D L Hess

Oregon Health and Science University, Portland, Oregon, United States

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Publications (83)401.87 Total impact

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    ABSTRACT: Estrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), although the mechanisms are unclear. We hypothesize that estrogen inhibits CRPC in anorchid animals by suppressing tumoral androgens, an effect independent of the estrogen receptor. The human CRPC xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo, 17beta-estradiol or 17beta-estradiol and estrogen receptor antagonist ICI 182,780. Effects of 17beta-estradiol on tumor growth were evaluated and tissue testosterone (T) and dihydrotestosterone (DHT) evaluated by mass spectrometry. Treatment of LuCaP 35V with 17beta-estradiol slowed tumor growth compared to controls (tumor volume at day 21: 785 +/- 81 mm3 vs. 1195 +/- 84 mm3, p = 0.002). Survival was also significantly improved in animals treated with 17beta-estradiol (p = 0.03). The addition of the estrogen receptor antagonist ICI 182,780 did not significantly change survival or growth. 17beta-estradiol in the presence and absence of ICI 182,780 suppressed tumor testosterone (T) and dihydrotestosterone (DHT) as assayed by mass spectrometry. Tissue androgens in placebo treated LuCaP 35V xenografts were; T = 0.71 +/- 0.28 pg/mg and DHT = 1.73 +/- 0.36 pg/mg. In 17beta-estradiol treated LuCaP35V xenografts the tissue androgens were, T = 0.20 +/- 0.10 pg/mg and DHT = 0.15 +/- 0.15 pg/mg, (p < 0.001 vs. controls). Levels of T and DHT in control liver tissue were < 0.2 pg/mg. CRPC in anorchid animals maintains tumoral androgen levels despite castration. 17beta-estradiol significantly suppressed tumor T and DHT and inhibits growth of CRPC in an estrogen receptor independent manner. The ability to manipulate tumoral androgens will be critical in the development and testing of agents targeting CRPC through tissue steroidogenesis.
    BMC Cancer 05/2010; 10:244. DOI:10.1186/1471-2407-10-244 · 3.32 Impact Factor
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    ABSTRACT: Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription-PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59-0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03-0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment.
    Cancer Research 06/2008; 68(11):4447-54. DOI:10.1158/0008-5472.CAN-08-0249 · 9.28 Impact Factor
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    ABSTRACT: This study was designed to evaluate the timecourse of ovarian and pituitary endocrine events throughout the menstrual cycle in the vervet monkey, and whether circulating luteinizing hormone (LH) or the uterus regulates the functional lifespan of the vervet corpus luteum. Daily saphenous blood samples were collected from adult females (1) during spontaneous menstrual cycles (n = 7), and (2) during cycles in which a gonadotropin-releasing hormone antagonist (acyline) was administered for 3 days at midluteal phase (n = 3), and (3) for 30 days following recovery from hysterectomy (n = 4). Estradiol (E) and progesterone (P) levels were assayed using electrochemoluminescent assays. Gonadotropin levels were measured by radioimmunoassay using reagents developed for the assay of follicle-stimulating hormone and LH in macaques. Spontaneous cycles exhibited a midcycle E rise (476+/-49 pg/ml), engendering an LH surge, 12+/-1 days after onset of menses, followed by a luteal phase with peak P levels of 4.7+/-0.9 ng/ml. Histologic evaluation of the ovaries at late follicular phase or early luteal phase revealed the presence of a single, large Graafian follicle or developing corpus luteum, respectively. Acyline treatment caused a significant (P<0.05) decline in P levels (2.9+/-0.5 vs 0.5+/-0.3 ng/ml, 0 vs 48 h post-treatment) and premature menstruation compared with untreated controls (P<0.05). Hysterectomy had no apparent effect on the monthly pattern or levels of circulating E or P. Thus, the characteristics and regulation of the ovarian cycle in vervets appear similar to those in women and macaques, with cyclicity dependent on pituitary gonadotropin hormones and independent of a uterine luteolytic factor.
