Reprod Fertil Dev. 2003 Aug 13;15(4):197-205.
Effect of ovarian steroids on basal and oxytocin-induced prostaglandin F(2alpha) secretion from pig endometrial cells.

Hu J, Braileanu GT, Mirando MA.

Department of Animal Sciences and Center for Reproductive Biology, Washington State University, Pullman, WA 99164-6353, USA. Present address: Department of Animal Science, Texas A&M University, College Station, TX 77843-2471, USA. To whom correspondence should be addressed. email: jianbamu.edu

These studies were undertaken to determine how treatment with 100 nM progesterone and/or 10 nM oestradiol-17beta acutely (3 h; Experiment 1) or chronically (72 h; Experiments 2-4) influenced basal and oxytocin (OT)-stimulated prostaglandin (PG) F(2alpha) secretion, in enriched cultures of pig endometrial luminal epithelial, glandular epithelial and stromal cells obtained on Day 16 (Experiments 1, 2 and 4) or Day 12 (Experiment 3) after oestrus. In Experiment 1, acute treatment with progesterone stimulated PGF(2alpha) secretion from each cell type on Day 16, whereas acute oestradiol treatment inhibited the stimulatory action of progesterone on PGF(2alpha) secretion only in glandular epithelial cells. In Experiment 2, OT stimulated phospholipase (PL) C activity in luminal epithelial cells on Day 16 only in the presence of chronic oestradiol treatment. For glandular epithelial cells on Day 16, OT stimulated PLC activity only in the presence of chronic treatment with steroid. In stromal cells on Day 16, OT stimulated PLC activity in the absence of steroids and the response to OT was further enhanced by oestradiol. In the absence of chronic treatment with steroid, OT did not stimulate PGF(2alpha) secretion from luminal epithelial cells, but oestradiol induced a response to OT. For glandular epithelial cells, OT-induced PGF(2alpha) secretion was not altered by steroids, whereas the stimulatory response to OT was inhibited by oestradiol or progesterone in stromal cells. For endometrial cells obtained on Day 12 aft




Am J Physiol Lung Cell Mol Physiol. 2004 Apr;286(4):L694-700. Epub 2003 Aug 15.
Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic signaling pathways.

Yu J, Astrinidis A, Howard S, Henske EP.

Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111, USA.

Lymphangioleiomyomatosis (LAM) is a progressive lung disease affecting almost exclusively women. The reasons for this strong gender predisposition are poorly understood. Renal angiomyolipomas occur in 50-60% of sporadic LAM patients. The smooth muscle cells of pulmonary LAM and renal angiomyolipomas are nearly indistinguishable morphologically. Here, we report the first successful cell culture of a LAM-associated renal angiomyolipoma. The cells carried inactivating mutations in both alleles of the TSC2 gene and expressed estrogen receptor , estrogen receptor , and androgen receptor. To elucidate the cellular pathways through which steroid hormones influence LAM pathogenesis, we treated the cells with both estradiol and tamoxifen. Cell growth was stimulated by estradiol, associated with phosphorylation of p44/42 MAPK at 5 min and an increase in c-myc expression at 4 h. Tamoxifen citrate also stimulated cell growth, associated with increased phosphorylation of p44/42 MAPK and expression of c-myc, indicating that tamoxifen has agonist effects on angiomyolipoma cells. This response to tamoxifen in human angiomyolipoma cells differs from prior studies of Eker rat leiomyoma cells, possibly reflecting cell type or species differences in cells lacking tuberin. Our data provide the first evidence that estradiol stimulates the growth of angiomyolipoma cells, that tamoxifen has agonist effects in angiomyolipoma cells, and that estradiol and tamoxifen impact both genomic and nongenomic signaling pathways in angiomyolipoma cells. The responsiveness of angiomyolipoma cells to estradiol may be related to the underlying reasons that LAM affects primarily women.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12922981&dopt=Abstract estradiol




Eur J Neurosci. 2003 Aug;18(4):923-30.
An antagonist of estrogen receptors blocks the induction of adult neurogenesis by insulin-like growth factor-I in the dentate gyrus of adult female rat.

