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PubMed1978

Relationship between insulin and estrogen binding to growth response in 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors.

Insulin and estrogen binding have been determined in 7,12-dimethylbenz(a)anthracene-induced mammary tumors of rats in various endocrine states. Hormonal therapy, such as diabetes and ovariectomy, resulted in differential effects on growth patterns and hormone binding of tumors coexisting in the same host or in different hosts. It was observed that tumors that continued to grow after the host was made diabetic (insulin independent) or started to regress after ovariectomy (ovarian dependent) demonstrated decreased insulin binding. Tumors that regressed in diabetic hosts (insulin dependent) or continued to grow in ovariectomized animals (ovarian independent) showed an increased insulin-binding capacity. No significant change in insulin binding was observed in tumors that remained static after ovariectomy or induction of diabetes. Estrogen binding in tumor cells from diabetic rats paralleled the pattern of tumor growth response to diabetes; insulin-independent tumors demonstrated a significant increase in binding compared to tumors from intact hosts, and insulin-dependent tumors showed decreased estrogen receptor levels. From these results, we conclude that (a) insulin plays a positive role in regulating estrogen-binding capacity, (b) ovarian hormones may play a role in regulating insulin-binding capacity, and (c) a relationship between insulin and ovarian hormones and the growth of 7,12-dimethylbenz(a)anthracene-induced tumors is strongly suggested and may have therapeutic implications.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2004

Studies on the interactions between drugs and estrogen. III. Inhibitory effects of 29 drugs reported to induce gynecomastia on the glucuronidation of estradiol.

To determine the inhibition effects of drugs on the glucuronidation of estradiol (E2), 29 drugs that have been reported to induce gynecomastia were examined in the presence of UDP-glucuronic acid using human hepatic microsomes (pooled) as the enzyme source. The percentage inhibition of the E2 glucuronidation was determined at drug concentrations of 1 microM (approximate therapeutic concentration) and 100 microM (non-clinical overdose concentration) based on the rate constants for the 3- and 17-glucuronidation of E2 (11.2 and 2.52 pmol/min/mg protein, respectively). The only drug that exhibited 50% or higher inhibition of the 3-glucuronidation at a concentration of 1 microM was manidipine (54.4%). When the concentration was 100 microM, manidipine exhibited 100% inhibition of the 3-glucuronidation, and other drugs that exhibited 50% or higher inhibition of the 3-glucuronidation were nicardipine (92%), nisoldipine (90%), nifedipine (84%), domperidone (81%), tacrolimus (80%), nitrendipine (77%) and ketoconazole (69%). Conversely, ipriflavone accelerated the formation of estradiol 3-glucuronide in the activity of 165% at the concentration of 100 microM. On the 17-glucuronidation, all of the drugs showed less than 50% inhibition at the concentration of 1 microM, but at the concentration of 100 microM, drugs that exhibited 50% or higher inhibition consisted of manidipine (79%), chlormadinone acetate (74%), nisoldipine (66%), nitrendipine (60%) and ketoconazole (55%). Although IC(50) values of these drugs were all lower than the K(m) value (285 microM) for the 3-glucuronidation of E2, they were higher than the K(m) value for the 17-glucuronidation (18.8 microM). Thus, the effect of the drugs on the E2 glucuronidation should be greater for hydroxy group at the C-3 than that at the C-17 of E2 molecule. On the other hand, metabolic clearances (V(max)/K(m)) of the 3- and 17-glucuronidation were about 1/14th and 1/18th of that of the 2-hydroxylation of E2, respectively. The result implies that, when the contribution of the glucuronidation to enterohepatic circulation is taken into consideration, the effect of this metabolic inhibition in the estrogen pool cannot be ignored.

Chromatography, High Pressure Liquid↗
PubMed1990

Estrogen induced suppression of collagen arthritis. V: Physiological level of estrogen in DBA/1 mice is therapeutic on established arthritis, suppresses anti-type II collagen T-cell dependent immunity and stimulates polyclonal B-cell activity.

