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Results for “Selective Estrogen Receptor Modulators”

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At least 19 recordsLinked to original sources
PubMed2026

Differential Effectiveness of Adjuvant Endocrine Therapy According to Menopausal Status, Body Mass Index, and Molecular Subtype in Hormone Receptor-Positive Breast Cancer.

The effectiveness of adjuvant endocrine therapy for hormone receptor-positive (HR+) breast cancer (BC) varies according to menopausal status, body mass index (BMI), and tumor biology. We evaluated the association between selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), and BC-specific mortality according to menopausal status, BMI, and molecular subtype in a nationwide Korean cohort. We analyzed data from 31,030 patients with HR+ BC who were registered in the Korean Breast Cancer Society Registry, diagnosed between 2000 and 2008, and followed through 2013. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for BC-specific mortality after adjusting for demographic and clinical factors. Of the 31,030 patients, 19,634 received SERM therapy, and 3,354 received AI therapy. SERM use was associated with lower BC-specific mortality in premenopausal women (HR, 0.75; 95% CI, 0.63-0.91), whereas AI therapy was more strongly associated with lower BC-specific mortality among postmenopausal women (HR, 0.76; 95% CI, 0.61-0.94). Lower BC-specific mortality was observed among patients with a BMI ≥ 23 kg/m² who received SERM (HR, 0.84; 95% CI, 0.72-0.98) or AI therapy (HR, 0.78; 95% CI, 0.62-0.99). The strongest association with lower BC-specific mortality was observed in postmenopausal women with luminal B tumors (HR, 0.59; 95% CI, 0.42-0.83). The association between adjuvant endocrine therapy and BC-specific mortality differed according to menopausal status, BMI, and molecular subtype. These findings suggest that menopausal status, BMI, and molecular subtype are important considerations when evaluating endocrine treatment strategies.

Aromatase Inhibitors↗
PubMed1988

Evidence that the phagocytosis mediated by the peanut agglutinin-like activity of IgG(Fc) receptors of human monocytes is selectively modulated by estradiol and natural estrogens.

The percentage of human monocytes (MCs) that are able to form rosettes with, and to phagocytose, IgG-coated sheep red blood cells (IgG-SRBCs) has been first determined in vitro by a classical rosette assay in 12 postmenopausal (PM) women. Half of them never received any suppletive estrogen (E) therapy at the time of testing, whereas the other six were chronically treated with E. Three different preparations of the same anti-SRBC IgG antibody batch were coated to SRBCs: the first one was the starting antibody preparation [IgG(total] and the other two were purified by affinity chromatography either on Sepharose-concanavalin A (Con A) or on agarose-peanut agglutinin (PNA) columns specifically recognizing terminal, and/or accessible, alpha-mannosyl [IgG(Con A)] or beta-galactosyl [IgG(PNA)] residues of the Fc domain, respectively. The three IgG preparations exhibited similar hemagglutinating antibody titers (1/100). All experiments were conducted using a coating range of 5000 to 6000 IgG antibody molecules per SRBC. In PM women with E, the rosetting capacity of autologous MCs (percentage of MCs rosetting at least three IgG-SRBCs), their phagocytosing capacity (percentage of MCs ingesting at least three IgG-SRBCs), and the phagocytosis index (number of SRBCs ingested/100 MCs) were similar for each IgG-SRBC preparation considered. In contrast, in PM women without E, the capacity of MCs to phagocytose IgG(PNA)-SRBCs, as well as the phagocytosis index measured with those SRBCs, was strongly reduced (P less than 0.01 at least), when compared to the same parameters determined using IgG(total)-SRBCs and IgG(Con A)-SRBCs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1976

Estrogen receptor in the mammalian liver.

The cytosol from livers of adult female mammals contains [3H]estradiol-binding proteins that can translocate to the nucleus and attach to chromatin. In comparison to the prepubescent rat, adults have higher estrogen binding in the liver and greater increases in plasma renin substrate after administration of estrogen. The protein in the liver which binds estrogen may be an estrogen receptor involved in modulating hepatic synthesis of selective plasma proteins.

4-Chloromercuribenzenesulfonate↗
PubMed1992

Toremifene and its metabolites enhance doxorubicin accumulation in estrogen receptor negative multidrug resistant human breast cancer cells.

