High Doses Of Estradiol Research Articles

Outcomes in in vitro fertilization (IVF) cycles which display dysynchronous follicular growth

Diminished ovarian reserve can cause advanced follicular recruitment (dysynchrony) due to inappropriate rises of FSH during the luteal phase. Dysynchrony is considered poor prognosis. Previous data have shown that high dose estradiol during the preceding luteal phase can synchronize the follicular cohort. Though there is no precise definition of dysynchrony during in vitro fertilization cycles, it can be defined as one follicle significantly larger than the remaining cohort on stimulation day 6 (early), or when the two lead follicles reach maturity two days prior to the cohort reaching maturity (late). This study tried to determine: 1) the frequency of dysynchronous cycles, 2) to see if dysynchrony causes lower pregnancy and live-birth rates. Retrospective chart review of all couples undergoing in vitro fertilization with microdose agonist protocol. We compared two groups. Group A had early dysynchrony: 1 follicle ≥4 mm ahead of the cohort at first ultrasound (stimulation day 6); or late dysynchrony: 1–2 follicles reaching maturity (mean diameter 18 mm3) two or more days prior to the cohort reaching maturity. Group B: all other patients. The student t-test was used for continuous variables and Chi-Square for non-parametric data. 227 microdose GnRHa cycles were evaluated from 2003 through 2006. Dysynchrony occured in 1 out of 4 IVF cycles. There were no differences in average age of the female partner, primary diagnosis, antral follicle count, cycle day 3 estradiol, gonadotropin dose, cycle cancellation, or pregnancy rates among groups. Women displaying dysynchrony had slightly higher cycle day 3 FSH values; however, cycle day 3 FSH did not predict dysynchrony. Dysynchronous cycles had fewer eggs retrieved (7.4 ± 5.0, vs. 10.3 ± 7.1, P≤.05). Dysynchronous cycles showed trends for fewer grade 1–2 embryos available for transfer on post-retrieval day 3 (2.3 ± 2.5 vs. 3.0 ± 3.1, P=.08) and lower live-birth rates, compared to cycles without dysynchrony, (23% vs. 29%, P=0.29). In our population, dysynchrony occured in 1 of 4 women undergoing stimulation with the microdose GnRHa protocol for advanced maternal age or diminished ovarian reserve. Currently there is not enough evidence to say that dysynchrony leads to lower live-birth or pregnancy rates. Therefore, cycles displaying these characteristics do not need to be cancelled for dysynchrony alone. High-dose luteal estradiol to suppress FSH is not inidicated.

Low- vs High-Dose Estradiol Vaginal Ring in Treatment of Sexual Difficulties

Low- vs High-Dose Estradiol Vaginal Ring in Treatment of Sexual Difficulties

Low- vs High-Dose Estradiol Vaginal Ring in Treatment of Sexual Difficulties—Reply

Low- vs High-Dose Estradiol Vaginal Ring in Treatment of Sexual Difficulties—Reply

Diverse physiological consequences of long-term sucrose consumption in female rats

Although a considerable amount of work has addressed the short-term consequences of sucrose ingestion on a variety of morphological, physiological and hematological measures, relatively few studies have investigated these parameters following long-term sucrose intake. Results of the present experiments indicated that female rats given ad libitum access to a 10% sucrose solution for 9 months were conspicuously larger and had significantly heavier thyroid and spleen weights compared to rats offered either a restricted (20 min) daily sucrose option or control rats given only water. Rats given free access to sucrose also displayed abnormal serum levels of creatinine, sodium, phosphorus, alkaline phosphatase, alanine aminotransferase, uric acid and cholesterol which could indicate dysfunction in many organs including the kidney and liver. In the brain, however, chronic sucrose access was not associated with any discernable changes in neuronal or glial cell density within selected brain regions, but brain weight was found to be highly negatively correlated (r = −0.97) with total sucrose intake. Finally, we report that high doses of estradiol can significantly attenuate the intake of sucrose in female rats. Together these findings demonstrate that free access to a sucrose solution for long periods can induce profound effects on rat physiology and may have important implications for the management of diet in humans.

