the receptor at the level of N/C coupling. Perfusion studies with salbutamol suggest that the decline in beta-adrenergic sensitivity is general and not restricted to lymphocytes. Possible abnormalities in cyclic AMP signal amplification and recognition in various disease states is discussed. Increased prostaglandin E-1-stimulated cyclic AMP accumulation is observed in lymphocytes obtained from patients with Alzheimer's disease compared to age-matched controls and correlated with severity of the disease state.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗
PubMed2001

Neurotrophic and neuroprotective actions of estrogens and their therapeutic implications.

Originally known for its regulation of reproductive functions, estradiol, a lipophilic hormone that can easily cross plasma membranes as well as the blood-brain barrier, maintains brain systems subserving arousal, attention, mood, and cognition. In addition, both synthetic and natural estrogens exert neurotrophic and neuroprotective effects. There is increasing evidence that estrogen actions are mediated by nongenomic as well as direct and indirect genomic pathways. Although in vitro models have provided the most extensive evidence for neurotrophic and neuroprotective actions to date, there are also in vivo studies that support these actions.

Animals↗
PubMed2006

Targeting fatty acid synthase in breast and endometrial cancer: An alternative to selective estrogen receptor modulators?

There is an urgent need to identify and develop a new generation of therapeutic agents and systemic therapies targeting the estradiol (E2)/estrogen receptor (ER) signaling in breast cancer. In this regard, new information on the mechanisms of E2/ER function and/or cross talk with other prosurvival cascades should provide the basis for the development of other ideal anti-E2 therapies with the intent to enhance clinical efficacy, reduce side effects or both. Our very recent assessment of the mechanisms by which cancer-associated increased lipogenesis and its inhibition alters the E2/ER signaling discovered that fatty acid synthase (FASN), the enzyme catalyzing the terminal steps in the de novo biosynthesis of long-chain fatty acids, differentially modulates the state of sensitivity of breast and endometrial cancer cells to E2-stimulated ER transcriptional activation and E2-dependent cell growth and survival: 1) pharmacological inhibition of FASN activity induced a dramatic augmentation of E2-stimulated ER-driven gene transcription, whereas interference (RNAi)-mediated silencing of FAS gene expression drastically lowered E2 requirements for optimal activation of ER transcriptional activation in breast cancer cells; conversely, pharmacological and RNAi-induced inhibition of FASN worked as an antagonist of E2- and tamoxifen-dependent ER transcriptional activity in endometrial adenocarcinoma cells; 2) pharmacological and RNAi-induced inhibition of FASN synergistically enhanced E2-mediated down-regulation of ER protein and mRNA expression in breast cancer cells, whereas specific FASN blockade resulted in a marked down-regulation of E2-stimulated ER expression in endometrial cancer cells; and 3) FASN inhibition decreased cell proliferation and cell viability by promoting apoptosis in hormone-dependent breast and endometrial cancer cells. In this review we propose that, through a complex mechanism involving the regulation of MAPK/ER cross talk as well as critical E2-related proteins including the Her-2/neu (erbB-2) oncogene and the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(Kip1), a previously unrevealed connection exists between FASN and the genomic and nongenomic ER activities in breast and endometrial cancer cells. From a clinical perspective, we suggest that if chemically stable FASN inhibitors or cell-selective systems able to deliver RNAi targeting FASN gene demonstrate systemic anticancer effects of FASN inhibition in vivo, additional preclinical studies to characterize their anti-breast cancer actions should be of great interest as the specific blockade of FASN activity may also provide a protective means against endometrial carcinoma associated with tamoxifen-based breast cancer therapy.

Breast Neoplasms↗
PubMed1999

Extracellular matrix inhibits apoptosis and enhances endothelial cell differentiation by a NfkappaB-dependent mechanism.