The enhanced accumulation of doxorubicin by agents known to reverse multidrug resistance provides a good functional test for evaluating modulating activity. In the present study, the non-steroidal triphenylethylene toremifene selectively increased doxorubicin accumulation in multidrug resistant estrogen receptor negative MDA A-1 human breast cells compared to the MDA 231 wild type cells. MDA A-1 cells were noted to be 1,000 fold resistant to doxorubicin (IC 50 = less than 0.1 microgram/ml MDA 231; IC 50 = 100 micrograms/ml MDA A-1). Total accumulation of doxorubicin, expressed as area under the time concentration curve (AUC), was increased significantly in doxorubicin resistant cells (156% increase) versus wild type MDA 231 cells (6% increase). Correction of the accumulation defect to doxorubicin in drug resistant cells required a 18-20 hour pre-incubation with toremifene. The effects of toremifene on cell cycle in MDA A-1 cells was analyzed by flow cytometric techniques. Toremifene had a dose response relationship in blocking cells in G0-G1 reducing the number of cells entering S phase of the cell cycle. This effect was maximal at concentrations which increased the accumulation of doxorubicin in MDA A-1 cells. Several metabolites of toremifene were also noted to increase doxorubicin accumulation in MDA A-1 doxorubicin resistant cells. Tore XVIII (deaminocarboxytoremifene), Tore IV (4-hydroxy-N-desmethyltoremifene) and N-desmethyltoremifene all increased the accumulation of doxorubicin significantly (114%, 128% and 42% respectively). Finally, we show evidence that toremifene and its active metabolites are present in high concentrations in human plasma following a single 200 mg oral dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1990

Hormone epidermal growth factor interactions in development.

Epidermal growth factor (EGF) is the most important member of a family of growth factors which exert their effects via a single 170,000 Mr plasma membrane receptor. Other members include transforming growth factor-alpha (TGF-alpha), amphiregulin and several viral growth factors. The receptor is widely distributed in fetal and postnatal tissues. The predominant family member in the fetus appears to be TGF-alpha. EGF production in tissues matures in the perinatal period. Activation of the receptor in the fetal and neonatal periods in rodents evokes important growth and development actions. Tissue EGF and EGF receptor concentrations are modulated by thyroid hormones, estrogen, testosterone and growth hormone, suggesting that selected growth and developmental actions of thyroid and steroid hormones may be mediated by EGF.

Animals↗
PubMed1992

Mu-, delta-, and kappa-opioid receptor agonists selectively modulate sexual behaviors in the female rat: differential dependence on progesterone.

Previous studies suggested that opioid receptor agonists infused into the lateral ventricles can inhibit (through mu receptors) or facilitate (through delta receptors) the lordosis behavior of ovariectomized (OVX) rats treated with estrogen and a low dose of progesterone. The present study investigated the behavioral and hormonal specificity of those effects using more selective opioid receptor agonists. Sexually experienced OVX rats were implanted stereotaxically with guide cannulae aimed at the right lateral ventricle. One group of rats was treated with estradiol benzoate (EB, 10 micrograms) 48 hr and progesterone (P, 250 micrograms) 4 hr before testing, whereas the other group was treated with EB alone. Rats were infused with different doses of the selective mu-receptor agonist DAMGO, the selective delta-receptor agonist DPDPE, or the selective kappa-receptor agonist U50-488. The females were placed with a sexually vigorous male in a bilevel chamber (Mendelson and Gorzalka, 1987) for three tests of sexual behavior, beginning 15, 30, and 60 min after each infusion. DAMGO reduced lordosis quotients and magnitudes significantly in rats treated with EB and P, but not in rats treated with EB alone. In contrast, DPDPE and U50-488H increased lordosis quotients and magnitudes significantly in both steroid-treatment groups. Surprisingly, measures of proceptivity, rejection responses, and level changes were not affected significantly by mu or kappa agonists, although proceptivity and rejection responses were affected by DPDPE treatment. These results suggest that the effects of lateral ventricular infusions of opioid receptor agonists on the sexual behavior of female rats are relatively specific to lordosis behavior. Moreover, the facilitation of lordosis behavior by delta- or kappa-receptor agonists is independent of progesterone treatment, whereas the inhibitory effect of mu-receptor agonists on lordosis behavior may require the presence of progesterone.