Tritrichomonas foetus: Pathogenesis of acute infection in normal, estradiol-treated, and stressed mice

Environmental stress and endocrine control can affect pathogenesis of sexually transmitted diseases such as trichomoniasis. Acute Tritrichomonas foetus infection was compared in female BALB/c mice to infections in mice treated with high doses of estradiol or housed in constant bright illumination (stressed). In untreated mice, T. foetus readily colonized the reproductive tract, causing minimal epithelial damage and inflammation. Several fold increases of IFN-γ, TNF-α, MCP-1, and IL-6 cytokines were detected after estradiol-treatment of mice, resulting in greatly enhanced inflammation and tissue damage throughout the reproductive tract. Interestingly, estradiol-treatment of mice resulted in reduced T. foetus colonization compared to untreated mice. Infection in stressed mice resulted in increased tissue damage, inflammation, and inflammatory cytokine expression, although parasite colonization within the reproductive tract was similar to that in untreated mice. These results indicate that either estradiol-treatment or stress result in pathogenesis often observed during severe disease. Alternatively, infection in non-treated mice results in chronic colonization, with little inflammation or pathology.

Impairment of spatial learning by estradiol treatment in female mice is attenuated by estradiol exposure during development

High doses of estradiol (E 2) can impair spatial learning in the Morris water maze, in ovariectomized mice, but the same dose has no effect on adult castrated males. Here, we test the hypothesis that this sex difference is caused by neonatal actions of E 2. In Experiment 1, C57BL/6J pups were given daily estradiol benzoate (EB) or oil injections from the day of birth until postnatal Day 3. Adults were gonadectomized and received EB (s.c.) or oil 28 h before the first day of training, and 4 h before each of four daily training sessions on the Morris water maze. Females given oil as neonates, and EB prior to training displayed the poorest performance. Females that received EB as neonates and EB prior to training were insensitive to the deleterious effects of adult EB and performed better than males given the same hormone treatments. We conducted a second experiment using aromatase enzyme knockout (ArKO) mice. Adult male and female ArKO and wild-type (WT) littermates were gonadectomized and received either injections of oil or EB prior to and during water maze training (as described above). Hormone treatment failed to affect performance, yet, female but not male ArKO mice showed impaired learning compared to WT littermates. Thus, exposure to estradiol during neonatal development can counteract the deleterious effects of EB on adult spatial learning.

High-dose 17β–estradiol treatment prevents development of heart failure post–myocardial infarction in the rat

Prognosis of heart failure remains poor despite therapeutic advances, such as angiotensin converting enzyme inhibition or beta-receptor blockade. Thus, more effective forms of treatment are urgently needed. Since estrogens have been shown to modulate migration and proliferation of cardiac fibroblasts and to modulate the expression of estrogen receptors of cardiomyocytes we examined whether high-dose estrogen treatment can affect post-myocardial infarction left ventricular remodeling. Female rats were treated with 17beta-estradiol (7.5 mg/90 d) or placebo for ten weeks, starting two weeks prior to experimental myocardial infarction. Eight weeks after infarction, in vivo echocardiographic and hemodynamic measurements as well as isolated heart perfusion were performed. In vivo, chronic estrogen treatment almost completely prevented the development of all signs of heart failure that occur in untreated infarcted hearts, such as increased left ventricular diameters (dilatation), reduced fractional shortening (systolic dysfunction) or increased left ventricular end-diastolic pressure (diastolic dysfunction). In vitro, the right- (indicating structural dilatation) and downward (indicating left ventricular dysfunction) shift of left ventricular pressure-volume curves occurring in untreated infarcted hearts was completely prevented by estrogen. High dose estradiol treatment prevented development of post-MI remodeling, as assessed by in vivo and in vitro parameters of LV dysfunction. Estrogen may hold the potential of becoming a new form of heart failure treatment.However, the mechanisms responsible for this striking and unexpected beneficial action of estrogen in heart failure remain to be elucidated.