Hormonal and environmental factors that control the growth, differentiation, and regression of the vasculature are of fundamental importance in tumorigenesis and in the choice of therapeutic strategies. To test the hypothesis that estradiol (E2) and basement membrane proteins would affect the survival of vascular endothelial cells (EC), immortalized human umbilical vein endothelial cells (ECV304) were examined for their response to the chemotherapeutic drugs taxol and etoposide. ECV cell apoptosis was inhibited by E2 (taxol only) or attachment to extracellular matrix (ECM) (taxol or etoposide). E2 increased ECV growth, while ECM binding resulted in growth arrest and differentiation. Apoptosis was associated with decreased levels of Bcl-2 and p21 proteins. E2 prevented down-regulation of p21 and Bcl-2 induced by taxol but did not prevent the down-regulation of p21 induced by etoposide, consistent with the failure of E2 to inhibit etoposide-induced cell death. However, ECM prevented p21 and Bcl-2 down-regulation induced by taxol or etoposide. Persistent activation of NFkappaB occurred after attachment of ECV cells to ECM, suggesting a role in survival or differentiation. IkappaBalpha levels were not affected by taxol but were reduced by etoposide treatment, while IkappaBbeta levels did not change with drug treatment. E2 did not alter the levels of IkappaBalpha or IkappaBbeta. Interestingly, levels of IkappaBalpha and IkappaBbeta declined in etoposide-treated ECV cells on ECM concomitant with the elevation of NFkappaB, suggesting that in these cells degradation of IkappaB may be responsible for NFkappaB activation. In agreement with these data, anti-sense NFkappaB treatment of ECV cells inhibited differentiation on ECM, but did not affect cell survival. In conclusion, culture of ECV cells on ECM or treatment with E2 inhibited apoptosis. NFkappaB activation by ECM was necessary for cellular differentiation, rather than inhibition, of apoptosis.

Apoptosis↗
PubMed1975

[Effects of estrogenic hormones on blood lipids].

The authors have followed the effects of application of the deposit estradiolbenzoat on the blood lipides level of women at the beginning of menopause and women with arteriosclerosis. They have registered a moderate drop of the concentration of cholesterol, beta-lipoproteins, and slight changes of the non-esterified fatty acids level. Women using contraceptive hormonal mixtures were found with higher level of cholesterol in the blood serum than those being watched. The application of a single dose of androgen did not have any substantial effects on the blood lipides level.

Adult↗
PubMedDate not supplied

[Application of new therapeutic approaches in the prevention of osteoporosis in women].

The prevention of female osteoporosis is based on: a) promoting the achievement of optimal bone mass at the time of menopause; b) minimizing subsequent rarefaction especially in fast bone losers. Both these objectives can be partly attained by appropriate behaviour (balanced diet with adequate calcium intake, physical exercise) but often with additional preventive treatment that is undoubtedly easier to undertake since the introduction of new therapeutic approaches like the use of transdermal estradiol (TDE) and the salmon calcitonin (CT) nasal spray. Certain situations, chronic hypo-estrogenism (amenorrhea caused by primary ovarian deficit and primary or secondary hypothalamic hypogonadotropinemia) should be rectified by replacement estrogen-progestin treatment before the onset of menopause. Protracted treatment of this kind can also be used beneficially in patients identified as at risk of osteoporosis during the climacteric and where it is advisable to minimise the hepatocellular action of the estrogens TDE will be the treatment of choice. In both phases the CT spray can be used preventively wherever there are contraindications to the use of the estrogens and a real risk of osteoporosis.

Administration, Cutaneous↗
PubMed1987

Diagnosis of primary generalized epilepsy in a cow.

On the basis of history, electrodiagnostic and neuropharmacologic studies, and results of laboratory testing and necropsy, a seizure disorder of 1.5 years' duration in an 8-year-old Hereford cow was diagnosed as primary generalized epilepsy. Evidence of metabolic, toxicologic, head trauma, or genetic cause of the seizures was not found. A morphologic cause for the convulsions also was not detected. One naturally occurring seizure was recorded electroencephalographically, but interictal EEG abnormalities were not seen. Attempts to evoke a seizure with photostimulation or therapeutic doses of acepromazine, ketamine, tripelennamine, and estradiol cypionate were unsuccessful. The seizure threshold for the CNS stimulant pentylenetetrazol was found to be less than 6 mg/kg, IV; the seizure threshold in a control cow was found to be greater than 12 mg/kg, IV. The pharmacologic protocol used for this cow may be useful for diagnosis of epilepsy in other animals.

Animals↗
PubMed2002

Clinical equivalence of intranasal estradiol and oral estrogens for postmenopausal symptoms.

