Arch AIDS Res. 1996;10(1-2):41-8.
Binding sites specific to steroid hormones on the plasma membrane of hormone-dependent breast tumors.

Calzada L, Wusterhaus AH, Salazar EL.

PIP: Hormone receptor assays and electron microscopy were conducted on tissue samples of mammary carcinoma tumors excised from women attending the oncology service of the Luis Castelazo Ayala Hospital of Obstetrics and Gynecology of the Mexican Social Security Institute in Mexico City. Researchers aimed to quantify binding sites of the plasma membrane of the tumor cell specific to estradiol or progesterone so they can better understand changes on the surface of the tumor cell caused by the plasma membrane's ability to accumulate and retain steroids. The binding union specific values for cytosolic receptors to estradiol ranged from 275 to 535 fmol/mg protein and those for progesterone ranged from 75 to 150 fmol/mg protein. The accumulation of estradiol or progesterone ceased within 10-20 minutes. No increase occurred after 60 minutes of incubation. Thus, accumulation of estradiol and progesterone by the plasma membrane is saturable and time-dependent. Further, at 30 minutes, the specific binding capacity of estradiol and progesterone was about four times less at 4 degrees Celsius than it was at 37 degrees Celsius. This suggests that the accumulation of estradiol or progesterone is also temperature-dependent. These findings suggest that hormone-binding sites play a critical role in changes in the plasma membrane structure. Specifically, they may help in the recognition, orientation, and mediation for the subsequent incorporation of estradiol and progesterone by a mechanism mediated by the plasma membrane.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12320021&dopt=Abstract estradiol




Med Hypotheses. 2002 Jun;58(6):516-8.
Estrogen therapy for hepatectomy patients with poor liver function?

Chiu EJ, Lin HL, Chi CW, Liu TY, Lui WY.

Department of Surgery, Veteran General Hospital-Taipei, Taipei, Taiwan, Republic of China.

Estrogen is well known to promote liver regeneration after partial hepatectomy. Administration of estradiol prior to partial hepatectomy also induces increased activity of DNA synthesis. Endogenous aromatase plays a key role in the conversion of testosterone to estradiol. The aromatase activity was induced by IL-6, which is a key factor for liver regeneration. It has been reported that IL-6 interacts with gp80/130 receptor and regulates the STAT1/3 pathway to induce DNA synthesis in hepatocyte. The IL-6 induced aromatase activity results in increased serum estradiol level. This corresponded well with observation that estradiol was elevated after partial hepatectomy. Therefore, it is very likely that estradiol and IL-6 synergize in stimulation of hepatocyte proliferation during liver regeneration. We propose that a short-term estradiol treatment may be beneficial for patients with poor liver function after hepatectomy.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12323121&dopt=Abstract estradiol




West J Surg Obstet Gynecol. 1964 May-June;72:160-3.
Menstrual regulation by sequential hormone therapy.

Beaton JH.

PIP: 134 patients who could not use the rhythm method of contraception effectively were treated with sequential doses of estrogen and progesten to regulate the menstrual cycle for 638 cycles. 3 different formulas were used: .05 mg ethinyl estradiol followed by 12.5 mg dimethisterone (IT); .1 mg ethinyl estradiol followed by 25 mg dimethisterone and .1 mg ethinyl estradiol (IZ); and .1 mg ethinyl estradiol followed by .1 mg ethinyl estradiol and 5 mg megestrol acetate (IH). 1 patient on each formula became pregnant during the study. The patient on the IT formula aborted at 6 weeks, the patient on the IZ formula conceived during the eleventh month of therapy with an ectopic implantation and the patient on the IH therapy conceived during the second cycle. 7 patients became pregnant immediately after therapy. Blood chemistries performed on 12 patients who had been on therapy a minimum of 12 months were all normal. Most of the patients reverted to the previously irregular cycles after cessation of therapy.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12332438&dopt=Abstract estradiol




JAMA. 1971 Jan 18;215(3):(3): 492-493.
Estrogens: why harmless as menopausal therapy but hazardous in the "Pill"?

Edwards CC, Drill VA.

PIP: An inquiry as to why the use of estrogens in large doses has been sanctioned in a variety of therapeutic situations and condemned when used in smaller doses as contraceptives is answered by 2 consultants. Dr. C.C. Edwards of the U.S. Food and Drug Administration answers that there is considerable difference between the conjugated equine estrogens used in therapy and the synthetic estrogens, ethinyl estradiol and mestranol, used in contraceptive medications. The same menopausal symptoms relieved by 1.25 mg of conjugated equine estrogens daily require only .02 mg of ethinyl estradiol. .05 mg ethinyl estradiol daily has a potent ovulation inhibiting effect while 3.75 mg of conjugated equine estrogens daily is ineffective in inhibiting ovulation consistently. Oral contraceptives with .02 mg of ethinyl estradiol might be virtually without serious estrogenic adverse reactions, but studies to date have shown .02 mg daily to be ineffective as an ovulation inhibitor. Dr. V.A. Drill of G.D. Searle and Company contends that the British investigators who reported an increased incidence of thromboembolism in oral contraceptive users compared the estrogens taken simply on a milligram basis rather than in relationship to their estrogenic potency. Errors were also made statistically. Dr. Drill asserts that the controversy regarding thromboembolic disease which followed the British announcement is not based on established facts. Early appraisals of the possible role of different doses of mestranol and ethinyl estradiol in the British study are premature.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12332746&dopt=Abstract estradiol