Perez-Martin M, Azcoitia I, Trejo JL, Sierra A, Garcia-Segura LM.

Instituto Cajal, C.S.I.C., E-28002 Madrid, Spain.

Interdependence between estradiol and insulin-like growth factor-I has been documented for different neural events, including neuronal differentiation, synaptic plasticity, neuroendocrine regulation and neuroprotection. In the present study we have assessed whether both factors interact in the regulation of neurogenesis in the adult rat dentate gyrus. Wistar albino female rats were bilaterally ovariectomized and treated with estradiol, insulin-like growth factor-I and/or the estrogen receptor antagonist ICI 182,780. Estradiol was administered in a subcutaneous silastic capsule. Insulin-like growth factor-I and ICI 182,780 were delivered in the lateral cerebral ventricle. Animals received six daily injections of 5-bromo-2-deoxyuridine and were killed 24 h after the last injection. The total number of 5-bromo-2-deoxyuridine-positive neurons was significantly increased in animals treated with insulin-like growth factor-I, compared with rats treated with vehicles, while rats treated with both insulin-like growth factor-I and estradiol showed a higher number of 5-bromo-2-deoxyuridine-positive neurons than rats treated with insulin-like growth factor-I or estradiol alone. The antiestrogen ICI 182,780 blocked the effect of insulin-like growth factor-I on the number of 5-bromo-2-deoxyuridine neurons with independence of whether the animals were treated or not with estradiol. These findings suggest that estrogen receptors are involved in the induction of adult neurogenesis by insulin-like growth factor-I in the dentate gyrus, and that estradiol and insulin-like growth factor-I have a cooperative interaction to promote neurogenesis. The interaction between insulin-like growth factor-I and estradio




Anticancer Res. 2003 Jul-Aug;23(4):3207-13.
Estradiol and progesterone can prevent rat mammary cancer when administered concomitantly with carcinogen but do not modify surviving tumor histology, estrogen receptor alpha status or Ha-ras mutation frequency.

Swanson SM, Christov K.

Department of Medicinal Chemistry & Pharmacognosy, Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612-7231, USA. swansoic.edu

An early full-term pregnancy is protective against mammary cancer in both humans and rodents. Treating rats with two hormones of pregnancy, estradiol and progesterone, for 5 weeks renders the rat mammary glands refractory to carcinogenesis. Our objectives was to determine if a shortened regimen (3 weeks) would be as effective as the 5-week regimen and to determine if the mammary gland was vulnerable to carcinogenic insult during the hormone treatments. We also examined cancers that survived the chemopreventive regimen to see if those tumors were particularly aggressive compared to control tumors (i.e., less differentiated, estrogen receptor alpha (ER alpha)-negative or harbored mutations in Ha-ras). In the first experiment, Lewis rats were injected with N-methyl-N-nitrosourea (MNU, 50 mg/kg) at 50 days of age. At 60 days of age, the rats were either mated and allowed to nurse their young for 3 weeks, treated with hormone vehicle for 5 weeks, or 17 beta-estradiol (E, 20 micrograms) and progesterone (P, 4 mg) 5 times per week for 3 or 5 weeks. All the rats exposed to MNU but not estradiol and progesterone developed multiple mammary cancers. Pregnancy reduced multiplicity to 0.40 cancers/rat. Treatments of estradiol and progesterone for 3 or 5 weeks reduced cancer multiplicity and increased latency to a similar degree as pregnancy. Mammary cancers from each group displayed a similar spectra of histologic class, estrogen receptor alpha (ER alpha) content and Ha-ras mutation status. In the second experimen




Angiology. 2003 Jul-Aug;54(4):391-9.
The effects of transdermal estradiol alone or with cyclical dydrogesterone on markers of cardiovascular disease risk in postmenopausal women with type 2 diabetes: a pilot study.

Stojanovic ND, Kwong P, Byrne DJ, Arnold A, Jagroop IA, Nair D, Press M, Hurel S, Mikhailidis DP, Prelevic GM.

Department of Medicine, Royal Free and University College Medical School, London, UK.