Sex Steroids Are Involved in the Regulation of Gonadotropin-Releasing Hormone and Dopamine D2 Receptors in Female Tilapia Pituitary1

Although molecular mechanisms underlying steroid effects on GnRH and dopamine receptors are well documented in mammals, little is known in fish. Herein, we describe the expression of pituitary GnRH and dopamine receptors relative to gonadotropin expression and release. We exposed female tilapia to graded doses of estradiol or 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP) in vitro, and of estradiol in vivo, and determined mRNA levels of gnrhr1, gnrhr3, drd2, lhb, and fshb by real-time PCR. We also determined gonadotropin levels using specific ELISAs. Exposure to low doses of estradiol caused increased gnrhr3 mRNA levels in vivo and in vitro, probably related to positive feedback on FSH release. Increasing concentrations of estradiol resulted in increased drd2 mRNA levels in vivo and in vitro, inhibition of LH and FSH release, and inhibition of lhb mRNA levels in vivo, possibly related to negative feedback. At high doses of estradiol, FSH release increased in preparation for a new generation of follicles. Exposure to nanomolar doses of DHP resulted in increased drd2 mRNA levels, probably related to negative feedback on LH release. A decrease in drd2 levels at the micromolar range of DHP (concomitant with increased gnrhr3 and fshb mRNA levels) may be related to the recruitment of a new generation of oocytes. Exposure to DHP also resulted in increased lhb mRNA levels toward final oocyte maturation. Salmon GnRH analog (sGnRHa) increased mRNA levels of gnrh1and gnrh3; when combined with DHP, sGnRHa synergistically increased expression of gnrh3 only. These results emphasize the role of sex steroids on positive and negative feedbacks controlling the reproductive cycle.

Estrogen effects on thyroid iodide uptake and thyroperoxidase activity in normal and ovariectomized rats

Sex steroids interfere with the pituitary–thyroid axis function, although the reports have been controversial and no conclusive data is available. Some previous reports indicate that estradiol might also regulate thyroid function through a direct action on the thyrocytes. In this report, we examined the effects of low and high doses of estradiol administered to control and ovariectomized adult female rats and to pre-pubertal females. We demonstrate that estradiol administration to both intact adult and pre-pubertal females causes a significant increase in the relative thyroid weight. Serum T3 is significantly decreased in ovariectomized rats, and is normalized by estrogen replacement. Neither doses of estrogen produced a significant change in serum TSH and total T4 in ovariectomized, adult intact and pre-pubertal rats. The highest, supraphysiological, estradiol dose produced a significant increase in thyroid iodide uptake in ovariectomized and in pre-pubertal rats, but not in control adult females. Thyroperoxidase activity was significantly higher in intact adult rats treated with both estradiol doses and in ovariectomized rats treated with the highest estradiol dose. Since serum TSH levels were not significantly changed, we suggest a direct action of estradiol on the thyroid gland, which depends on the age and on the previous gonad status of the animal.

Lipopolysaccharide-Induced IL-1β Production by Human Uterine Macrophages Up-Regulates Uterine Epithelial Cell Expression of Human β-Defensin 2

The uterine endometrium coordinates a wide spectrum of physiologic and immunologic functions, including endometrial receptivity and implantation as well as defense against sexually transmitted pathogens. Macrophages and epithelial cells cooperatively mediate innate host defense against bacterial invasion through the generation of immunologic effectors, including cytokines and antimicrobial peptides. In this study, we demonstrate that stimulation of peripheral blood monocytes and uterine macrophages with bacterial LPS induces the production of biologically active proinflammatory IL-1beta. High doses of estradiol enhance LPS-induced IL-1beta expression in an estrogen receptor-dependent manner. Furthermore, both peripheral blood monocyte- and uterine macrophage-derived IL-1beta induce secretion of antimicrobial human beta-defensin 2 by uterine epithelial cells. These data indicate dynamic immunologic interaction between uterine macrophages and epithelial cells and implicate a role for estradiol in the modulation of the immune response.