    American Journal of Primatology 09/2007; 69(8):890-900. DOI:10.1002/ajp.20395 · 2.14 Impact Factor
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    ABSTRACT: Androgen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer. The efficacy of ADT has not been rigorously evaluated by demonstrating suppression of prostatic androgen activity at the target tissue and molecular level. We determined the efficacy and consistency of medical castration in suppressing prostatic androgen levels and androgen-regulated gene expression. Androgen levels and androgen-regulated gene expression (by microarray profiling, quantitative reverse transcription-PCR, and immunohistochemistry) were measured in prostate samples from a clinical trial of short-term castration (1 month) using the gonadotropin-releasing hormone antagonist, Acyline, versus placebo in healthy men. To assess the effects of long-term ADT, gene expression measurements were evaluated at baseline and after 3, 6, and 9 months of neoadjuvant ADT in prostatectomy samples from men with localized prostate cancer. Medical castration reduced tissue androgens by 75% and reduced the expression of several androgen-regulated genes (NDRG1, FKBP5, and TMPRSS2). However, many androgen-responsive genes, including the androgen receptor (AR) and prostate-specific antigen (PSA), were not suppressed after short-term castration or after 9 months of neoadjuvant ADT. Significant heterogeneity in PSA and AR protein expression was observed in prostate cancer samples at each time point of ADT. Medical castration based on serum testosterone levels cannot be equated with androgen ablation in the prostate microenvironment. Standard androgen deprivation does not consistently suppress androgen-dependent gene expression. Suboptimal suppression of tumoral androgen activity may lead to adaptive cellular changes allowing prostate cancer cell survival in a low androgen environment. Optimal clinical efficacy will require testing of novel approaches targeting complete suppression of systemic and intracrine contributions to the prostatic androgen microenvironment.
    Cancer Research 06/2007; 67(10):5033-41. DOI:10.1158/0008-5472.CAN-06-3332 · 9.28 Impact Factor
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    ABSTRACT: Prostate safety is a primary concern when aging men receive testosterone replacement therapy (TRT), but little information is available regarding the effects of TRT on prostate tissue in men. To determine the effects of TRT on prostate tissue of aging men with low serum testosterone levels. Randomized, double-blind, placebo-controlled trial of 44 men, aged 44 to 78 years, with screening serum testosterone levels lower than 300 ng/dL (<10.4 nmol/L) and related symptoms, conducted at a US community-based research center between February 2003 and November 2004. Participants were randomly assigned to receive 150 mg of testosterone enanthate or matching placebo intramuscularly every 2 weeks for 6 months. The primary outcome measure was the 6-month change in prostate tissue androgen levels (testosterone and dihydrotestosterone). Secondary outcome measures included 6-month changes in prostate-related clinical features, histology, biomarkers, and epithelial cell gene expression. Of the 44 men randomized, 40 had prostate biopsies performed both at baseline and at 6 months and qualified for per-protocol analysis (TRT, n = 21; placebo, n = 19). Testosterone replacement therapy increased serum testosterone levels to the mid-normal range (median at baseline, 282 ng/dL [9.8 nmol/L]; median at 6 months, 640 ng/dL [22.2 nmol/L]) with no significant change in serum testosterone levels in matched, placebo-treated men. However, median prostate tissue levels of testosterone (0.91 ng/g) and dihydrotestosterone (6.79 ng/g) did not change significantly in the TRT group. No treatment-related change was observed in prostate histology, tissue biomarkers (androgen receptor, Ki-67, CD34), gene expression (including AR, PSA, PAP2A, VEGF, NXK3, CLU [Clusterin]), or cancer incidence or severity. Treatment-related changes in prostate volume, serum prostate-specific antigen, voiding symptoms, and urinary flow were minor. These preliminary data suggest that in aging men with late-onset hypogonadism, 6 months of TRT normalizes serum androgen levels but appears to have little effect on prostate tissue androgen levels and cellular functions. Establishment of prostate safety for large populations of older men undergoing longer duration of TRT requires further study. Trial Registration clinicaltrials.gov Identifier: NCT00161304.
    JAMA The Journal of the American Medical Association 11/2006; 296(19):2351-61. DOI:10.1001/jama.296.19.2351 · 29.98 Impact Factor
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    ABSTRACT: The impact of serum androgen manipulation on prostate tissue hormone levels in normal men is unknown. Studies of men with prostate cancer have suggested that prostatic androgens are preserved in the setting of castration. Tissue androgens might stimulate prostate growth, producing adverse clinical consequences. The objective of the study was to determine the effect of serum androgen manipulation on intraprostatic androgens in normal men. Thirteen male volunteers ages 35-55 yr (prostate-specific antigen < 2.0 ng/ml; normal transrectal ultrasound) were randomly assigned to: 1) a long-acting GnRH-antagonist, acyline, every 2 wk; 2) acyline plus testosterone (T) gel (10 mg/d); or 3) placebo for 28 d. Serum hormones were assessed weekly. Prostate biopsies were obtained on d 28. Extracted androgens were measured by RIA, and immunohistochemistry for androgen-regulated proteins was performed. The mean decrease in serum T was 94%, whereas prostatic T and dihydrotestosterone levels were 70 and 80% lower, respectively, in subjects receiving acyline alone compared with controls (P < 0.05). Despite this decrease in prostate androgens, there were no detectable differences in prostate epithelial proliferation, apoptosis, prostate-specific antigen, and androgen receptor expression. In this small study of healthy subjects, despite a 94% decrease in serum T with medical castration, intraprostatic T and dihydrotestosterone levels remained 20-30% of control values, and prostate cell proliferation, apoptosis, and androgen-regulated protein expression were unaffected. Our data highlight the importance of assessing tissue hormone levels. The source of persistent prostate androgens associated with medical castration and their potential role in supporting prostate metabolism deserves further study.