The objective of this open, longitudinal, controlled study was to assess the effect of transdermal estradiol alone or combined with cyclical dydrogesterone on the markers of cardiovascular disease (CVD) risk in postmenopausal women with type 2 diabetes. The control group consisted of postmenopausal diabetic women who declined menopausal hormone replacement therapy (HRT). Twenty-eight postmenopausal women (19 on HRT and 9 controls) with type 2 diabetes were followed up for 12 months. From the active treatment group 14 women with a uterus in situ had 80 microg/24 hr transdermal estradiol (Fematrix 80; Solvay Healthcare Ltd, Southampton, UK) and oral dydrogesterone 10 mg daily for the first 12 days of the calendar month, whereas 5 women with previous hysterectomy had 80 microg/24 hr transdermal estradiol (Fematrix 80) alone. CVD risk markers were measured before and at regular intervals after starting HRT. The main outcome measures were weight, systolic and diastolic blood pressure, fasting plasma glucose, glycated hemoglobin (HbA1c), glucose/insulin ratio, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein (a), high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and endothelin-1. Transdermal estradiol with or without dydrogesterone in women with type 2 diabetes did not adversely affect any of the measured markers of cardiovascular risk. There was a significant decrease in HbA1c, total cholesterol, and LDL cholesterol at 6 months in women receiving HRT. Some of the cardiovascular disease risk markers




J Anat. 2003 May;202(5):445-52.
Effects of sex hormones on the development of giant lysosomes in the proximal tubules of DBA/2Cr mouse kidney.

Yabuki A, Suzuki S, Matsumoto M, Nishinakagawa H.

Department of Veterinary Anatomy, Faculty of Agriculture, Kagoshima University, Korimoto, Kagoshima, Japan. yabet.agri.kagoshima-u.ac.jp

The DBA/2Cr mouse strain is characterized by giant lysosomes that are located in the proximal convoluted tubules of males and in the proximal straight tubules of females. In the present study, we used light microscopy and electron microscopy to investigate the effects of sex hormones on the development of these giant lysosomes. In the proximal convoluted tubules of males, giant lysosomes (large vacuolar structures observed under light microscopy) disappeared after orchiectomy but reappeared after testosterone treatment. No changes were observed after ovariectomy or estradiol treatment. In the proximal straight tubules of females, giant lysosomes (periodic acid Schiff-positive giant granules observed under light microscopy) disappeared after ovariectomy but reappeared after estradiol treatment. After orchiectomy and testosterone treatment, the giant lysosomes did not appear. However, a number of small lysosomes (smaller than a nucleus), which were periodic acid Schiff-positive, increased after orchiectomy and decreased after testosterone treatment. These findings suggest that lysosomes in DBA/2Cr mice are regulated by testosterone or estradiol as follows: (1) in the proximal convoluted tubules, the development of lysosomes is stimulated by testosterone but not by estradiol; (2) in the proximal straight tubules, development of lysosomes is stimulated by estradiol and inhibited by testosterone.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12739621&dopt=Abstract estradiol




Endocrinology. 2003 Jun;144(6):2350-9.
Estradiol exacerbates hippocampal damage in a model of preterm infant brain injury.

Nunez JL, McCarthy MM.

Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. jnune00maryland.edu

We have developed a model for prenatal hypoxia-ischemia in which muscimol, a selective gamma-aminobutyric acid A (GABA(A)) receptor agonist, administered to newborn rats, induces hippocampal damage. In the neonatal rat brain, activation of GABA(A) receptors leads to membrane depolarization and neuronal excitation. Because of our previous detection of sex differences in this model and the considerable interest in the neuroprotective effects of estradiol in the adult brain, we now investigate the effect of pretreatment with high physiological levels of estradiol in our model of prenatal hypoxia-ischemia. We used unbiased stereology to assess neuron number in the hippocampal formation of control, muscimol-treated, and estradiol- plus muscimol-treated animals. Muscimol decreased neuron number in the hippocampus, with damage exacerbated by pretreatment with estradiol. A hippocampal culture paradigm was developed to mirror the in vivo investigation. We observed elevated cytotoxicity (using the lactate dehydrogenase assay) by 48 h after treatment with estradiol plus muscimol, but decreased cytotoxicity between 2 and 24 h after treatment. To determine whether the actions of estradiol on muscimol-induced damage were via the estrogen receptor, hippocampal cultures were pretreated with ICI 182,780, a selective estrogen receptor antagonist. Treatment with ICI 182,780 blocked the potentiating effect of estradiol on the late period of cytotoxicity, but had no effect on the protective actions of estradiol during the early period of cytotoxicity. There appears to be a biphasic action of estradiol in our model of neonatal brain injury that involves early nongenomic, nonreceptor-mediated protection, followed by late deleterious receptor-media




