Androgen accumulation andbinding to macromolecules in seminal vesicles: inhibition cyproterone.

Cyproterone reduces the accumulation of testosterone and dihydrotestosterone in seminal vesicles 30 minutes after intravenous administration of tritiated testosterone to castrated rats. Testosterone, added in vitro, binds to macromolecules from the supernatant fraction of the seminal vesicle homogenates; this interaction is antagonized competitively by cyproterone. Cyproterone may diminish androgenic effects by competition for binding molecules.

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.

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer.

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m(-2) PPX or 75 mg m(-2) docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio=1.09, P=0.257), 1-year survival (PPX=25%, docetaxel=29%, P=0.134), and time to progression (PPX=2 months, docetaxel=2.6 months, P=0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (P<0.001) and febrile neutropenia (P=0.006). Grade 3 or 4 neuropathy (P<0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, P<0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210 mg m(-2) resulted in increased neurotoxicity compared with docetaxel.

Differences in breast cancer risk factors according to the estrogen receptor level of the tumor.

One hundred and forty-eight postmenopausal breast cancer cases and 585 postmenopausal controls were included in an investigation of whether various risk factors for breast cancer are associated with the level of estrogen (E) receptor (ER) protein in the tumor. In an intracase analysis, the tumor ER level was positively associated with nulliparity, late age at first live birth, a history of benign breast disease, and having breast-fed at least 1 child and was negatively associated with previous use of E replacement therapy. A case-control analysis suggested that the first three variables, established risk factors for breast cancer, are associated with an increased risk for malignant breast tumors that are ER-positive but not for those that are ER-negative. This analysis did not provide a clear interpretation of the findings in the intracase comparisons with regard to prior breast-feeding and the use of E replacement therapy.

Antiproliferative actions of tamoxifen to human ovarian carcinomas in vitro.

The cytosolic estrogen receptor (ERc) and progestin receptor (PRc) levels were measured in 56 human epithelial ovarian tumors. The maximum ERc content in a tumor sample was 163 fmol/mg cytosolic protein. Forty-six of the tumor samples were evaluable for clonogenic growth in soft agar, and 19 samples produced 15 or more colonies per 10(5) cells plated. Four of the samples that grew had ERc levels of greater than 30 fmol/mg cytosolic protein. No correlation, however, between growth in soft agar and ERc or PRc content was observed. The antiproliferative properties of the antiestrogen, tamoxifen, were studied. Although no decrease in colony formation was observed after a 1-hr exposure to 0.2 or 2 microM tamoxifen, continuous exposure of cells to 2 microM tamoxifen reduced clonogenicity in 8 of 18 solid ovarian carcinomas examined. The maximum diminution in colony formation was approximately 50% of that of the control and was seen in 2 tumor samples. Both tumors that displayed the maximum response to continuous tamoxifen treatment had ERc and PRc levels greater than 30 fmol/mg cytosolic protein. None of the 14 tumors with ERc levels less than or equal to 30 fmol/mg cytosolic protein exhibited a decrease in colony formation of more than 50%. Exposure of cells for 1 hr to the combination of doxorubicin and tamoxifen produced a significant antagonism of the individual doxorubicin or tamoxifen antiproliferative effects in 7 of 9 samples examined. These data suggest that in a subset of human ovarian epithelial carcinomas tamoxifen alone can have some direct antiproliferative action on the clonogenic cells. The maximum antiproliferative effect of tamoxifen observed was related to ERc content in ovarian tumors.

Autoradiographic localization of tritiated dihydrotestosterone in the flank organ of the albino hamster.