Immunization of castrated female DBA/1 mice with rat type II collagen (CII) induces severe polyarthritis with an onset 3-5 weeks after immunization and with 80-100% incidence. Estrogen treatment, inducing physiological 17 beta-estradiol (E2) levels, during a limited period before and after the immunization, or during another period before the expected onset of arthritis, delayed the arthritic onset by approximately 10 days but did not affect the incidence of severity of arthritis. Treatment with physiological doses of E2 after onset of arthritis decreased severity and duration of disease. The T-cell dependent anti-CII autoantibody response was suppressed if the E2 treatment was given immediately before and after CII immunization and was not significantly affected if E2 treatment was given after CII immunization. Neither the total anti-CII Ig levels nor the anti-CII IgG2a levels correlated with development of arthritis. We also titrated the serum levels of estrogen and recorded the vaginal smear response after injections of various doses of E2. This enabled us to work in a physiological range of estrogen levels, spanning the levels found at the end of pregnancy and those found during the normal estrous cycle. These levels were found to suppress antigen-specific T-cell functions but enhance certain B-cell activities since the delayed type hypersensitivity (DTH) reaction against CII was suppressed while the total number of splenic Ig-secreting cells increased. These findings suggest that estrogen in physiological doses is therapeutic for the development of collagen-induced arthritis and that estrogen exerts dualistic effects on the immune system by suppressing T-cell functions and stimulating certain B-cell activities. The suppressive effect on arthritis could not be explained by suppression of anti-CII autoantibody response and must therefore depend on other T-cell-mediated functions.

Analysis of Variance↗
PubMed1990

[Comparative analysis of therapeutic effects of carbocalcitonin and and conjugated estrogens in post-menopausal osteoporosis].

In order to assess the correlation between menopause and osteoporosis, both in pathogenetic and therapeutical terms, a study was carried out in four comparable group of patients at Department B of the Institute of Gynaecology and Obstetrics at the University of Turin. Patients were divided as follows: 24 patents affected by evident osteoporosis, 39 patients with the first symptoms of osteoporosis, 27 with hypercalcemia and 33 healthy controls. The following tests were performed in all subjects: serum assay of androstenedione, estrone, 17-beta-estradiol, PTH, calcium, phosphorus, alkaline phosphatase and creatinine. Laboratory tests were repeated monthly in all patients and control subjects. Dual chromatic ray bone densitometry was performed in all patients at the start and end of treatment. With regard to therapy, each group was subdivided into two equal subgroups which were treated with carbocalcitonin or conjugated estrogens. From the findings, it is clear that there is a non-significant difference between serum levels of androstenedione, estrone and estradiol in the three groups examined and control subjects. Although the possibility that the fall in steroid hormones might contribute to bone load cannot be excluded, it is not possible to demonstrate that this is the most important factor in the pathogenesis of osteoporosis given that many women do not develop osteoporotic symptoms after menopause. In addition, in therapeutic terms, all bone density parameters considered in patient osteoporosis improved after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2005

GREB 1 is a critical regulator of hormone dependent breast cancer growth.

BACKGROUND: Estrogen plays a central role in breast cancer pathogenesis and many potent risk factors for the development of the disease can be explained in terms of increased lifetime exposure to estrogen. Although estrogen regulated genes have been identified, those critically involved in growth regulation remain elusive.METHODS. To identify candidate genes involved in estrogen stimulated breast cancer growth, DNA microarray based gene expression profiles were generated from three estrogen receptor alpha (ER alpha) positive breast cancer cell lines grown under multiple stimulatory and inhibitory conditions. RESULTS: Only three genes were significantly induced by 17beta-estradiol (E2) relative to control in all three cell lines: GREB 1, stromal cell-derived factor 1 (SDF-1) and trefoil factor 1 (pS2). Quantitative real-time PCR assays confirmed that in all three cell lines, GREB 1 was induced by E2, but not by the antiestrogens tamoxifen (TAM) or ICI 182,780. GREB 1 expression level was strongly correlated with ER alpha positivity in 39 breast cancer cell lines of known ER alpha expression status. GREB 1 induction by E2 was rapid (7.3 fold by 2 h for MCF-7) and mirrored the fraction of cells entering S-phase when released from an estrogen deprivation induced cell arrest. Suppression of GREB 1 using siRNA blocked estrogen induced growth in MCF-7 cells and caused a paradoxical E2 induced growth inhibition. CONCLUSION: These data suggest that GREB 1 is critically involved in the estrogen induced growth of breast cancer cells and has the potential of being a clinical marker for response to endocrine therapy as well as a potential therapeutic target.