Am J Obstet Gynecol. 2003 May;188(5):1132-40.
Contrasting effects of two hormone replacement therapies on the cardiovascular and mammary gland outcomes in surgically postmenopausal monkeys.

Suparto IH, Williams JK, Cline JM, Anthony MS, Fox JL.

Comparative Medicine Clinical Research Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA .

OBJECTIVE: The purpose of this study was to compare the effects of two hormone replacement therapies on the intermediate end points of coronary heart disease and mammary gland hyperplasia in postmenopausal monkeys.Study Design: Surgically postmenopausal cynomolgus monkeys were fed an atherogenic diet for 12 months while receiving no treatment (control, n = 19), conjugated equine estrogens plus continuous medroxyprogesterone acetate (n = 19), or ethinyl estradiol plus norethindrone acetate (n = 21) at doses that were scaled from those doses taken by women. RESULTS: Quantitative coronary angiography revealed that the arteries of the control group and the conjugated equine estrogens plus continuous medroxyprogesterone acetate-treated animals constricted in response to acetylcholine (-5.4% +/- 1.4% and -6.2% +/- 1.5%, respectively), whereas those arteries in the animals in the ethinyl estradiol plus norethindrone acetate group did not (P =.002). The incidence of dobutamine-induced ST-segment depression in the ethinyl estradiol plus norethindrone acetate group (10.5%) was significantly less than in the control group (68.8%, P =.001) or the conjugated equine estrogens plus continuous medroxyprogesterone acetate group (50%, P =.01). Conjugated equine estrogens plus continuous medroxyprogesterone acetate, but not ethinyl estradiol plus norethindrone acetate, induced diffuse epithelial tissue proliferation in the mammary glands (P =.0006). CONCLUSION: Ethinyl estradiol plus norethindrone acetate protected against atherosclerosis-induced endothelium-mediated vasoconstriction of coronary arteries and heart rate-induced myo



Ceska Gynekol. 2003 Mar;68(2):117-21.
[Does grapefruit juice increase the bioavailability of orally administered sex steroids?]

[Article in Czech]

Fingerova H, Oborna I, Petrova P, Budikova M, Jezdinsky J.

Klinika porodnictvi a gynekologie LF UP v Olomouci.

OBJECTIVE: To verify if and to which extent the interaction with grapefruit juice can increase bioavailability of orally administered sexual steroids. DESIGN: Pilot pharmacokinetics study. SETTING: Department of Obstetrics and Gynecology and Institute of Pharmacology, Medical Faculty, Palacky University, Olomouc; Department of Nuclear Medicine, University Hospital, Olomouc. METHODS: 2 mg of estradiol valerate and 100 mg of micronized progesterone were given to eight healthy postmenopausal volunteers. Blood samples were collected at time 0, 2, 3, 5 and 24 hours after tablets application. The same trial was repeated a week later but tablets were swallowed with 200 ml of grapefruit juice. Serum levels of estradiol and progesterone were measured by RIA. Results were statistically evaluated using the Wilcoxon's nonparametric paired test. RESULTS: Though grapefruit juice on average slightly increased serum levels of estradiol (E2) and progesterone, this increase reached statistical significance only for the E2 level 24 hours after application of tablets. The mean area under curve (AUC) of estradiol rose significantly to 117%. The even greater increase in the mean AUC of progesterone (to 125%) was not statistically significant because of marked individual variability of response. CONCLUSIONS: Our results suggest that grapefruit juice may increase bioavailability of orally administered estradiol and progesterone. The response varies markedly between individuals. This observation may be of some importance also for users of OC and HRT.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12749182&dopt=Abstract estradiol