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PubMed1979

Effect of flutamide on estradiol metabolism.

The effect of flutamide, a potent nonsteroidal antiandrogen, on the metabolism of iv tracers of [3H]estradiol was studied in five patients with advanced prostate cancer. The drug produced no change in the percentage of the injected radioactivity recovered in urine or in the glucuronide or nonglucuronide conjugate fractions. Of the five individual metabolites that were quantitated, estrone, estradiol, and estriol were unaffected by flutamide, but the drug caused striking decreases in conversion of estradiol to 2-hydroxyestrone (4.0% vs. 7.4%) (P less than 0.005) and 2-methoxyestrone (1.1% vs. 2.6%; P less than 0.05); every one of the patients showed a marked fall in recovery of both of these compounds. This depression of the formation of 2-oxygenated metabolites is reminiscent of the findings in liver disease; the same abnormality occurs regularly in cirrhosis and frequently in extrahepatic biliary obstruction. Taken together with our previous studies of the effects of flutamide on testosterone and cortisol metabolism, this study demonstrates that flutamide produces multiple functional, reversible, cirrhosis-like disturbances of steroid metabolism. Because these disturbances are universal in the patients studied regardless of whether they had clinical responses to flutamide, we doubt that the steroid metabolic changes play a role in the therapeutic effect of the drug.

Anilides↗
PubMedDate not supplied

The acute release of maternal prolactin by instrumental cervical dilatation simulates the second stage of labor.

OBJECTIVE: We hypothesize that artificial stimulation of the cervix causes an acute secretion of maternal prolactin (PRL) that mimics PRL secretion during the second stage of human labor. METHODS: Eighteen women scheduled for first-trimester therapeutic abortion had a blood sample drawn at the following times: before and after laminaria tent (LT) insertion for cervical ripening, 18-24 hours later upon entry in the procedure room, after LT removal, during instrumental cervical dilatation and uterine evacuation by suction curretage, soon after evacuation, and 1/2 hour and 1 hour after evacuation. Local cervical anesthesia, intravenous analgesics, and sedation were administered before the procedure. Blood serum was assayed for PRL, human chorionic gonadotropin (hCG), and estradiol. RESULTS: The initial PRL levels were 34 ng/mL +/- 4.2 standard error of the mean (SEM) and did not change after 18-24 hours of LT placement nor after LT removal. However, PRL increased significantly (t = 5.8; P = .00001) over basal levels by 204% +/- 15 at the time of instrumental dilatation and rose to 378% +/- 33 at 1/2 hour postevacuation. After 1 hour, PRL had declined to 173% +/- 10%. Serum levels of estradiol and hCG changed only after evacuation. CONCLUSION: Artificial stimulation of the cervix causes an immediate surge in PRL levels. We suggest that the acute increase in pituitary PRL secretion that occurs during the second stage of labor results from a neural signal from the cervix and not from endocrine changes associated with labor.

Abortion, Therapeutic↗
PubMed1983

Estrogen replacement therapy by transdermal estradiol administration.

To determine whether the nonoral administration of estradiol (E2) might provide physiologic replacement without alteration of hepatic function, 20 postmenopausal women were studied before and after 3 weeks of treatment with either E2-containing transdermal therapeutic systems or placebo. Twenty premenopausal women were also studied. With E2-containing systems, serum E2 and estrone levels were restored to the premenopausal range. Variable responses of the different biochemical and biologic markers of the actions of E2 were observed. The most sensitive marker was vaginal cytology, with the E2 dosage reverting the maturation index to premenopausal values. Hot flashes, measured objectively, were reduced in frequency but not abolished. Serum levels of follicle-stimulating hormone and luteinizing hormone were lowered but remained higher than the premenopausal range. No significant changes were noted in urinary calcium/creatinine and hydroxyproline/creatinine ratios, which were used as markers of bone resorption. With active systems, no significant changes were noted in the concentrations of the hepatic proteins renin substrate and thyroxine-binding globulin or in the binding capacities of cortisol-binding globulin and sex hormone-binding globulin. These results indicate that transdermal E2 administration may be used to provide estrogen replacement while exerting limited effects on hepatic function.