In the hamster flank organ, the growth of hair and growth of sebaceous glands are androgen-dependent functions. Although dihydrotestosterone (DHT) is known to be a potent stimulator of flank organ growth, there is no information about localization of DHT receptor sites in this organ. The purpose of this study was to use steroid autoradiography to localize DHT receptors in the hamster flank organ. Because steroid hormones are functional when translocated to nuclear receptors, nuclear localization by autoradiography defines receptor sites. In order to be able to visualize autoradiographic grains from radiolabeled androgens around hair follicles, albino hamsters were studied to avoid confusion between the grains and pigment granules which are abundant in the more common Golden Syrian hamster. Mature male hamsters castrated 24 hours earlier were given tritium-labeled dihydrotestosterone ( [3H]DHT). Using the technique of thaw-mount steroid autoradiography, 4-micron unfixed frozen sections were mounted in the dark onto emulsion-coated glass slides and allowed to develop for 4-6 months. [3H]DHT was found to be concentrated over sebocyte nuclei. The label was present peripherally as well as in differentiating sebocytes. There was no nuclear localization of [3H]DHT in animals pretreated with excessive quantities of unlabeled DHT. Steroid metabolites of [3H] DHT were assessed by thin-layer chromatography in paired tissue samples. Most of the label remained with DHT. Uptake was inhibited in the flank organ of hamsters pretreated with unlabeled DHT. Specific DHT receptors in the albino hamster flank organ are located in peripheral and differentiating sebocytes. Steroid autoradiography is a useful tool to study androgen interaction in the skin.

17 Alpha-ethinyl estradiol is more potent than estradiol in receptor interactions with isolated hepatic parenchymal cells.

Estradiol (E2) and 17 alpha-ethinyl estradiol (EE2) were compared for their abilities to promote nuclear translocation of the hepatic estrogen receptor. High levels of nonradioactive E2 and EE2 were incubated in vitro with isolated rat liver parenchymal cells. Cytosol and nuclear receptors were then partially purified and measured by exchange with [3H]E2. E2 was required in an approximately 100-fold higher concentration than EE2 for promotion of receptor translocation (for example, 10(-5) M E2 was equivalent to 10(-7) M EE2). When the metabolisms of the estrogens by parenchymal cells were compared, it was found that [3H]E2 was metabolized much more extensively than [3H]EE2 after a short time interval. Inhibitors of estrogen metabolism were used to test the hypothesis that the high dose requirement for receptor translocation may be due to metabolism. In isolated liver cells, SKF 525A (beta-diethylaminoethyl-2,2-diphenylpentanoate; an inhibitor of hepatic mixed function oxidase) could increase levels of unmetabolized EE2, cytosol receptor deletion, and nuclear receptor accumulation. SKF 525A alone was not sufficient to increase levels of unmetabolized E2 or receptor translocation in the presence of this estrogen. When testosterone (a transient inhibitor of the 17-oxidoreductase active on E2) was included in cellular incubations (using female liver cells) with E2 and SKF 525A, levels of unmetabolized E2 were substantially increased in conjunction with increased depletion of cytosol receptors and increased levels of nuclear receptors. These data suggest that hepatic metabolism may limit the availability of estrogens for binding to receptors. The present study suggests that E2 is more extensively metabolized than EE2 to metabolites which are less capable of promotion of receptor translocation.

An unusual sex steroid-binding protein in mature male rat liver cytosol.

Mature male rat liver cytosol contains a moderate affinity and capacity estrogen-binding protein in at least a 200-fold higher level than mature female or immature male rat liver cytosol. Binding of estradiol to this protein is very rapid, is stabilized by EDTA, and is inhibited by divalent cations. This is the major binding protein for [3H]estradiol ([3H]E2) in mature male rat liver cytosol, and it has properties clearly distinguishing it from putative liver or uterine estrogen receptors. In addition to binding [3H]E2, this protein seems to rapidly bind a [3H]5alpha-dihydrotestosterone ([3H]DHT) metabolite at the same binding site. The binding of this androgen metabolite is stabilized by EDTA and is inhibited by divalent cations. The binding properties of the [3H]DHT metabolite suggest that these binding sites are not classical androgen receptors. Cytosol binding levels of both the [3H]E2 and the [3H]DHT metabolites change in a similar direction in resonse to endocrine manipulation. The putative liver estrogen receptor level, determined after partial purification (in a redissolved 30% ammonium sulfate-precipitated fraction), seems to change in an opposite direction in response to these same endocrine manipulations.

Estrogen receptor in adult male rat liver.