Animals↗
PubMed1985

Role of female gonadal hormones in the CNS: clinical and experimental aspects.

The large body of evidence presented indicates that in the brain the action of sex hormones cannot be thought as restricted to the regulation of endocrine functions and mating behavior. Estrogens and progesterone seem to act in numerous regions of the CNS to regulate motor as well as limbic functions. Furthermore, the data reviewed indicate that these hormones may modulate neuronal activity through a wide variety of mechanisms. More studies should focus on such mechanisms in order to better understand the role of sex hormones in the CNS and to devise ways of limiting their effects on depression, epilepsy etc. It is known that in peripheral target organs these hormones modulate cell activities by binding to specific receptors which can recognize the DNA sequence and activate the transcription of selected genes (135, 136). There is evidence supporting the hypothesis that this mechanism of action has been conserved also in the brain. First, the brain receptors for progesterone and estrogens are functionally and biochemically indistinguishable from those in the periphery (4, 5): they may be concentrated in neuronal nuclei and bind chromatin "in vitro" (7). Second, a temporal relationship has been observed between administration of steroids and the increase of polymerase II activity (137) and protein synthesis (4, 5). Third, various hormone-induced behaviors may be blocked by inhibitors of the protein synthesis (138, 139, 140, 141). However, sex hormones must be capable to regulate neuronal functions by mechanisms other then genomic. In fact, the topical application of estrogen or progesterone on nervous tissue results in a rapid change of membrane potential (60, 71). Such a rapid effect is not likely to be the consequence of nuclear action, but rather must be related to events occurring on the cell surface. It has been hypothesized that sex steroids affect the fluidity of the cell membrane, therefore modifying the ion transport or neurotransmitter receptor activity (142). If this were the case we would expect to observe a similar effect after application of any steroid. Experimental evidence demonstrates that not all the steroids affect the nervous membrane potential. Moreover, two steroids, estradiol and progesterone, have been described to modulate membrane potential in an opposite way (66, 67, 69, 75). At the moment, there is no evidence for the presence of steroid receptors on neuronal membranes which could mediate the described phenomena.(ABSTRACT TRUNCATED AT 400 WORDS)

Amygdala↗
PubMed1988

The effects of estradiol and mestranol on alpha-adrenoceptors in select regions of the rat brain.

The role of estrogens in modulating the concentration of CNS alpha-adrenoceptors has not been elucidated nor has it been determined how different estrogenic compounds affect these receptors. In this study brain alpha-1 and alpha-2-adrenoceptor binding was measured in female rats treated with estradiol and/or the synthetic estrogen mestranol. Rats treated biweekly for 12 weeks with mestranol (50 micrograms/100 g b.wt.) had a significant reduction in the apparent number of alpha-2-adrenoceptors in the frontal cortex and nucleus tractus solitarius (NTS), while apparent numbers of both alpha-1 and alpha-2-adrenoceptors were depressed in the locus coeruleus. Estradiol treatment (50 micrograms/100 g b.wt.) caused a significant elevation in apparent alpha-1-adrenoceptor numbers in the NTS relative to control. Alpha-adrenoceptor numbers in the rostral and caudal hypothalamus were not affected by either steroid treatment. These results suggest that regulation of apparent numbers of alpha-1 and alpha-2-adrenoceptors in the CNS depends on the type of estrogen used for treatment.

Animals↗
PubMedDate not supplied

Inhibition of rat uterine contractions by rat and human CGRP.

Effects of rat and human calcitonin gene-related peptide (r alpha CGRP and h beta CGRP, respectively) upon uterine contractile force were investigated using uterine horns from nonpregnant rats, r alpha CGRP and h beta CGRP were equipotent (pD2 = 8.85-9.09) in inhibiting spontaneous and electrically evoked uterine contractions. r alpha CGRP was relatively ineffective in inhibiting potassium-induced contractures of preparations from stilbestrol-pretreated rats. The use of selective antagonists established that r alpha CGRP did not release prostanoids, or release or act at receptors for catecholamines and histamine. The effects of the peptides were not significantly modulated by estrogen levels since pD2 values were similar (8.56-8.86) in field-stimulated preparations from rats in proestrus/estrus or metestrus/diestrus.