OBJECTIVES: The aim was to demonstrate the equivalent efficacy of intranasal estradiol (Aerodiol Servier, Istanbul, Turkey) 300 mg/day relative to a standard oral estradiol therapy of 2 mg/day and to assess the therapeutic value of the potential benefits of Aerodiol. METHODS: Two hundred and one postmenopausal women with severe menopausal symptoms were recruited to the trial. Women received either intranasal Aerodiol 300 microg/day (one spray delivery of 150 microg per nostril) or an oral estradiol 2 mg for 24 weeks. Severity of symptoms were compared based on the Kupperman index (KI) at the end of 24 weeks. RESULTS: The KI score decreased markedly in both groups between W0 and W24. At W24, the two treatments were shown to be statistically equivalent (P<0.001). The incidence of adverse events was very similar in both groups; those related to treatment were of mild or moderate intensity in 95% of cases for the nasal group and 90% for the oral group. CONCLUSIONS: In conclusion, pulsed estrogen therapy using Aerodiol is safe, easily used and highly efficient in alleviating postmenopausal symptoms with a dose of 300 microg. The dose of 300 microg in one administration per day offers the optimal therapy whilst being easily adaptable to each patient's clinical response.

Administration, Intranasal↗
PubMed2004

17beta-estradiol attenuates glutamate-induced apoptosis and preserves electrophysiologic function in primary cortical neurons.

Glutamate toxicity causes neuronal death in neurodegenerative diseases; hence, there is a need for therapeutic agents rendering functional neuroprotection. We tested the effects of 17beta-estradiol (estrogen) in rat primary cortical neurons after glutamate exposure. Wright staining and ApopTag assays indicated that 0.5 microM glutamate for 24 hr caused apoptosis. Glutamate-induced apoptosis correlated with upregulation of calpain, a proapoptotic shift in the Bax:Bcl-2 ratio, and increased activation of caspase-3. Pretreatment with 10 nM estrogen prevented apoptosis, attenuated calpain upregulation, shifted the Bax:Bcl-2 ratio toward survival, and decreased caspase-3 activation. Single-cell voltage-clamp techniques were used to record whole-cell currents associated with Na+ channels, N-methyl-D-aspartate receptor channels, and kainate receptor channels. No significant differences were recorded in membrane capacitance at -70 mV in neurons treated with estrogen or estrogen plus glutamate, relative to controls. Notably, no changes in capacitance indicated that neurons treated with estrogen and glutamate did not experience apoptosis-associated cell shrinkage. No membrane potential could be recorded in the neurons treated with glutamate due to apoptosis. All recorded currents were similar in amplitude and activation/inactivation kinetics in control neurons and neurons treated with estrogen plus glutamate. Estrogen thus preserved both neuronal viability and function in this in vitro glutamate toxicity model.

Animals↗
PubMed1992

Enzymatic regulation of estradiol-17 beta concentrations in human breast cancer cells.

Estradiol-17 beta is known to be involved in both the etiology and maintenance of growth of breast cancer. However, blood levels of the hormone do not reflect those found within the cells due to a number of transformations catalysed by enzymes which may be under metabolite and/or hormonal regulation. Recognition of the importance of the hormone microenvironment within the cell focuses attention on these enzymes and provides the subject for this review. An interplay between the sex hormones, estrogen and progestin, can control estradiol-17 beta concentrations in breast cancer cells at the level of key transforming enzymes. In addition, some enzymes catalyse production of biologically inert derivatives which are rapidly eliminated from the cell. Other enzymes catalyse the formation of derivatives which are exclusively intracellular and can act as reserve forms of the hormone. Yet others lead to estradiol-17 beta metabolites which are cytotoxic. An improved understanding of the enzymes and the role of the related metabolites can provide the opportunity for the development of new therapeutic agents.

Breast Neoplasms↗
PubMedDate not supplied

[Mechanism of action of progestins in the treatment of hormone-dependent breast cancer (author's transl)].

The in vitro interference of some gestagens with the binding of 3H-17-beta-oestradiol to cytosol specific receptors was investigated with a view to elucidating the mechanism of action of progestins in the treatment of human hormone-dependent breast cancer. A decrease (up to 85%) of oestradiol binding capacity was observed with high concentrations of progesterone, clogestone and medrogestone. These findings are in good agreement with those previously obtained by the same progestins in our laboratory on rat uterine estrogen receptors in vitro or in vivo. These results provide the support for the hypothesis that the mode of action of progestins in the therapy of mammary and perhaps uterine carcinomas is to some extent related to the inhibition of oestradiol binding to cytosol specific receptors.