A 30% ammonium sulfate precipitation has previously been utilized to partially purify the estrogen receptor(s) of female rat liver cytosol. This procedure has now been used to fractionate the estradiol-binding sites of adult male rat liver cytosol. The 30% ammonium sulfate precipitation partially purifies a group of estradiol-binding sites which have properties quite distinct from the large number of sites present in male liver cytosol. The partially purified male sites seem to have the same properties as the partially purified female estradiol-binding sites. They seem to be proteins that are estrogen specific and have a high estradiol affinity (Kd = 1 X 10(-10) M) and a low estrogen capacity (2.3 fmol/mg liver). The estradiol-binding sites of prepubescent male rat liver cytosol have also been fractionated by 30% ammonium sulfate precipitation. The redissolved ammonium sulfate precipitates from prepubescent male rat liver cytosol contain fewer estradiol-binding sites then those from adult male or female rats. It seems that adult male as well as adult female rat liver contains estrogen receptors.

Estrogen receptor in rat liver: translocation to the nucleus in vivo.

Following in vivo ethinyl estradiol (EE2) administration (100 microgram sc) to adult female rats, the estradiol-specific binding sites (ESBS) of liver cytosol were markedly reduced at 30 and 60 min. The reduction at 30 min was to one-quarter of that found in rats treated with vehicle alone. Coincident with this reduction, nuclear ESBS were increased. The ESBS of partially purified cytosol and of dense sucrose-purified nuclei were determined by gel filtration after incubations with tritiated estradiol using exchange assay conditions. An elevated temperature during the exchange assay incubations was necessary to demonstrate most of the ESBS in purified nuclei of EE2-treated rats and suggested that estrogens are attached at these sites. Following administration of 5 microgram EE2, the decrease in cytosol ESBS and the increase in nuclear ESBS were smaller. In contrast, 5 microgram EE2 was as effective as 100 microgram EE2 in substantially increasing the ESBS observed in uterine nuclear fractions. The low level of ESBS found in whole brain purified nuclei was unchanged by 100 microgram EE2 administration. The steroid specificity and proteolytic enzyme sensitivity of the purified nuclear ESBS of treated rats were similar to that of the partially purified cytosol ESBS of rats treated with vehicle alone. The data are consistent with the ESBS being estrogen receptor proteins which translocate from the liver cytosol to the nucleus after estrogen administration in vivo.

Androgen receptor in the rabbit liver and apparent translocation to the nucleus in vivo.

The present study demonstrates that the liver of a mammal, the rabbit, contains an androgen receptor. Rabbit liver cytosol or purified nuclei were incubated with the radioactive androgen R-1881 (methyltrienolone). The cytosol of adult female rabbit liver contained androgen-binding sites of high affinity, Kd 0.9 nM, and a capacity of 7000 fmol/g liver or 79 fmol/mg cytosol protein. After partial purification by 35% ammonium sulfate precipitation (AS cytosol), the binding specificity pattern was consistent with that of androgen receptor. Apparent translocation from cytosol to nucleus was examined by administering 100 micrograms nonradioactive R-1881 in vivo. One hour later, almost all of the receptor was detected in liver nuclei. The receptor concentration in purified nuclei, as determined by an exchange procedure, was 2100 fmol/g liver, which is an increase of 6-fold relative to the low levels in nuclei of untreated rabbits. The binding affinity, specificity pattern, and protease sensitivity for the sites in the nucleus after in vivo androgen in general resembled those as AS cytosol binding in untreated liver. Androgen receptors were also present in AS cytosol of the immature female rabbit liver and, in lower concentration, of the intact adult male rabbit. The properties of liver androgen binding are quite different from those of testosterone binding protein present in serum. Accordingly, an androgen binding protein with high affinity and specificity and capable of translocation to the nucleus in vivo has been detected in mammalian liver. An androgen receptor in the mammalian liver may mediate androgen effects on liver function, including modulation of synthesis of selective plasma proteins.

Cysteamine causes reduction of prolactin monomers followed by aggregation in the rat pituitary gland.