Animals↗
PubMed2006

Role of cocaine- and amphetamine-regulated transcript in estradiol-mediated neuroprotection.

Estrogen reduces brain injury after experimental cerebral ischemia in part through a genomic mechanism of action. Using DNA microarrays, we analyzed the genomic response of the brain to estradiol, and we identified a transcript, cocaine- and amphetamine-regulated transcript (CART), that is highly induced in the cerebral cortex by estradiol under ischemic conditions. Using in vitro and in vivo models of neural injury, we confirmed and characterized CART mRNA and protein up-regulation by estradiol in surviving neurons, and we demonstrated that i.v. administration of a rat CART peptide is protective against ischemic brain injury in vivo. We further demonstrated binding of cAMP response element (CRE)-binding protein to a CART promoter CRE site in ischemic brain and rapid activation by CART of ERK in primary cultured cortical neurons. The findings suggest that CART is an important player in estrogen-mediated neuroprotection and a potential therapeutic agent for stroke and other neurodegenerative diseases.

Animals↗
PubMed1991

Effects of vehicle supplementation on total estradiol absorption from a transdermal estradiol delivery system.

OBJECTIVE: To evaluate the effects of vehicle supplementation on serum estradiol (E2) delivery pharmacokinetics from the Ciba-Geigy (Summit, NJ) 0.1-mg Estraderm Patch. DESIGN: Postmenopausal women were randomized to a 28-day crossover treatment protocol separated by a 14-day wash out period. SETTING: Normal human volunteers were studied in an academic research environment. PATIENTS, PARTICIPANTS: The subject pool included eight healthy postmenopausal women between 32 and 60 years of age. INTERVENTIONS: In treatment A, a 0.1-mg Estraderm Patch was worn for 7 days; in treatment B, and identical patch was worn into which 0.6 mL of ethanol was injected on day 3 of use. MAIN OUTCOME MEASURES: Serum E2 levels were measured in both groups. RESULTS: Although E2 absorption showed characteristic interpatient variability, addition of ethanol significantly extended the mean time for serum E2 levels to return to baseline, without increasing peak absorption. The mean extension was 50 hours. CONCLUSION: The addition of ethanol to the Estraderm Patch increased the duration of elevated serum E2 levels measured in menopausal women, thus potentially increasing the effective life span of the transdermal therapeutic system.

Absorption↗
PubMed2003

Transdermal delivery of sex steroids for hormone replacement therapy and contraception. A review of principles and practice.