Breast Neoplasms↗
PubMed1997

Comparison of endometrial growth produced by unopposed conjugated estrogens or by micronized estradiol in postmenopausal women.

OBJECTIVE: When unopposed estrogen replacement treatment is used, what is the pattern of endometrial growth? Does endometrial growth differ for various dosages and formulations? STUDY DESIGN: A total of 87 postmenopausal women, median age 57 years (mean 56.7 +/- 5.6 years, range 45 to 69 years), were studied in a prospective, randomized, open clinical trial lasting 24 weeks. The treatment arms consisted of micronized estradiol, 0.5 or 1.0 mg (Estrace, Bristol-Myers Squibb, Princeton, N.J.), and conjugated estrogens, 0.625 mg (Premarin, Wyeth-Ayerst, Philadelphia). Endometrial thickness was evaluated by vaginal probe ultrasonography at outset and after 6, 12, and 24 weeks of treatment. RESULTS: Endometrial growth was progressive over time; more than half the total 24-week growth occurred in the first 6 weeks. The mean weekly rate (+/-SD) of endometrial growth was similar for micronized estradiol, 1.0 mg, and conjugated estrogens, 0.625 mg (0.19 +/- 0.15 mm for micronized estradiol, 1.0 mg, and 0.19 +/- 0.14 mm for conjugated estrogens, 0.625 mg). These rates differed to a statistically significant degree (p < 0.05) from the growth rate produced by micronized estradiol, 0.5 mg (0.08 +/- 0.16 mm). Both unscheduled and scheduled uterine bleeding was less likely among women using micronized estradiol, 0.5 mg, than among women using micronized estradiol, 1.0 mg, or conjugated estrogens, 0.625 mg. CONCLUSIONS: In a 24-week trial the therapeutically equivalent estrogen doses produced the same mean increment in endometrial thickness, but half-strength estradiol produced half as much endometrial growth.

Endometrium↗
PubMed2003

Effects of triiodothyronine and estrogen administration on bone mass, mineral content and bone strength in male rats.

Experimental hyperthyroidism had a negative effect on bone mineral density, but did not significantly alter mechanical properties of femur and femoral bone thickness. Estradiol at a dose used in humans for the treatment of osteoporosis decreased seminal vesicle weight and concentration of testosterone but increased bone density in male rats compared to intact animals. In these rats, the mechanical analysis revealed an increased mechanical femur strength higher than the increase in bone density and femoral cortical thickness. When hyperthyroid male rats with low bone density were treated with estradiol in spite of a low plasma testosterone, the changes in bone density resulting from hyperthyroidism were entirely prevented. Estrogens protect the male skeleton against resorbing action of T (3). Treatment with estradiol in male rats with hyperthyroidism did not increase mechanical bone strength or femoral cortical thickness as it did with estradiol administration alone. Our results suggest that exogenously administered estrogens may have therapeutic value in preventing bone loss accompanying triiodothyronine administration, even in male rats with a low testosterone levels. At the concentration studied, estradiol increased in spite of low plasma testosterone, bone mineral density, mechanical strength of femur, and femoral cortical thickness.

Animals↗
PubMed1988

Clinical response to busramustine (KM-2210) in chronic lymphocytic leukemia: a pilot evaluation of estrogen receptor in relation to its therapeutic effect.

Busramustine (KM-2210), the benzoate of a 17 beta-estradiol-chlorambucil conjugate, was administered to 11 patients with chronic lymphocytic leukemia (CLL) which included eight cases of B-cell CLL and three cases of T-cell CLL. Four patients had received prior chemotherapy. Busramustine was given orally at an initial daily dose of 50-100 mg continuously, and the dose was modified according to hematological improvement. Two cases of B-cell CLL achieved clinical complete responses, six cases including two of T-cell CLL and four of B-cell CLL achieved partial responses and one case of B-cell CLL achieved improvement. The partial and complete response rate was 72.7%. Four patients showed estrogen receptor activity of CLL cells ranging from 3.5 to 57.5 fmol/mg cytosol protein, but there seemed to be no correlation between the estrogen receptor activity of the CLL cells and the therapeutic effects of busramustine. Toxic effects included diarrhea (2/11) and estrogen-related symptoms including breast pain (4/11), genital bleeding (2/5), gynecomastia (2/6) and loss of libido (2/6). The findings of this preliminary study suggest that busramustine is effective in the treatment of CLL, irrespective of the presence of the estrogen receptor.

Adult↗