Storage forms of PRL were studied in control and cysteamine-treated cultures of estradiol-induced tumors in Fischer 344 rats and in secretory granules isolated from these tumors to further investigate the mechanism of action of cysteamine on PRL. The two major bands visible when protein is stained after electrophoresis of isolated granules migrate to the position of PRL and GH monomers. Electrophoresis under reducing conditions changes the position, but does not noticeably increase the amount of each band. [3H]PRL in cells labeled for 8 h with [3H]leucine also exists predominantly as monomer. Immunoreactivity of PRL in cell lysates or isolated granules is not affected by incubation with reducing agents beta-mercaptoethanol or glutathione at concentrations up to 5 mM, but cysteamine decreases PRL immunoreactivity in isolated granules at concentrations of 3 mM and higher. Electrophoresis of isolated granules after incubation with 25 mM cysteamine for 1 h demonstrates that cysteamine converts PRL to the reduced form. After 4 h, or after dilution of the granules before solubilization, the amount of reduced monomer is decreased, and larger molecular weight species appear. The reduced monomer can be recovered by electrophoresis under reducing conditions. The fully immunoreactive form can be recovered by incubation for 1 h with dithiothreitol at concentrations of 0.3 mM-3 mM. These data indicate that: PRL exists predominantly in monomeric form in the rat pituitary gland, and cysteamine reduces PRL, and formation of disulfide-linked aggregates of PRL occurs subsequently under some conditions.

Assessment of possible transneuronal changes in the retina of rats with inherited retinal dystrophy: cell size, number, synapses, and axonal transport by retinal ganglion cells.

In pigmented RCS rats with inherited retinal dystrophy, most photoreceptor cells disappear between postnatal days 20 and 100. We have examined the time course of the degeneration of photoreceptor nuclei and synapses and determined whether transneuronal changes occur in the inner nuclear layer (INL), inner plexiform layer (IPL), and retinal ganglion cells following loss of photoreceptor cells in these animals. Electron microscopic photomontages of the entire thickness of the IPL of dystrophic (RCS-p+) and control (RCS-rdy+ p+) rats 334 to 515 days old were prepared, and synapses were counted and identified as either conventional (amacrine) or ribbon (bipolar) types. Neither the incidence of synapses in the IPL nor the ratio of conventional to ribbon synapses differed in the dystrophic and control retinas. Ganglion cell diameter, perimeter, area, and density were measured from drawings of wholemount preparations of dystrophic and control rats 105 days and older. Diameter, perimeter, area and number of ganglion cells were not significantly different in the two genotypes. Anterograde axonal transport was measured by studying the displacement of labeled material as it traveled along ganglion cell axons and accumulated in the superior colliculus. The normal and dystrophic rats showed no significant difference in (1) the rates of rapidly moving components (approximately 110-180 mm/day) and slowly moving components (1.7-2.5 mm/day) or (2) the amount of radioactive material transported to the superior colliculus. The absence of transneuronal changes in retinal ganglion cells of RCS rats contrasts with results obtained earlier in rd mice (Graftstein et al., '72). Unlike the RCS rat, retinal degeneration in rd mice occurs before the maturation of the retina. We hypothesize that the ganglion cells may be more affected by loss of input early in development, and, therefore, ganglion cells of retinal dystrophic rats are less affected despite little or no synaptic input for several months. Furthermore, any reduction in the electrical activity of retinal ganglion cells that might follow loss of photoreceptor cells does not result in a significantly decreased rate of axonal transport.

Müller cell expression of glial fibrillary acidic protein after genetic and experimental photoreceptor degeneration in the rat retina.

Glial fibrillary acidic protein (GFAP) is normally found in astrocytes. In the normal rat retina at all ages, only astrocytes stain for GFAP. This staining pattern is also found in RCS rats with inherited retinal dystrophy younger than 38 days. Beginning on day 38, when about 61% of the photoreceptors have degenerated, a few GFAP-positive fibers span the retina from the inner limiting membrane to the external limiting membrane. By day 41 and at all later ages examined, the radial fibers of Müller cells is a response to photoreceptor necrosis or might be a direct effect of the mutant gene, we induced photoreceptor degeneration in normal, adult Sprague-Dawley rats by exposing them to constant light for variable periods of time. After 3 days in constant light, there is a 20% reduction in the number of photoreceptors and many Müller cells are positive for GFAP. Immunoblot studies confirmed that the anti-GFAP reacted with a single protein from retina that corresponded in molecular weight and Triton-insolubility to GFAP. The immunoblots also corroborated the results from anti-GFAP immunostaining of control and experimental retinas. These results indicate that Müller cells express GFAP immunoreactivity in response to experimentally as well as genetically induced photoreceptor degeneration.