Effects of Estradiol and Progesterone on Gastric Mucosal Response to Early Helicobacter pylori Infection in Female Gerbils

Gender differences have been shown regarding the changes in the inflammatory response, gastrin secretion, and gastric acidity during Helicobacter pylori infection. To investigate the role of estradiol and progesterone in the changes of the gastric mucosa induced by H. pylori during the early stage of infection in female gerbils. Thirty-three adult ovariectomized female gerbils were infected with H. pylori (SS1); 7 days after infection they were treated with low and high doses of estradiol (50 and 250 microg/60 days pellet), progesterone (15 and 50 mg/60 days pellet) and vehicle. Non-ovariectomized infected gerbils were used as control. Gerbils were euthanized after 6 weeks of infection. Histologic evaluation, immunohistochemical detection of proliferation cell nuclear antigen (PCNA), gastrin, and apoptosis by terminal deoxynucleotide nick end labeling (TUNEL) assay were performed. Positive cells for PCNA, TUNEL, and gastrin were counted in 10 oriented glands per animal. Two-sided p = .05 was considered significant. Estradiol-treated groups showed more intense and extended acute and follicular gastritis compared to the vehicle group, whereas progesterone-treated groups presented less gastritis than the other groups. Proliferation and apoptosis indexes were significantly lower in the vehicle group when compared with those of the control; both indexes were increased in the high-dose estradiol and progesterone groups as compared with those of the vehicle. Grade I nonmetaplastic atrophy was observed in the vehicle and progesterone groups. The high-dose progesterone group showed a significant reduction in the number of gastrin cells. Estradiol and progesterone participate in the gastric mucosal response to early H. pylori infection in gerbils.

Rapid changes in production and behavioral action of estrogens

It is well established that sex steroid hormones bind to nuclear receptors, which then act as transcription factors to control brain sexual differentiation and the activation of sexual behaviors. Estrogens locally produced in the brain exert their behavioral effects in this way but mounting evidence indicates that estrogens also can influence brain functioning more rapidly via non-genomic mechanisms. We recently reported that, in Japanese quail, the activity of preoptic estrogen synthase (aromatase) can be modulated quite rapidly (within minutes) by non-genomic mechanisms, including calcium-dependent phosphorylations. Behavioral studies further demonstrated that rapid changes in estrogen bioavailability, resulting either from a single injection of a high dose of estradiol or from the acute inhibition of aromatase activity, significantly affect the expression of both appetitive and consummatory aspects of male sexual behavior with latencies ranging between 15 and 30 min. Together these data indicate that the bioavailability of estrogens in the brain can change on different time-scales (long- and short-term) that match well with the genomic and non-genomic actions of this steroid and underlie two complementary mechanisms through which estrogens modulate behavior. Estrogens produced locally in the brain should therefore be considered not only as neuroactive steroids but they also display many (if not all) functional characteristics of neuromodulators and perhaps neurotransmitters.

The Hormonal Control of Uterine Luminal Fluid Secretion and Absorption

The secretion of uterine luminal fluid initially provides a transport and support medium for spermatozoa and unimplanted embryos, while the absorption of uterine luminal fluid in early pregnancy results in the closure of the lumen and allows blastocysts to establish intimate contact with the uterine epithelium. We have established an in vivo perfusion technique of the lumen to study the hormonal control of the events in the peri-implantation period. Fluorescein-labelled dextran was included in the perfusion medium to monitor fluid movements and the concentrations of Na(+) and CI(-) ions in the effluent were monitored. Using an established regimen of steroid treatment of ovariectomized rats mimicking early pregnancy, oestradiol caused fluid secretion, while progesterone resulted in an amiloride-sensitive fluid absorption. Fluid absorption peaked at about the expected time of implantation. The effect of progesterone could be inhibited by treatment with a high dose of oestradiol, by the anti-progestin RU486, and by the presence of an intra-uterine contraceptive device. Studies of expression of Na(+) and CI(-) channels (ENaC, CFTR) indicated that these channels were subject to tissue-specific regulation within the uterus, but more work is required to determine their role and the factors controlling their abundance and localization in early pregnancy.