Calcium↗
PubMed1993

Inhibition of angiogenesis by antiestrogens.

In this study, we have determined the ability of the partial estrogen antagonists, clomiphene, tamoxifen, and nafoxidine, and the pure estrogen antagonists, ICI 164,384 and ICI 182,780, to inhibit angiogenesis in the chick egg chorioallantoic membrane. All of the partial estrogen antagonists and the pure estrogen antagonist, ICI 182,780, showed significant angiostatic activity in a dose-related manner. The addition of up to 5-fold of 17 beta-estradiol to the disks containing clomiphene, tamoxifen, or ICI 182,780 did not alter the angiostatic activity of these antiestrogens. These novel findings show that the antiestrogens are effective inhibitors of angiogenesis. The finding that angiostatic activity is not altered in the presence of excess estrogens suggests that this activity is exerted via mechanisms other than their inhibition of estrogen action. This angiostatic activity may contribute to the therapeutic effect of antiestrogens in estrogen receptor-negative tumors.

Animals↗
PubMed1986

Use of growth-stimulatory hormones to improve the in vitro therapeutic index of doxorubicin for human breast tumors.

Tumor-specific growth factors that increase the proliferative rate of tumor cells should, in theory, enhance the efficacy of cytotoxic drugs that have cell-cycle-dependent activity. To test this hypothesis, we measured the cytotoxicity of doxorubicin for clonogenic breast tumor cells in the presence and the absence of hormones that stimulate their in vitro growth (17 beta-estradiol, epidermal growth factor, hydrocortisone, and insulin). These growth factors increased the sensitivity to doxorubicin of the clonogenic cell populations from 20 of 25 breast tumors. Their effect was greatest on tumors from hormone-responsive patients. In contrast, these hormones increased the clonogenicity and sensitivity to doxorubicin of bone marrow progenitor cells to a much lesser degree. Hence, under the effect of these growth factors, the in vitro therapeutic index of doxorubicin improved for most of the tumors tested, while tamoxifen citrate, a tumor growth-inhibitory hormone, had the opposite effect. We conclude that tumor tissue-specific growth-stimulatory hormones can improve the in vitro efficacy of cell cycle-active anticancer drugs.

Bone Marrow↗
PubMed2001

Temporal changes in cardiac function and cerebral blood flow during sequential postmenopausal hormone replacement.

OBJECTIVE: The purpose was to assess the temporal changes in cardiac function and cerebral blood flow during postmenopausal administration of estrogen with and without progestogen. STUDY DESIGN: Sixteen postmenopausal volunteers were assessed during estradiol plus sequential norethindrone acetate and placebo in two 12-week periods. Temporal changes were measured by magnetic resonance flow mapping 8 times. RESULTS: Systemic vascular resistance was reduced during estradiol (-6.9%; P <.05), declined further during the addition of norethindrone acetate, and was accompanied by an increase in stroke volume (maximum increase, 5.2%; P <.05) without fluid retention. Both systolic (-5 mm Hg; P =.03) and diastolic (-3 mm Hg; P =.03) blood pressure were reduced during estradiol. Cerebral blood flow was reduced after 9 weeks of hormone replacement therapy (-37 mL/min; P =.01) but increased to baseline after the addition of norethindrone acetate. CONCLUSIONS: Sequential hormone replacement therapy is associated with changes in cardiac function, which are of therapeutic potential in cardiovascular disorders. Sequential hormone replacement therapy exhibits an overall neutral effect on cerebral blood flow.

Blood Pressure↗
PubMed2005

Gonadal steroid attenuation of developing hamster facial motoneuron loss by axotomy: equal efficacy of testosterone, dihydrotestosterone, and 17-beta estradiol.