Animals↗
PubMed1985

Antiestrogen action in breast cancer cells: modulation of proliferation and protein synthesis, and interaction with estrogen receptors and additional antiestrogen binding sites.

Antiestrogens have proven to be effective in controlling the growth of hormone-responsive breast cancers. At the concentrations of antiestrogens achieved in the blood of breast cancer patients taking antiestrogens (up to 2 X 10(-6) M), antiestrogens selectively inhibit the proliferation of estrogen receptor-containing breast cancer cells, and this inhibition is reversible by estradiol. Antiestrogens also inhibit estrogen-stimulation of several specific protein synthetic activities in breast cancer cells, including increases in plasminogen activator activity, progesterone receptor levels and production of several secreted glycoproteins and intracellular proteins. Antiestrogens bind with high affinity to the estrogen receptor and to additional microsomal binding sites to which estrogens do not bind. These latter sites, called antiestrogen binding sites (AEBS), are present in equal concentrations in estrogen receptor-positive and -negative breast cancer cells and are present in a wide variety of tissues, with highest concentrations being found in the liver. The antiestrogenic and growth suppressive potencies of a variety of antiestrogens correlate best with their affinity for estrogen receptor and not with affinity for AEBS. Antiestrogens undergo bioactivation and metabolism in vivo and hydroxylated forms of the antiestrogen have markedly enhanced affinities for the estrogen receptor. Detailed studies with high affinity radiolabelled antiestrogens indicate that antiestrogens induce important conformational changes in receptor that are reflected in the enhanced maintenance of a 5 S form of the estrogen receptor complex; reduced interaction with DNA; and altered activation and dissociation kinetics of the antiestrogen-estrogen receptor complex. These conformational changes effected by antiestrogens likely result in different interactions with chromatin, causing altered cell proliferation and protein synthesis. Analyses of the rates of synthesis and turnover of the estrogen receptor through pulse-chase experiments utilizing the covalently attaching antiestrogen, tamoxifen aziridine, and studies employing dense amino acid labeling of estrogen receptor reveal that the antiestrogen-occupied receptor is degraded at a rate (t 1/2 = 4 h) similar to that of the control unoccupied receptor. Hence, antiestrogens do not prevent estrogen receptor synthesis and they do not either accelerate or block estrogen receptor degradation.(ABSTRACT TRUNCATED AT 400 WORDS)

Breast Neoplasms↗
PubMed1990

Gamma-aminobutyric acidA receptors mediate 3 alpha-hydroxy-5 alpha-pregnan-20-one-induced gonadotropin secretion.

3 alpha-Hydroxy-5 alpha-pregnan-20-one (3 alpha, 5 alpha-THP), can selectively release LH in estrogen-primed ovariectomized rats. This progesterone metabolite does not bind to the progesterone receptor. Recently, 3 alpha,5 alpha-THP has been reported to be a potent modulator of the gamma-aminobutyric acidA (GABAA) receptor in the brain. Therefore, the purpose of this study was to determine whether 3 alpha,5 alpha-THP's effect on gonadotropin secretion is GABAA receptor mediated. Ovariectomized immature rats were primed for 2 days with estradiol (2 micrograms/rat.day). On the morning of the third day, 3 alpha,5 alpha-THP was administered either with or without prior treatment with progesterone receptor antagonist (RU486) or the GABAA receptor antagonist picrotoxin. When 3 alpha,5 alpha-THP was administered alone, a dose-related effect on LH and FSH release was observed. The 0.8 mg/kg BW dose of 3 alpha,5 alpha-THP stimulated both LH and FSH release, whereas the 1.6 mg/kg BW dose released only LH. The GABAA receptor antagonist picrotoxin had no significant effect on LH or FSH secretion. However, administration of picrotoxin 30 min before 0.8 mg/kg BW 3 alpha,5 alpha-THP resulted in antagonism of 3 alpha,5 alpha-THP's ability to release LH and FSH. The effects of 1.6 mg/kg BW 3 alpha,5 alpha-THP on serum LH were also blocked by picrotoxin. Picrotoxin was ineffective in altering the gonadotropin-stimulating response of progesterone and deoxycorticosterone. These steroids do not bind to the GABAA receptor. The progesterone receptor antagonist RU486 administered alone had no effect on serum LH or FSH levels. When RU486 was administered before 3 alpha,5 alpha-THP treatment, it was ineffective in blocking 3 alpha,5 alpha-THP's ability to release LH. These studies indicate that the GABAA receptor is responsible for mediating 3 alpha,5 alpha-THP-induced gonadotropin secretion.