Am J Cardiol. 2002 Jul 3;90(1A):22F-25F.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12106636&dopt=Abstract estradiol




Comp Biochem Physiol C Toxicol Pharmacol. 2002 Jun;132(2):203-11.
Characterization of the estrogenic response to genistein in Japanese medaka (Oryzias latipes).

Zhang L, Khan IA, Foran CM.

Department of Pharmacology, The University of Mississippi, University, MS 38677, USA.

This study was designed to determine the estrogenic effect of the phytoestrogen genistein on several measures of endocrine function in adult Japanese medaka (Oryzias latipes) relative to 17-beta-estradiol. Adult animals of both sexes were exposed to 75, 750 and 30,000 ng/fish (average fish weight equals 0.26 g) of genistein by i.p. injection, with a positive control group treated with 300 ng/fish of 17-beta-estradiol, while a negative control group received a vehicle-only (corn oil) injection. Content of vitellogenin, the yolk glycoprotein made in the liver in response to estradiol stimulation, was measured using Western blots. Circulating estradiol and testosterone levels were measured using a steroid-enzyme immunosorbant assay. The ability of ovaries and testes to synthesize and release estradiol and testosterone was determined by ex vivo incubation of gonads with 25-hydroxycholesterol. Vitellogenin, while induced by 17-beta-estradiol, was not increased in the liver of individuals treated with genistein. In females, genistein treatment at 750 and 30,000 ng increased the estradiol production of ovaries more than the 17-beta-estradiol treatment. In males, genistein treatment resulted in decreased testosterone production from ex vivo testis and a comparable reduction in circulating testosterone level. The changes in vitellogenin, circulating steroids and ex vivo steroidogenesis in medaka in response to genistein are similar to that of 17-beta-estradiol. However, some endpoints are more sensitive to estradiol treatment (vitellogenin), while others are more sensitive to genistein (male testosterone and ovarian estrogenesis).

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12106897&dopt=Abstract estradiol




Cancer Res. 2003 Apr 1;63(7):1538-49.
Novel 2-methoxyestradiol analogues with antitumor activity.

Tinley TL, Leal RM, Randall-Hlubek DA, Cessac JW, Wilkens LR, Rao PN, Mooberry SL.

Department of Physiology and Medicine, Southwest Foundation for Biomedical Research, San Antonio, Texas 78227, USA.

2-Methoxyestradiol (2-ME2) is a natural estrogen metabolite that, while devoid of estrogenic effects, has both antiangiogenic and antitumor effects. 2-ME2 is currently being evaluated in Phase I and Phase II clinical trials for the treatment of multiple types of cancer. Novel analogues of 2-ME2 were tested for activities that predict antiangiogenic and antitumor effects. Selected analogues were tested for inhibitory activity against endothelial cell proliferation and invasion. The results show that these analogues are effective inhibitors of endothelial cell activities that may predict antiangiogenic activity, and one analogue, 2-methoxy-14-dehydroestradiol (14-dehydro-2-ME2), was 6-15-fold more potent than the parental compound in these assays. The analogues were also evaluated for inhibition of proliferation and cytotoxicity against multiple tumor cell lines and found to be potent and effective. 14-Dehydro-2-ME2 was approximately 15-fold more potent than 2-ME2 against various tumor cell lines, and 2-methoxy-15-dehydroestradiol was particularly effective against DU 145 and PC3 prostate cancer cell lines. In vivo antitumor activity was observed for the three analogues tested in the murine xenograft MDA-MB-435 model; however, 2-ME2 provided no antitumor activity in this trial. The two most effective analogues, 14-dehydro-2-ME2 and 2-methoxyestradiol-15 alpha,16 alpha-acetonide, provided 29.4% and 26.7% inhibition of tumor burden, respectively. Mechanism of action studies indicate that the analogues cause mitotic spindle disruption, mitotic arrest, microtubule depolymerization, and inhibition of the assembly of purified tubulin similar to the effects of 2-ME2. Consistent with antimitotics that inhib




Endocrine. 2002 Apr;17(3):161-8.
Estradiol and luteinizing hormone regulation of insulin-like growth factor binding protein production by bovine granulosa and thecal cells.

Spicer LJ, Chamberlain CS.