In the hamster facial nerve injury paradigm, we have established that androgens enhance both functional recovery from facial nerve paralysis and the rate of regeneration in the adult, through intrinsic effects on the nerve cell body response to injury and via an androgen receptor (AR)-mediated mechanism. Whether these therapeutic effects of gonadal steroids encompass neuroprotection from axotomy-induced cell death is the focus of the present study. Virtually 100% of adult hamster facial motoneurons (FMNs) survive axotomy at the stylomastoid foramen (SMF), whereas, before postnatal day 15 (P15), developing FMNs undergo substantial axotomy-induced cell death. The first part of the present study focuses on determining when ARs are first expressed in developing hamster FMNs. Using AR immunocytochemistry, it was found that males express ARs by P2 and females by P4, which is the earliest demonstration of AR expression in mammalian motoneurons reported thus far in the literature. The second half examines the neuroprotective effects of testosterone propionate, 17-beta estradiol, and dihydrotestosterone on FMNs of P7 hamsters after facial nerve transection at the SMF. The results demonstrate that androgens and estrogens are equally able to rescue approximately 20% of FMNs from axotomy-induced cell death, with the effects permanent. This study is the first to investigate the effects of both androgens and estrogens on axotomy-induced cell death in one system and, with our previously published work, to validate the hamster FMN injury paradigm as a model of choice in the investigation of both neurotherapeutic and neuroprotective actions of gonadal steroids.

Age Factors↗
PubMed1996

Estradiol-dependent uterine leiomyomas in transgenic mice.

Uterine leiomyomas are a major health problem for women of reproductive age. The molecular biology of these tumors is poorly understood partly because of the lack of relevant animal models. We have produced transgenic mice expressing the simian virus 40 T antigen driven by the promoter of the Calbindin-D9K (CaBP9K) gene and either -1,000 or -117 bp of regulatory sequences so as to establish in vivo, uterine smooth muscle tumor models. Six transgenic mouse lines were obtained. Leiomyomas developed in all of them, with an almost complete penetrance of the phenotype. The smooth muscle tumors arose in different parts of the female reproductive tract. Leiomyomas usually developed in the corpus of the uterus, but one mouse line developed leiomyomas in the horn of the uterus, and another in the vagina. The CaBP9K regulatory sequences directing the expression of the Tag gene possess an estradiol responsive element, and accordingly, development of the tumors was strictly under the control of estrogen. Expression of the Tag gene is not only necessary for the initiation of the tumor but also for its development and maintenance. These transgenic mouse models should be useful for studying the pathobiology of uterine leiomyomas and could be instrumental in designing new therapeutic approaches to this disease.

Animals↗
PubMed2000

[Severe gastrointestinal hemorrhage secondary to diffuse angiodysplasia: efficacy of estrogen-progesterone treatment].

BACKGROUND: Vascular abnormalities are being reported with increasing frequency as a cause of major lower gastrointestinal hemorrhage in the elderly. They are occasionally very difficult to treat by conventional means. CASE REPORT: A 66-year-old white man with a history of type 2 diabetes mellitus, coronary artery disease, congestive heart failure, severe peripheral arterial occlusion disease and chronic renal insufficiency presented for five years recurrent major bleeding due to gastrointestinal angiodysplasia, requiring repeated transfusions. He was treated with efficacy using ethinyl-estradiol (30 micrograms) and norethisterone acetate (1 mg) given orally once daily. After six months of treatment, transfusion requirements fell to 0 unit and the patient's hemoglobin was stable at 13 g/dl. Attempts to stop hormone therapy (by the patient himself, without complaint of side effects) led to a fall in hemoglobin. CONCLUSION: Hormonal therapy should be considered when multiple degenerative mucosal vascular bleeding lesions are beyond the reach of therapeutic endoscopy leading to high transfusion needs and when surgical risk is unacceptably high.

Aged↗
PubMed1993

Action of danazol on the conversion of estrone sulfate to estradiol and on the sulfatase activity in the MCF-7, T-47D and MDA-MB-231 human mammary cancer cells.