The percutaneous route is an effective method for delivery of reproductive hormones. Several transdermal therapeutic systems (TTS) releasing estrogens, progestogens and androgens from patches attached to the skin are currently in clinical use. For women, transdermal systems have been developed for hormonal replacement therapy (HRT) and recently for contraception. HRT with patches releasing only estradiol (E2) should be supplemented with a progestogen to protect the endometrium. Patches simultaneously releasing both E2 and a progestogen are also available. Combined regimens are either continuous or sequential. In the latter, estrogen-only patches are applied for 14 days, followed by 14-day application of patches releasing both hormones. Transdermal HRT successfully treats menopausal symptoms and has a bone-sparing effect. Transdermal contraceptive patches deliver ethinyl E2 in combination with the progestogen norelgestromin. This system provides an effective contraceptive and acceptable bleeding pattern not different from that of oral contraceptives. The types of adverse events experienced are approximately the same as with oral contraceptives. Reactions at the application site cause about 3% women to discontinue the use of patches. Transdermal systems also have been designed to supplement testosterone in hypogonadal men. Testosterone released from patches produces positive effects on mood and sexual behavior and significantly increases bone mass. Men using testosterone patches have to be regularly monitored for an increase in prostate volume and changes in prostate-specific antigen. Reproductive steroids delivered by the skin avoid first-pass liver metabolism, typical of oral dosing; consequently, the liver tissue is affected to a lesser degree. Other advantages include rapid onset and termination of action, noninvasive self-administration and attainment of therapeutic hormone levels with low daily doses. Reduced frequency of dosing has the potential to improve patient compliance. While compliance is important for any hormone, it is particularly important for contraceptive purposes. Like oral delivery of sex steroids, percutaneous absorption is characterized by intra- and interindividual variability. New technologies under development, combining electronics and low-frequency ultrasound, have the potential to provide precise dosing as well as drug delivery "on demand."

Administration, Cutaneous↗
PubMed2004

Development and validation of a high-sensitivity liquid chromatography/tandem mass spectrometry (LC/MS/MS) method with chemical derivatization for the determination of ethinyl estradiol in human plasma.

An ultra-sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the analysis of oral contraceptive ethinyl estradiol (EE) was developed and validated over the curve range of 2.5-500 pg/mL using 1 mL of human plasma sample. Ethinyl estradiol and the internal standard, ethinyl estradiol tetra-deuterated (EE-d4), were extracted from the plasma matrix with methyl t-butyl ether, derivatized with dansyl chloride and then back-extracted into hexane. The hexane phase was evaporated to dryness, reconstituted and injected onto the LC/MS/MS system. The chromatographic separation was achieved on a Luna C(18) column (50 x 2 mm, 5 micro m) with an isocratic mobile phase of 20:80 (v/v) water:acetonitrile with 1% formic acid. The offline derivatization procedure introduced the easily ionizable tertiary amine function group to EE. This greatly improved analyte sensitivity in electrospray ionization and enabled us to achieve the desired lower limit of quantitation at 2.5 pg/mL. This high sensitivity method can be used for therapeutic drug monitoring or supporting bio-equivalence and drug-drug interaction studies in human subjects.

Chromatography, Liquid↗
PubMed2002

Idoxifene causes endothelium-dependent, nitric oxide-mediated vasorelaxation in male rats.

Selective estrogen receptor modulators are estrogen-like compounds that lack the deleterious effects of estrogen. The present study was designed to determine whether idoxifene, a new selective estrogen receptor modulator, may have a vasodilatory effect on aortic vessels from male animals, and if so, to investigate the mechanism (i.e., endothelium-independent, direct vasorelaxation vs. endothelium-dependent, nitric oxide mediated vasorelaxation) by which idoxifene may exert its vasodilatory effect. Superior mesenteric arterial rings from adult male Sprague-Dawley rats were suspended in Krebs-Henseleit ring baths. Rings were contracted with 50 nM U-46619 (9,11-epoxymethano-PGH(2)), a thromboxane A(2) mimetic. Cumulative dose-response vasorelaxation to idoxifene (0.01 to 3 microM) was studied in the presence and absence of 200 microM N(omega)-nitro-L-arginine methyl ester (L-NAME, a nitric oxide synthase (NOS) inhibitor). The results obtained from idoxifene were compared with those from 17beta-estradiol. Our experimental results demonstrated that addition of idoxifene to superior mesenteric arterial rings isolated from male rats resulted in a dose-dependent vasorelaxation in the range of 0.1 microM (minimal vasodilatory concentration) to 3 microM (maximal vasodilatory concentration). Pre-treatment with L-NAME to block nitric oxide (NO) production virtually abolished idoxifene-induced vasodilatation, indicating that idoxifene caused an NO-mediated vasorelaxation in vessels from male animals. Addition of 17beta-estradiol also resulted in an endothelium-dependent vasorelaxation in aortic rings from male rats. However, these vessels were 30-fold less sensitive to 17beta-estradiol than to idoxifene in their vasorelaxation responses. Taken together, these results demonstrate that selective estrogen receptor modulators are superior to traditional estrogen in their vascular protection and may thus have potential therapeutic use in protection against cardiovascular disease, especially in male patients.