Animals↗
PubMed1991

Binding of [3H]cholecystokinin in the ventromedial hypothalamus is modulated by an afferent brainstem projection but not by ovarian steroids.

The ventromedial nuclei (VMN) of the hypothalamus are innervated by cholecystokinin-immunoreactive (CCK-IR) fibers originating in the dorsal parabrachial nuclei (PBS). They also contain high levels of receptors for CCK and binding of [125I]CCK to these receptors is modulated by estrogen. In the present study, we show that unilateral lesion of the PBS increases the binding of the sulphated octapeptide of [3H]cholecystokinin ([3H]CCK) within the ipsilateral VMN of the hypothalamus, but not within other brain nuclei that contain receptors for CCK. Thus, CCK fibers originating in the PBS selectively innervate the VMN and CCK receptors within the VMN are postsynaptic to parabrachial afferents. However, treatment of ovariectomized rats with estradiol benzoate and progesterone did not affect the binding of [3H]CCK in the VMN, even after lesion of the parabrachial afferents.

Animals↗
PubMed1991

Electrophysiological actions of oxytocin on hypothalamic neurons in vitro: neuropharmacological characterization and effects of ovarian steroids.

Oxytocin (OT) neurotransmission in the brain has a facilitatory effect on sexual receptivity in rats. This effect of OT is dependent on priming by ovarian steroids, estrogen and progesterone. These steroids modulate OT binding in specific brain nuclei, including the ventrolateral portion of the ventromedial hypothalamic nucleus (vlVMN). In the present study, single-unit activity was recorded from the vlVMN in hypothalamic slices to characterize the electrophysiological actions of OT. To examine the effects of ovarian steroids on OT actions, we used brain slices prepared from ovariectomized rats either treated with estrogen or not, and some slices were treated with progesterone in vitro. OT had little modulatory action on neuronal responses to other agents, but affected the activity of large numbers of vlVMN units. Of those neurons affected, 94% responded with excitation. This predominant stimulatory action of OT is consistent with its lordosis-facilitating effect, because increases in the activity of VMN neurons are generally associated with the facilitation of lordosis. Pharmacological analyses with selective OT agonists and antagonists as well as structurally related peptides showed that the excitatory action of OT is mediated by OT receptors. Estradiol modulated several aspects of OT transmission. First, it increased neuronal responsiveness to OT, especially at the lowest concentration used (0.2 nM). In addition, it caused neuronal responses to OT to correlate significantly with responses to acetylcholine and norepinephrine, which also can act on the ventromedial hypothalamus to facilitate lordosis. Finally, estradiol enhanced the excitability of laterally projecting neurons, which have been implicated in lordosis. In estrogen-pretreated slices, addition of progesterone in vitro caused little further effect on responses of individual neurons to exogenous OT. Altogether, the present electrophysiological findings are consistent with the hypothesis that estrogen potentiates OT action by increasing functional OT receptors preferentially in lordosis-relevant neurons, thereby enabling OT to efficiently facilitate female reproductive behavior.

Acetylcholine↗
PubMed1990

Regulation of the primate fetal adrenal cortex.