Immunocytochemical localization of interphotoreceptor retinoid-binding protein in developing normal and RCS rat retinas.

Interphotoreceptor retinoid-binding protein (IRBP) was localized immunocytochemically in developing normal and RCS rat retinas. IRBP was present in normal and RCS neural retinas on the day after birth (postnatal day 2, P2) to P8 in the space between the neuroblastic layer and the retinal pigment epithelium (RPE). The presence of IRBP prior to the development of outer segments (OS) suggests that OS formation is not linked temporally with IRBP secretion. On P10, staining was confined to the interphotoreceptor space with an intense band of label adjacent to the RPE. This staining pattern persisted in normal rats throughout development and until P18 in RCS rats. On P18, anti-IRBP staining in the RCS was spread evenly throughout the OS layer with no intense band of label adjacent to the RPE and after P18, there was decreased staining with anti-IRBP. On P45 and later, no staining of the RCS retina was found with anti-IRBP. Immunoblots of normal and RCS retinas corroborated the results from immunocytochemical staining. These findings suggest that IRBP may be synthesized in the photoreceptors, but is not abnormal in amount or distribution prior to onset of retinal degeneration in the RCS rat.

Oral contraceptives--possible mediation of side effects via an estrogen receptor in liver.

PIP: Most of the side effects of oral contraceptives may be caused by direct estrogen interaction in the liver resulting in alteration in liver function, including the synthesis of critical plasma proteins affecting the cardiovascular system. This study has succeeded in demonstrating an estrogen receptor in the mammalian liver. The liver receptors were found to consist, at least partly, of protein, and bound estrogens with high specificity. A strong binding affinity was indicated. The steroid hormones first bind to cytoplasmic receptors, after which the cytoplasmic receptor-steroid complex translocates from the cytoplasm to the nucleus and attaches to chromatin. Estrogen binding and translocation were shown in rat liver in vitro and in vivo. Minimizing the liver interaction thus might reduce the risk of side effects, but the estrogen-receptor function in the hypothalmic-pituitary axis and in the endometrium would have to be maintained. Possible differences in receptor characteristics of the 2 organs might be exploited to reduce liver interaction and, at the same time, possibly improve therapeutic benefits. Studies of receptor characteristics in rats indicate that a higher dose of estrogen is required in the liver than in the uterus and other organs to induce at least some direct effects. There seems to be a possibility that the newer combined oral contraceptives, which contain lower amounts of estrogen, ethinyl estradiol (reduced from 50 ug to 30 ug), and progestin, might produce smaller changes in estrogen-related plasma protein and at the same time achieve contraceptive effectiveness and regular menstrual bleeding patterns. Another possibility would be the future development or selection of another and safer estrogen.^ieng

Developmental correlation of higher levels of estrogen binding by macromolecules in rat liver supernatant and of increases in plasma renin substrate levels after estrogen administration.

PIP: Developmental correlation of higher levels of estrogen binding by macromolecules in rat liver supernatant and of increases in plasma renin substrate levels after estrogen administration is reported. Gel filtration columns were used to separate bound from free radioactivity in studying binding of radioactive estradiol to tissue supernatants. The liver of the prepubescent female rat has less estrogen-specific binding macromolecules than the adult (p less than .01). This difference in quantity was maintained when binding activities were partially purified by precipitation with ammonium sulfate at 30% saturation. After administration in vivo of 100 mcg of ethinyl estradiol (sc), plasma renin substrate (PRS) levels increased 167% above control in the adult female rat (p less than .05). The corresponding increase was only 15% in the prepubescent rat. In contrast, renin substrate levels were significantly increased in both the prepubescent and adult by administration of 4 mg/kg of dexamethasone (p less than .05). The marked increase in the amount of estrogen binding and PRS responsiveness to estrogen administration with sexual maturation indicates that the estrogen-binding protein may be an estrogen receptor involved in modulating synthesis of at least 1 plasma protein.^ieng

Estrogen receptors in ovarian epithelial carcinoma.