Department of Animal Science, Oklahoma State University, Stillwater 74078, USA. igf1Lekstate.edu

To determine the effects of estradiol and luteinizing hormone (LH) on insulin-like growth factor-binding protein (IGFBP) production by bovine granulosa and thecal cells, both cell types were collected and cultured in serum-free medium with various hormone treatments, arranged in three experiments. In thecal cells, insulin stimulated (p < 0.05) production of IGFBP-2 and IGFBP-5, but had no effect (p > 0.10) on IGFBP-3 and IGFBP-4 production; LH stimulated (p < 0.05) production of IGFBP-2 and IGFBP-3 but had no effect (p > 0.05) on IGFBP-4 and IGFBP-5. Estradiol had no effect (p > 0.10) on IGFBP-2, IGFBP-3, IGFBP-4, and IGFBP-5 production by thecal cells. Production of IGFBP-2/-5 by granulosa cells from small follicles was inhibited (p < 0.05) by insulin, but estradiol and LH did not influence (p > 0.10) insulin's inhibitory effect on basal IGFBP-2/-5 production. Insulin, LH, and estradiol each inhibited IGFBP-4 production by small-follicle granulosa cells, but their effects were not additive. IGFBP-3 was not produced by small-follicle granulosa cells. In large-follicle granulosa cells, insulin and LH inhibited (p < 0.05) production of IGFBP-2/-5 and IGFBP-3, whereas estradiol had no effect. Insulin alone had no effect (p > 0.10) on production of IGFBP-4, but estradiol and LH inhibited (p < 0.05) production by large-follicle granulosa cells, and their effects were not additive. These results suggest that production of IGFBP-2, IGFBP-3, IGFBP-4, and IGFBP-5 by granulosa and thecal cells is differentially affected by hormonal stimuli.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12108515&dopt=Abstract estradiol




Ann Neurol. 2002 May;51(5):599-603.
Effects of ovarian hormones on human cortical excitability.

Smith MJ, Adams LF, Schmidt PJ, Rubinow DR, Wassermann EM.

Brain Stimulation Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1430, USA.

Ovarian steroids appear to alter neuronal function in women, but direct physiological evidence is lacking. In animals, estradiol enhances excitatory neurotransmission. Progesterone-derived neurosteroids increase GABAergic inhibition. The effect of weak transcranial magnetic stimulation of the motor cortex on the motor evoked potential (MEP) from transcranial magnetic stimulation given milliseconds later is changed by GABAergic and glutamatergic agents. Using this technique previously, we showed more inhibition in the luteal phase relative to the midfollicular menstrual phase, which is consistent with a progesterone effect. To detect the effects of estradiol, we have now divided the follicular phase. We tested 14 healthy women during the early follicular (low estradiol, low progesterone), late follicular (high estradiol, low progesterone), and luteal (high estradiol, high progesterone) phases, with interstimulus intervals from 2 to 10msec (10 trials at each interval and 40 unconditioned trials). We calculated the ratio of the conditioned MEP at each interval to the mean unconditioned MEP: the higher the ratio, the less inhibition and the more facilitation caused by the first stimulus. The combined ratios increased significantly from the early follicular phase to the late follicular phase and then decreased again in the luteal phase. These findings demonstrate an excitatory neuronal effect associated with estradiol and confirm our earlier finding of inhibition associated with progesterone.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12112106&dopt=Abstract estradiol




Synapse. 2002 Aug;45(2):143-51.
Serotonin mediates CA1 spine density but is not crucial for ovarian steroid regulation of synaptic plasticity in the adult rat dorsal hippocampus.

Alves SE, Hoskin E, Lee SJ, Brake WG, Ferguson D, Luine V, Allen PB, Greengard P, McEwen BS.

Atherosclerosis and Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA. stephen_alveerck.com

The activity of the serotonin (5-hydroxytryptamine, 5-HT) system is sensitive to estradiol and progesterone. During the ovarian cycle, dendritic spines on CA1 pyramidal neurons of the dorsal hippocampus are increased by estradiol and later decreased by progesterone. We sought to determine whether 5-HT is involved in maintaining CA1 spine density and/or in steroid regulation of synaptic plasticity in dorsal hippocampus. Ovariectomized rats were treated (sc) over 10 days with the tryptophan hydroxylase inhibitor parachlorophenylalanine (pCPA) to deplete 5-HT, followed by estradiol benzoate on days 10 and 11. A subset of animals received progesterone on day 12. The day after the last treatment, rats were perfused and brains were processed for Golgi impregnation. Separate groups were processed for radioimmunocytochemistry (RICC) for the spine-associated protein, spinophilin, or high-performance liquid chromatography (HPLC) for monoamine analysis. Golgi and RICC data indicate that CA1 apical spine density was significantly decreased by pCPA (17-20%). Estradiol increased spine density in both saline- and pCPA-treated rats compared to respective controls (30%); however, pCPA animals maintained significantly fewer spines. No differences in spine densities were observed between saline- and pCPA-treated rats given estradiol and progesterone. Depletion of 5-HT by pCPA was confirmed in the CA1 (-90%) and dorsal raphe (-80%) by HPLC analysis. While 5-HT depletion was associated with a 57% decrease in CA1 norepinephrine (NE), there was no difference in dorsal raphe NE. Thus, whereas 5-HT is involved in maintainin