Significant advances in our understanding of the regulation of fetal adrenal growth, differentiation, and steroidogenesis have been made in the past several years. In vitro studies employing molecular biological techniques have demonstrated that the placenta and several fetal tissues synthesize growth factors and/or oncogene-related products, which have the capacity to modulate growth and maturation of the fetal adrenal. Moreover, there is evidence that the fetal adrenal itself produces IGF-I and IGF-II and that the mRNAs for these growth factors are responsive to ACTH and perhaps other peptides originating in the fetal pituitary and/or the placenta. Most fascinating are the studies demonstrating that growth factors may also regulate the pattern of steroidogenesis elicited by the fetal adrenal. For example, TGF beta modulates binding, internalization, and degradation of LDL-cholesterol in adult adrenals while IGF-I increases fetal adrenal steroidogenesis by mechanisms that do not involve induction of P-450scc or enhanced metabolism of LDL. These studies, coupled with the observation that activation of protein kinase C by EGF or bFGF can block ACTH and/or other cAMP-induced increases in the activity of P-450(17 alpha), provide new insight into the subcellular mechanisms that underlie the regulation of fetal adrenal function. However, in vivo investigations must be aggressively pursued because the latter provide a major and perhaps exclusive means to elucidate the complex and multiple mechanisms that are apparently operative in utero in the regulation of fetal adrenal development. Moreover, in vivo studies remain the only valid means to delineate whether the factors that have been shown to modulate fetal adrenal function in vitro are indeed operable in vivo. Thus, in vivo investigations have shown that a multifactorial regulation of the fetal adrenal exists in utero in which PRL and perhaps other peptides as well as ACTH selectively stimulate fetal adrenal androgen production. Moreover, in vivo studies have demonstrated that a feedback mechanism operates in utero whereby estrogen produced in the placenta from androgen precursors of fetal adrenal origin feeds back to modulate the responsivity of the fetal adrenal to tropic peptides perhaps by regulating peptide binding to cell membrane receptors and/or other mechanisms. Evidence has also been provided from in vivo studies to support the concept that the placenta via metabolism of maternal cortisol and cortisone regulates fetal pituitary production of ACTH by modulating the extent to which maternal cortisol arrives at the fetus.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Cortex↗
PubMed1992

Estrogens modulate the responsiveness of osteoblast-like cells (ROS 17/2.8) stably transfected with estrogen receptor.

Recent studies have demonstrated the presence of estrogen receptor (ER) in both normal human osteoblast-like and osteoblast-like osteosarcoma cells. The number of ER in cultured osteoblastic cells is very low (200-500 sites/cell). This has complicated characterization of the biological role of estrogens in bone cells. To study the responsiveness of bone cells to estrogens, we established osteoblast-like cell lines expressing higher ER levels. ROS 17/2.8, an osteoblastic cell line, was stably transfected with the cDNA encoding for the mouse ER. After a selection period, positive clones were isolated and evaluated for the presence of ER by both Northern blot analysis and ligand binding assays. Using these techniques, we detected a significant increase in the level of both ER transcript and binding compared to that in wild-type cells. The levels of expressed ER protein were similar to those reported in normal human osteoblast-like cells in primary culture (approximately 2000 sites/cell). To test whether the exogenously inserted ER was responsive, both wild-type and ER stably transfected cells were transiently transfected with a reporter construct containing an estrogen-responsive element linked to a truncated thymidine kinase promoter and a chloramphenicol acetyltransferase (CAT) reporter gene. Exposure of the cells to increased concentrations of estradiol induced a slight increase in CAT activity in wild-type cells (approximately 1.5-fold) at maximal stimulation; however, it provoked a clear concentration-dependent increase in CAT activity in the ER stably transfected cells, with a maximal stimulation of approximately 10-fold. This event was receptor mediated, since ICI 164,384, an ER antagonist, blocked the enhancement of estradiol-induced CAT activity, and it was specific, since other steroid hormones did not stimulate CAT activity. Finally, we evaluated the ability of ER to modulate an endogenous estrogen-responsive gene by measuring the activity of the enzyme alkaline phosphatase. In addition, diethylstilbestrol, a synthetic estrogen agonist, increased the activity of both the CAT reporter gene and the endogenous alkaline phosphatase enzyme. In summary, we have established osteoblast-like cells expressing high levels of an exogenously inserted ER, which has characteristics similar to those of the endogenous ER in terms of its Kd. Finally, the exogenous ER regulates both exogenously inserted construct (VITERECAT) and endogenous properties of the cells (enzymatic activity and proliferation).

Alkaline Phosphatase↗
PubMed1985

Progestin modulation of estrogen-dependent marker protein synthesis in the endometrium.