Animals↗
PubMed1976

Inadequate cervical mucus--a cause of "idiopathic" infertility.

The purpose of this study was to investigate and treat a group of patients referred for "idiopathic" infertility in whom no apparent cause for infertility, apart from inadequate cervical mucus, was found. Hormone investigations revealed that these patients could be divided into two groups: those with low sex steroid profiles despite apparent ovulation, and a second group with normal sex steroid profiles. All patients were treated with ovulation-inducing agents in an attempt to produce "controlled" ovarian hyperstimulation and an improved cervical mucus. Four of six patients conceived. The rationale behind the use of ovulation-inducing agents in this situation is discussed.

Adult↗
PubMed1978

Comparative studies of the ethynyl estrogens used in oral contraceptives: effects with and without progestational agents on plasma androstenedione, testosterone, and testosterone binding in humans, baboons, and beagles.

The effects of ethynylestradiol or mestranol given in cyclic fashion, with and without a progestational compound (norethindrone acetate, dl-norgestrel, or megestrol acetate), on plasma androgens and their binding were examined in adult women, female baboons, and beagles. The two estrogens are equivalent in their effect, and there were essentially no dose-related differences over the range examined. In human subjects, the estrogens increased total testosterone and testosterone binding, and decreased free testosterone. In baboons, estrogen produced a transient decrease in total testosterone and an increase in binding. The levels of progestational agents used did not affect total testosterone in humans, as is commonly observed with commercial agents, but did decrease it in baboons. Percentage binding was decreased in both species by the 19-nor compounds, but not by megestrol. Androstenedione levels were unaffected in human subjects, but effects of both estrogens and progestins were seen in baboons. Because of the very low levels of androgens in female beagles, this species did not lend itself well to a study of this kind. However, an increase in testosterone binding was induced by estrogen even in the absence of testosterone/estrogen-binding globulin.

Androstenedione↗
PubMed2004

Concentrations of endometrial protein PP 14 and CA-125 in uterine flushings performed in natural and stimulated cycles.

BACKGROUND: Impaired implantation in assisted reproduction cycles with high serum estradiol (E(2)) concentrations may be attributed to abnormal endometrial development. This study compared concentrations of endometrial proteins in uterine flushings of infertile patients between natural and stimulated cycles. METHODS: Patients received a standard regimen of ovarian stimulation. Seven days after the LH surge in natural cycles or the hCG injection in stimulated cycles, uterine flushings were performed by slowly injecting and aspirating normal saline through a paediatric Foley catheter. Natural cycles were considered as group A whereas stimulated cycles with serum E(2) <20 000 pmol/l and serum E(2) >20 000 pmol/l were classified as groups B and C respectively. PP 14 and CA-125 in uterine flushings were measured and expressed per total protein content. RESULTS: Concentrations of the total protein, PP 14 and CA-125 in the uterine flushings were similar among the three groups. PP 14 per total protein in the uterine flushings was significantly correlated with serum E(2) on the day of hCG (r = 0.459; P = 0.009) in natural cycles only but not in stimulated cycles. CONCLUSION: There was no significant difference between natural and stimulated cycles in concentrations of PP 14 and CA-125 in uterine flushings performed in the mid-luteal phase.

Adult↗
PubMed1982

[Endocrine findings during hormonal treatment of metastasizing prostatic carcinoma].