Specimens from 53% (16 of 30) of patients with untreated ovarian epithelial cancers between October 1976 and February 1979 had estrogen binding levels greater than 30 fmoles/mg of cytosol protein (receptor rich). The likelihood of a specimen being receptor rich appeared to be independent of patient age, histologic grade of tumor, clinical stage, and amount of residual tumor left after surgery. For 20 patients with previously untreated advanced disease a life-table analysis showed no significant difference when receptor-rich and -poor groups were compared in terms of either survival or time to first progression of disease. Analysis of more recent specimens (predominantly obtained after February 1979) indicates high-affinity binding of the estrogen consistent with receptor; occasional substantial heterogeneity in estrogen binding results between different sites of tumor involvement; and progestin-specific binding in some specimens. In an analogy to breast cancer, patients whose tumors are cytosol estrogen receptor rich might theoretically be responsive to the administration of antiestrogens.

Preservation of steroid receptors in frozen brain and pituitary tissue: use of the cryoprotective agent, dimethylsulfoxide.

This paper examines the effects of freezing and thawing on steroid receptor concentrations in the brain and pituitary of the rat. Storage at -70 degrees C for 1-2 weeks had no detectable effect on levels of cytoplasmic estrogen receptors. However, freezing and thawing resulted in measurable losses of cytoplasmic androgen, progestin and glucocorticoid receptors. Cell nuclear receptors were measured by exchange assay after in vivo administration of non-radioactive steroids. Nuclear estrogen, androgen and progestin receptor concentrations were all reduced by freezing compared to the levels in fresh tissue. In all cases except that of cytoplasmic glucocorticoid receptors, these losses could be prevented by freezing the tissue in 10% aqueous dimethylsulfoxide.

Concentration of [16 alpha-125I]iodoestradiol in human ovarian tumors in vivo and correlation with estrogen receptor content.

The gamma emitting estrogen [16 alpha-125I]iodoestradiol was administered to 11 patients with ovarian cancer and 1 patient with endometrial cancer. At specific times after the administration of the tracer, portions of the tumor and of control tissues, fat and muscle, were removed and counted. The amount of radioactivity in these tissues was compared to the cytosolic estrogen receptor content of the tumor, measured by Sephadex LH-20 gel filtration, in biopsy specimens taken before the injection of the tracer. There was a strong correlation (p less than 0.005) between the estrogen receptor concentration in the biopsied tumor and the amount of radioactivity in the tumor. There was no correlation between the isotope in the muscle and the tumor receptor, nor between the radioactivity in the tumor and that in fat or muscle. As would be expected for a steroid receptor mediated process, the bulk of the total tissue radioactivity was present in the nuclear compartment of the tumors. This pattern was not observed in the muscle. Furthermore, the nuclear radioactivity in the tumors was positively correlated with the cytosolic estrogen receptor content. These experiments demonstrate that under in vivo conditions this gamma emitting estrogen is concentrated in tumors in a manner that is dependent upon the estrogen receptor. It was also found that the concentrations of radioactivity in the blood were high, producing low tumor to blood ratios. The blood level of isotope was not due to the presence of the unmetabolized steroid, which disappeared from blood rapidly, but was caused by circulating metabolites of the injected steroid. Since the concentration of the isotope in the tumor was dependent upon the estrogen receptor level, it would appear from these experiments that it is theoretically possible to use such compounds to image and monitor tumors that contain estrogen receptors. However, rapid metabolism would seem to preclude the use of 16 alpha-iodoestradiol itself for this purpose. These studies point to the possibility that the synthesis of analogs of 16 alpha-iodoestradiol, sterically protected against inactivation by rapid metabolism, may lead to a radiopharmaceutical agent that would be useful for imaging and monitoring estrogen receptor containing tumors.