In the present studies the action of Danazol on the conversion of estrone sulfate (E1S) to estradiol (E2) as well as on the sulfatase activity in the MCF-7 and T-47D, hormone-dependent, and MDA-MB-231, hormone-independent, mammary cancer cell lines was explored. Using intact cells we observed that Danazol blocks very significantly the radioactivity uptake and the conversion of [3H]E1S to E2 in all the cells studied. In particular, a very strong effect (85% decrease of these parameters versus the control values) is observed in the T-47D cells. In another series of studies using cell homogenates it is observed that Danazol inhibits the sulfatase activity in all these cell lines. The effect of Danazol is dose-dependent and significant from a concentration of 1 microM. At concentrations of 8 microM E1S, 10(-5) M Danazol, the inhibition of sulfatase activity is 38% in MCF-7, 36% in MDA-MB-231, and 27% in T-47D cells. Analysis by Lineweaver-Burk plot shows that the inhibitory effect is competitive. As E1S is one of the main sources of E2 in human mammary tumors, the present data could open new possibilities for therapeutic applications in hormone-dependent breast cancer.

Breast Neoplasms↗
PubMed1980

Chronic effects of the stimulatory luteinizing hormone-releasing hormone analogue D-Ser (TBU) 6-EA 10-LRH on the gonadotrophin and gonadal steroid secretion in women with amenorrhoea.

The agonistic analogue of luteinizing hormone-releasing hormone (LRH) D-Ser-(TBU) 6-EA10-LRH was given subcutaneously or intranasally to 21 women with longstanding secondary amenorrhoea in an attempt to induce follicular maturation and ovulation. Seven women were given daily subcutaneous injections of 10 /micrograms of the LRH analogue for 21 days. The pituitary and ovarian responses were monitored by follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestradiol (E2) and progesterone (P) in serum. A significant increase of the E2 levels in blood was seen during the first three days of treatment but the E2 elevations were not sustained. No signs of follicular maturation were detected during the treatment. Intranasal treatment with the LRH agonist was instituted in 14 women. Repeated daily low intranasal spray doses (1 - 10 /micrograms) were given. The treatment was continued for 2 - 4 weeks. Intranasal doses of 5 /micrograms and below were ineffective in increasing gonadotrophin and gonadal steroid secretion. An initial gonadotrophin release was observed after intranasal doses of 10 /micrograms and there was a slight increase of the E2 concentrations in serum during the first 2 - 3 days. The pituitary responsiveness to the agonist then decreased markedly during the treatment. None of the 14 women showed signs of follicular maturation during or after the treatment. The pituitary desensitization caused by this potent agonistic LRH analogue seems to limit its therapeutic use for treatment of anovulatory infertility.

Adolescent↗
PubMedDate not supplied

Injectable depot medroxyprogesterone acetate contraception: an update for U.S. clinicians.

Injectable contraceptions appeal to women who value the efficacy, convenience, and safety provided by this reversible birth control option. Since FDA approval for contraceptive use in 1992, depot medroxyprogesterone acetate (DMPA)--already used by millions of women worldwide--has been used by several million U.S. women. Although women using this 3-month progestin-only injectable often experience irregular bleeding and spotting (initially), long-term DMPA use typically results in amenorrhea. Many users, including adolescents, choose DMPA because of its convenience--nearly 100% contraceptive effectiveness is achieved with 4 injections per year. Because DMPA does not contain estrogen, it represents an appropriate contraceptive choice for postpartum or lactating women, as well as those whose medical status precludes use of contraceptive doses of estrogen. Some examples include: women over age 35 who smoke, those with increased thromboembolism risk, women with cardiovascular or liver disease, as well as women with complex migraines. Although fertility resumes on the average 10 months following the last injection, suppression of ovulation occasionally persists for as long as 22 months. Consequently, DMPA is not an appropriate choice for women who may wish to conceive within the next two years. Since the use of DMPA lowers ovarian estradiol production, reversible loss of bone mineral density (BMD) may occur. Studies currently in progress may clarify DMPA's long-term impact, if any, on BMD. Therapeutic uses of DMPA include treatment of: dysmenorrhea, menorrhagia (including that associated with fibroid uterine tumors), endometriosis, endometrial hyperplasia, ovulatory pain, pain associated with ovarian adhesive disease, premenstrual dysphoria and perimenopausal symptoms.