The establishment of the hemangioma model in nude mouse

Background/Purpose Hemangioma is one of the most common benign tumors in children. Most of them could regress spontaneously; however, the pathogenesis and triggering of regression are still unknown. Here, we introduce a new means in which the specimen of human hemangioma was transplanted into nude mice subcutaneously. At the same time, high dose of estradiol was administered to the experimental nude mice intramuscularly to promote implantation and proliferation of hemangioma endothelial cells. By this means, a credible animal model of human hemangioma was established. Further studies on pathogenesis and medical intervention of hemangioma could be carried on with this model. Methods The specimen of grafted hemangioma was taken from a 6-month-old girl, in whom the hemangioma grew rapidly, by surgery. The fresh estrogen receptor–positive strawberry hemangioma specimens were sliced and inoculated subcutaneously into 16 nude mice that were divided randomly into 2 groups, namely, group 1 (n = 8) with normal diet and group 2 (n = 8) with normal diet and 10 −7 mg estradiol administered intramuscularly every week additionally. The size of grafts was measured weekly. All of the experimental mice were killed at 90 days after graft. Hemangioma tissues were harvested and sliced into 4 to 5 μm sections. Living grafts were subjected to histopathologic examination and immunohistochemistry for CD34 and Ki-67. Results All of the sizes of hemangioma tissues in group 1 were diminished distinctly in 30 days. Thirteen samples of hemangioma were almost absorbed and disappeared completely in 90 days. The sizes of hemangioma in group 2 were larger than primary specimens. It was observed from the section of hemangioma that endothelial cells proliferate vividly and fresh capillary blood vessels grew up into the body of hemangioma. The mean positive cell rate of CD34 in group 2 was 48.49 ± 3.90 and the Ki-67 was 15.04 ± 2.44. The transplanted tumor cell retained the histologic characters of original tumor. Conclusion The capillary hemangioma model established in nude mice retains almost all the biologic character of original human hemangioma and could be widely used in further study on hemangioma.

Characterization of Osteocrin Expression in Human Bone

Osteocrin (Ostn), a bone-active molecule, has been shown in animals to be highly expressed in cells of the osteoblast lineage. We have characterized this protein in human cultured primary human osteoblasts, in developing human neonatal bone, and in iliac crest bone biopsies from adult women. In vivo, Ostn expression was localized in developing human neonatal rib bone, with intense immunoreactivity in osteoblasts on bone-forming surfaces, in newly incorporated osteocytes, and in some late hypertrophic chondrocytes. In adult bone, Ostn expression was specifically localized to osteoblasts and young osteocytes at bone-forming sites. In vitro, Ostn expression decreased time dependently (p<0.02) in osteoblasts cultured for 2, 3, and 6 days. Expression was further decreased in cultures containing 200 nM hydrocortisone by 1.5-, 2.3-, and 3.1-fold (p<0.05) at the same time points. In contrast, alkaline phosphatase expression increased with osteoblast differentiation (p<0.05). Low-dose estradiol decreased Ostn expression time dependently (p<0.05), whereas Ostn expression in cultures treated with high-dose estradiol was not significantly changed. These results demonstrate that Ostn is expressed in human skeletal tissue, particularly in osteoblasts in developing bone and at sites of bone remodeling, suggesting a role in bone formation. Thus, Ostn provides a marker of osteoblast lineage cells and appears to correlate with osteoblast activity.

Influence of estrogen therapy at conventional and high doses on the degree of mineralization of iliac bone tissue: a quantitative microradiographic analysis in postmenopausal women