While it is well known that progestins have significant effects on estrogen-dependent processes in the uterus, very little is known about the molecular details of these effects. To understand these processes we have developed an immunocytochemical staining technique to help clarify the progestin regulation of estrogen receptor (ER), and we have also studied the effects of progestins on estrogen-dependent specific protein synthesis and secretion in the immature rat uterus. The immunocytochemical method for identifying estrogen receptor in tissue sections uses biotinylated monoclonal antibody to the estrogen receptor protein and shows a largely nuclear localization of the receptor protein in the rat uterine endometrium and myometrium. This method can be used to explore changes in the intercellular and intracellular localization of the uterine ER during progestin action. In an effort to correlate these changes with specific biological responses in the uterus we have been studying the effects of the administration of estrogens and progestins in vivo on the synthesis of specific proteins in uterine target cells in vitro. We previously reported that one-dimensional SDS-PAGE analysis of labeled secreted uterine proteins and cellular proteins extracted from the luminal epithelium and from the stroma plus myometrial fractions of the uterus revealed that estradiol-17 beta preferentially stimulated the synthesis of 110,000, 74,000, and 66,000 dalton secreted proteins, and 180,000 and 110,000 dalton epithelial proteins. We found that while progestins administered alone in vivo did not have any stimulatory effect on the synthesis of these secreted or cellular uterine proteins, concomitant administration of either progesterone or megestrol acetate and estradiol in vivo substantially reduced the estrogen-stimulated increase in labeling of the 110,000, 74,000, and 66,000 dalton secreted uterine proteins in vitro. In animals first primed with the progestin prior to combined estrogen/progestin treatment, the progestins were even more effective antagonists of estrogen. In addition, progestins alone given 24 hours after estradiol substantially inhibited the estrogen-stimulated synthesis of these proteins. These results suggest that progestins can both modulate the initial level of estrogen stimulation of synthesis of specific proteins and selectively terminate their synthesis, by affecting the continued transcription of their estrogen-regulated genes, altering the processing, half-life, or translation of their mRNAs, or by modulating the translation or the posttranslational processing of the nascent peptide chains.

Animals↗
PubMed1986

Noradrenergic modulation of hypothalamic progestin receptors in female guinea pigs is specific to the ventromedial nucleus.

The concentration of estrogen-induced cytosolic progestin receptors (CPRs) in the hypothalamus of alpha 1-noradrenergic antagonist-treated female guinea pigs is reduced relative to non-drug-treated controls. The present study determined where within the hypothalamus this reduction occurs. Ovariectomized, estradiol-treated guinea pigs were given either the alpha 1-noradrenergic antagonist prazosin or vehicle. Microdissected brain regions were assayed for CPR levels. Prazosin caused a selective relative decrease in CPR levels of the ventromedial nucleus of the hypothalamus. No significant effects of prazosin were seen in other hypothalamic or preoptic area nuclei.

Animals↗
PubMed1987

Selective modulation of FSH and LH secretion by steroids.

Significant divergence between the pattern of FSH and LH secretion has been observed in the ovulatory cycle, after ovariectomy and during puberty. The presence of an FSH-releasing factor, gonadal FSH inhibiting and releasing peptides and changes in the pulsatile pattern of LHRH secretion are among the postulates used to explain the divergent secretion of FSH and LH. Experiments in our laboratory have shown considerable evidence of differential regulation of FSH and LH secretion by steroids in the absence of gonadal regulatory peptides. Natural and synthetic estrogens show significant differences in the suppression of FSH and LH in the ovariectomized rat using a standard uterine response to the estrogen as the end point. In the immature ovariectomized rat treated with a low dose of estradiol that is sufficient for the synthesis of progesterone receptors to ensure progesterone sensitivity, but not large enough to induce estrogen triggered LH surges, progesterone administration resulted in a pattern of LH and FSH secretion similar to that observed on the day of proestrus in the cycling rat. Selective secretion of FSH was induced in the estrogen primed immature rat model by the administration of progesterone metabolite 5 alpha-dihydroporgesterone (5 alpha-DHP) while selective LH secretion was induced by 3 alpha, 5 alpha-tetrahydroprogesterone (3 alpha,5 alpha-THP). The selective secretion of FSH and LH induced by progesterone metabolites was confirmed in the immature female rat primed with PMSG and maintained in constant light. 5 alpha-DHP was also able to induce a greater release of FSH when administered to the adult cycling rat on proestrus. The priming of the pituitary gonadotrope in secreting a high baseline level of FSH or responding to LHRH in releasing a greater amount of FSH appeared to be an important factor in selective FSH release and such priming can be brought about by 5 alpha-DHP in the absence of gonadal regulatory peptides.

Animals↗