Adolescent↗
PubMed2005

Attenuation of estrogen receptor alpha (ERalpha) signaling by selenium in breast cancer cells via downregulation of ERalpha gene expression.

Numerous studies have shown that selenium provides beneficial effects as a cancer chemoprevention agent. Although long-term intervention trials failed to confirm selenium protection against breast cancer in humans because of insufficient cases, the evidence of effective selenium chemoprevention in animal mammary tumor models or human breast cancer cells is substantial and convincing. The present study demonstrates that the selenium compound methylseleninic acid (MSA) inhibits estrogen receptor alpha (ERalpha) signaling in ER-positive MCF-7 breast cancer cells as evidenced by decreased estradiol-dependent cell growth and gene expression. MSA diminishes estradiol induction of endogenous ER-regulated pS2 and c-myc genes as well as the expression of an ER-regulated reporter gene. A major mode of MSA action on ER signaling is through a downregulation of ERalpha gene expression that precedes a decrease in ERalpha protein level. This study provides a mechanism driven rationale for using selenium as a chemopreventive agent for women at high risk for developing breast cancer or as a therapeutic strategy for ER-positive breast cancer.

Breast Neoplasms↗
PubMed2000

Structure-activity relationships of 17alpha-derivatives of estradiol as inhibitors of steroid sulfatase.

The steroid sulfatase or steryl sulfatase is a microsomal enzyme widely distributed in human tissues that catalyzes the hydrolysis of sulfated 3-hydroxy steroids to the corresponding free active 3-hydroxy steroids. Since androgens and estrogens may be synthesized inside the cancerous cells starting from dehydroepiandrosterone sulfate (DHEAS) and estrone sulfate (E(1)S) available in blood circulation, the use of therapeutic agents that inhibit steroid sulfatase activity may be a rewarding approach to the treatment of androgeno-sensitive and estrogeno-sensitive diseases. In the present study, we report the chemical synthesis and biological evaluation of a new family of steroid sulfatase inhibitors. The inhibitors were designed by adding an alkyl, a phenyl, a benzyl, or a benzyl substituted at position 17alpha of estradiol (E(2)), a C18-steroid, and enzymatic assays were performed using the steroid sulfatase of homogenized JEG-3 cells or transfected in HEK-293 cells. We observed that a hydrophobic substituent induces powerful inhibition of steroid sulfatase while a hydrophilic one was weak. Although a hydrophobic group at the 17alpha-position increased the inhibitory activity, the steric factors contribute to the opposite effect. As exemplified by 17alpha-decyl-E(2) and 17alpha-dodecyl-E(2), a long flexible side chain prevents adequate fitting into the enzyme catalytic site, thus decreasing capacity to inhibit the steroid sulfatase activity. In the alkyl series, the best compromise between hydrophobicity and steric hindrance was obtained with the octyl group (IC(50) = 440 nM), but judicious branching of side chain could improve this further. Benzyl substituted derivatives of estradiol were better inhibitors than alkyl analogues. Among the series of 17alpha-(benzyl substituted)-E(2) derivatives studied, the 3'-bromobenzyl, 4'-tert-butylbenzyl, 4'-butylbenzyl, and 4'-benzyloxybenzyl groups provided the most potent inhibition of steroid sulfatase transformation of E(1)S into E(1) (IC(50) = 24, 28, 25, and 22 nM, respectively). As an example, the tert-butylbenzyl group increases the ability of the E(2) nucleus to inhibit the steroid sulfatase by 3000-fold, and it also inhibits similarly the steroid sulfatase transformations of both natural substrates, E(1)S and DHEAS. Interestingly, the newly reported family of steroid sulfatase inhibitors acts by a reversible mechanism of action that is different from the irreversible mechanism of the known inhibitor estrone sulfamate (EMATE).

Arylsulfatases↗