The beneficial skeletal effects of menopausal estrogen replacement therapy (HRT) are well documented. The role of secondary mineralization of bone as a determinant of bone quality is now well established in postmenopausal women treated with bisphosphonates or SERMs. The aim of present study was to investigate the effect of conventional and high doses of estrogen on the main parameters reflecting the degree of mineralization of bone (DMB). Bone biopsies were obtained from 20 women with osteopenia or osteoporosis before and after 24 months (18 to 38 months) of conventional HRT, and from 19 women who had received high doses of estradiol (implant 100 mg every 3–6 months for 1.5–20 years). DMB parameters (mean DMB, DMB Freq. Max. and Heterogeneity Index of the individual distributions of DMB) were measured using quantitative microradiography in cortical, cancellous, and total bone and expressed as g mineral/cm 3 bone. Values obtained in women before HRT were lower than those reported in pre- and postmenopausal control women. After conventional HRT, there was an increase in mean DMB (total bone) of 4.4 ± 1.9% (mean ± SEM) versus pre-treatment values (4.1 ± 2.1% in cortical bone, 4.5 ± 2.3% in cancellous bone); these differences did not reach statistical significance ( P = 0.055). Results were similar for DMB Freq. Max. but Heterogeneity Index was not significantly changed. After high dose estradiol therapy, mean DMB (total bone) was 6.9 ± 1.9% higher than in untreated women (8.6 ± 2.1% in cortical bone, 6.5 ± 2.1% in cancellous bone); this difference was statistically significant ( P ≤ 0.03). Results were similar for DMB Freq. Max. but once again Heterogeneity Index was not significantly modified. The increases in mean DMB were due to a shift of the curves towards high DMB with a decrease of the low DMB values, as confirmed by the absence of changes in the Heterogeneity Index. Estrogen therapy is associated with an increased degree of mineralization of bone induced by a prolongation of secondary mineralization, similar to that observed with other antiresorptive agents. However, this increase was about two-fold lower than that observed after alendronate therapy (10 mg/day/3 years) in postmenopausal osteoporotic women.

The 17alpha and 17beta isomers of estradiol both induce rapid spine synapse formation in the CA1 hippocampal subfield of ovariectomized female rats.

Previous studies have demonstrated that estradiol-17beta and estradiol-17alpha both induce short-latency effects on spatial memory in rats, estradiol-17alpha being at least as potent as its 17beta isomer. To determine whether the mechanisms underlying these behavioral responses might include effects on hippocampal synaptic plasticity, CA1 pyramidal spine synapse density (PSSD) was measured in ovariectomized rats within the first few hours after s.c. estrogen injection. PSSD increased markedly (by 24%) 4.5 h after the administration of 45 microg/kg estradiol-17beta. The PSSD response was significantly greater (44% above control) 30 min after estradiol-17beta injection and was markedly dose dependent; a 3-fold lower estradiol-17beta dose (15 microg/kg) did not significantly affect CA1 PSSD at either 30 min or 4.5 h. Estradiol-17alpha was a more potent inducer of PSSD than estradiol-17beta. Dose-response analysis determined an ED50 for the effect of estradiol-17alpha on PSSD of 8.92 +/- 1.99 microg/kg, with a maximal response at 15 microg/kg. These results demonstrate that high doses of estradiol induce rapid changes in CA1 PSSD. CA1 spine synapse formation appears to be more sensitive to estradiol-17alpha than to estradiol-17beta, paralleling previous data on the effects of these two steroids on spatial memory. Rapid remodeling of hippocampal synaptic connections may thus contribute to the enhancement of spatial mnemonic processing observed within the first few hours after estrogen treatment. The potency of estradiol-17alpha suggests that hormone replacement therapy using this steroid might be useful clinically in ameliorating the impact of low endogenous estrogen production on the development and progression of neurodegenerative disorders involving the hippocampus.

Dose- and photoperiod-dependent effects of 17 β-estradiol and the anti-estrogen ICI 182,780 on testicular structure, acceleration of spermatogenesis, and aromatase immunoexpression in immature bank voles

It has been known that administration of estrogens or deficiency of estrogens can affect development and/or maintenance of male gonadal functions. These hormones are able to control germ cell development, and especially spermatid production and epididymis sperm maturation. The aim of the present study was to show the effects of 17 β-estradiol and a pure anti-estrogen, ICI 182,780, on the bank vole testis. Immature bank voles reared under either short or long light cycles were injected intraperitoneally with two doses of either 17 β-estradiol (0.1 and 10 μg/g body weight, respectively) or pure anti-estrogen ICI 182,780 (10 and 100 μg/g body weight, respectively) both dissolved in 20 μl sesame oil. Control groups (from both photoperiods) received 20 μl sesame oil only. The injections were performed twice a week during 2 weeks. Exposure to the low dose of estradiol induced acceleration of the onset of spermatogenesis. This was particularly apparent in voles kept under short light cycle conditions. On the other hand, when males were treated with a high dose of estradiol or ICI 182,780, disruption of testicular structure and tubular atrophy were observed. Increased apoptosis of germ cells was evident. It is concluded that bank voles as seasonally breeding animals are a useful model for studying the role of estrogens in structure and function of the testis.