Endocrine findings of hypophyseal, testicular and adrenal function in the hormonal treatment of advanced prostatic carcinoma are described. Diethylstilbestrol (DES) reduces significantly the plasma levels of testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In contrast, those of prolactin, dehydoepiandrosterone (DHEA), and cortisol as well as sexual hormone binding globulin (SHBG) are elevated. The additional administration of bromocriptine decreases prolactin to normal levels and further decreases the testosterone levels. The adrenal steroids are influenced differently: DHEA decreases as compared to the DES-treated group, while the cortisol levels rise significantly. The addition of cyproterone acetate to the therapeutic regimen decreases the cortisol levels, and all other values, including SHBG, are not altered significantly compared to the group treated with DES plus bromocriptine. What is of interest is that the estradiol levels are not altered by any treatment schedule. In a group of patients, orchiectomized prior to our study, the endocrine values are compared to those mentioned above. Following orchiectomy FSH and LH levels rise significantly, but not prolactin and SHBG. The testosterone levels were as low as under treatment with DES. From our results it is concluded that the combination of DES plus bromocriptine plus cyproterone acetate best achieves the inhibition of androgenic influence onto the prostatic carcinoma.

Androgens↗
PubMed1984

The resistance of the mouse uterine lumen to flushing and possible contamination of samples by plasma and interstitial fluid.

The hydrostatic pressures generated during controlled flushing of the mouse uterus increased at implantation and under conditions of uterine closure. These pressures may be responsible for inducing tissue damage during flushing. The possibility that samples collected by flushing might be contaminated with interstitial fluid or plasma was studied using intravenously administered 51Cr-labelled EDTA and 125I-labelled human serum albumin as markers. The presence of both tracers was detected in all flushings and was greatest in flushings from uteri with luminal closure and early implantation sites. These observations raise serious doubts about the validity of the flushing technique for analysing uterine luminal constituents in mice.

Animals↗
PubMed2002

[Andropause and its management in the aged male].

THE "ANDROPAUSE": Also called the "male menopause" or "partial androgen deficiency of the aging male" etc., corresponds to the age at which the progressive decrease in androgen activity reaches a pathogenic threshold. Surveys made in various countries since the seventies conclude that testosterone blood levels start to decrease after the age of 25 and that 20 to more than 50% of the male population no longer benefit from optimal androgen stimulation after the age of 60. THE CONSEQUENCES OF HYPOANDROGENISM: The subsequent progressive hypoandrogenism participates in inducing the commonly-observed clinical symptoms (fatigue, morosity, weight loss, lack of interest in sexual activity); the most specific of which is the disappearance or rarification of "automatic" nocturnal or matinal erections. This appears to influence the prostatic pathology and the frequent cardiovascular risk factors, which, far more than a problem of erection, is a major public health issue. A COMPLEX BIOLOGICAL DIAGNOSIS: Added to the abnormalities in production and transport of testosterone are the abnormalities in its metabolisation by the target tissues. These abnormalities are often undetected in present day blood controls and may explain the elevation in the hepatocyte of SHBG synthesis, the relative inhibition of GnRH pulses and LH secretion in the hypothalamus and the pituitary gland and, in the arterial wall (including penile vascularisation) and the prostate, some of the frequent functional and histological disorders. In current practice today, the best approximation of androgen potential is obtained by the comparison of total testosterone concentrations and SHBG, measurements that require relatively reliable standardised kits. THERAPEUTIC CHOICE: Optimal replacement therapy, for some authors, must mimic the physiology of the young man and above all maintain or reinforce the estrogenic effects of testosterone, related to its aromatisation into estradiol and supposedly beneficial for the cardiovascular system and the bone. For other, the androgenic effects, enhanced by the 5 alpha reduction into dihydrotestosterone (DHT), should be reinforced in older men because the estrogenic effects are ineffective on bone and most of the other targets, and are probably pathogenic for the prostate. This debate is extremely important since the various formulations of androgens authorized by the French Medicines agency (AFSSAPS) induce clearly differing estradiol/DHT plasma ratios.

Adult↗