Sonic hedgehog-patched Gli signaling in the developing rat prostate gland: lobe-specific suppression by neonatal estrogens reduces ductal growth and branching

While prostate gland development is dependent on androgens, other hormones including retinoids and estrogens can influence this process. Brief exposure to high-dose estrogen during the neonatal period in rats leads to permanent, lobe-specific aberrations in the prostate gland, a phenomenon referred to as developmental estrogenization. We have previously shown that this response is mediated through alterations in steroid receptor expression; however, further downstream mechanisms remain unclear. Herein, we examined Sonic hedgehog ( Shh)-patched ( ptc)- gli in the developing rat prostate gland, its role in branching morphogenesis, and the effects of neonatal estrogens on its expression and localization to determine whether a disturbance in this signaling pathway is involved in mediating the estrogenized phenotype. Shh was expressed in epithelial cells at the distal tips of elongating ducts in discreet, heterogeneous foci, while ptc and gli1–3 were expressed in the adjacent mesenchymal cells in the developing gland. The addition of Shh protein to cultured neonatal prostates reduced ductal growth and branching, decreased Fgf10 transcript, and increased Bmp4 expression in the adjacent mesenchyme. Shh-induced growth suppression was reversed by exogenous Fgf10, but not noggin, indicating that Fgf10 suppression is the proximate cause of the growth inhibition. A model is proposed to show how highly localized Shh expression along with regulation of downstream morphogens participates in dichotomous branching during prostate morphogenesis. Neonatal exposure to high-dose estradiol suppressed Shh, ptc, gli1, and gli3 expressions and concomitantly blocked ductal branching in the dorsal and lateral prostate lobes specifically. In contrast, ventral lobe branching and Shh-ptc-gli expression were minimally affected by estrogen exposure. Organ culture studies with lateral prostates confirmed that estradiol suppressed Shh-ptc-gli expression directly at the prostatic level. Taken together, the present findings indicate that lobe-specific decreases in Shh-ptc-gli expression are involved in mediating estradiol-induced suppression of dorsal and lateral lobe ductal growth and branching during prostate morphogenesis.

Effect of high-dose estrogen on memory in men with prostate cancer

4650 Background: Estrogen replacement in women, and in female animal models, improves memory and changes the structure and physiology of relevant brain regions. Estrogen replacement in women improves long term verbal memory (hippocampal function) but may not affect short term working memory (prefrontal cortex function). Gonadectomy in male rats decreases synapse density in the hippocampus, a region important for long term memory. Testosterone, but not estrogen, replacement restores hippocampal synapse spine density. Testosterone supplementation in older men produces improvements in short term working memory. Little is known about the neural and cognitive effects of androgen suppression or estrogen therapy in men with prostate cancer. Methods: We compared the long term verbal memory (using the immediate and delayed Paragraph Recall test), and working memory (using Subject Ordered and Trails tests) of androgen-deprived men with androgen-independent prostate cancer before and 1 month after starting second-line hormonal therapy with transdermal estradiol 45.6 mg (six 7.6 mg patches) applied every 7 days. Results: Androgen deprived men treated with estradiol had a significant improvement in their paragraph recall performance but no change in working memory. Conclusions: High dose estradiol may have had beneficial but specific effects on cognitive performance. The mechanism of this effect is not clear. Previous studies have shown beneficial effects of testosterone on the brain and performance in androgen deprived male rats, but effects of estradiol have only been found for recovery of function after brain injury. Thus, the beneficial effects of estradiol in this study may be due to its use in combination with androgen suppression, disease and/or an aging brain. Further studies using additional cognitive measures and control subjects will further elucidate the brain and cognitive effects of estradiol in prostate cancer patients. No significant financial relationships to disclose.