    Journal of Clinical Endocrinology &amp Metabolism 10/2006; 91(10):3850-6. DOI:10.1210/jc.2006-0968 · 6.31 Impact Factor
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    ABSTRACT: To compare tissue androgen levels in the prostate gland of African-American and white men, looking for a possible explanation of the increased incidence of cancer in the former. The subjects were 25 African-American and 36 white men, undergoing prostate biopsy consecutively, in whom cancer was absent. Biopsy cores (18 gauge) from the peripheral zone were homogenized, subjected to ether extraction, and separation by chromatography. Tissue testosterone and dihydrotestosterone (DHT) levels were determined by radioimmunoassay. The groups were matched for mean age (67.6 +/- 9.6 years), prostate volume (37.9 +/- 21.0 cm3), body mass index (28.2 +/- 4.2 kg/m2), and serum prostate-specific antigen (2.8 to 3.4 ng/mL) and testosterone (330 +/- 114 ng/dL) levels (P = NS for all measures). No significant difference in tissue testosterone (median 0.8 ng/g) or DHT (median 4.6 ng/g) was found between groups (P = NS). Furthermore, the tissue DHT/testosterone ratio (approximately 5) was not significantly different between the two groups (P = NS). Prostatic tissue levels of testosterone and DHT were similar in African-American and white men; thus, the present data do not support a hypothesis of increased androgenic activity in African-American men. Because the ratio of DHT/testosterone in prostatic tissue was similar in the two groups, the possibility of increased 5-alpha-reductase activity in African-American men did not seem likely. Using needle biopsy specimens, both absolute values and the ratio of the androgens in prostatic tissue were similar to those found in previous studies using surgically excised glands. Thus, quick-frozen biopsy cores appear to be a valuable tissue source for evaluating the androgen status within the prostate.
    Urology 09/2006; 68(2):337-41. DOI:10.1016/j.urology.2006.03.013 · 2.13 Impact Factor
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    ABSTRACT: The higher prevalence of autoimmune disease among women compared with men suggests that steroids impact immune regulation. To investigate how sex steroids modulate cellular immune function, we conducted a randomized trial in 12 healthy men aged 35-55 yr treated for 28 days with placebo, a GnRH antagonist, acyline to induce medical castration, or acyline plus daily testosterone (T) gel to replace serum T, followed by a 28-day recovery period. Serum hormones were measured weekly and peripheral blood lymphocytes (PBLs) were collected biweekly for analyses of thymus-derived lymphocyte (T cell) subtypes and natural killer (NK) cells. Compared with the other groups and to baseline throughout the drug exposure period, men receiving acyline alone had significant reductions in serum T (near or below castrate levels), dihydrotestosterone, and estradiol (P < 0.05). Medical castration significantly reduced the percentage of CD4+ CD25+ T cells (P < 0.05), decreased mitogen-induced CD8+ T cell IFN-gamma expression, and increased the percentage of NK cells without affecting the ratio of CD4+ to CD8+ T cells and the expression of NK cell-activating receptor NKG2D or homing receptor CXCR1. No changes in immune composition were observed in subjects receiving placebo or acyline with replacement T. These data suggest that T and/or its metabolites may help maintain the physiological balance of autoimmunity and protective immunity by preserving the number of regulatory T cells and the activation of CD8+ T cells. In addition, sex steroids suppress NK cell proliferation. This study supports a complex physiological role for T and/or its metabolites in immune regulation.
    AJP Endocrinology and Metabolism 05/2006; 290(5):E856-63. DOI:10.1152/ajpendo.00484.2005 · 4.09 Impact Factor
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    ABSTRACT: Among vertebrates, maternal transfer of hormones to offspring has been studied extensively in mammals (placental transfer) and more recently in oviparous birds and reptiles (yolk transfer). The placental viviparous bonnethead shark, Sphyrna tiburo, allows the investigation of both yolk and placental hormone transfers in a single organism. In this species, yolk provides nutrition for the first half of embryonic development and placental transfer provides the second half. As sex determination is complete prior to development of placental connections, it was postulated that yolk hormones would have a prominent role in embryonic regulation. The goal of the current study was to determine serum and yolk hormone concentrations during five reproductive stages, from pre-ovulatory through pre-implantation (pre-placental) stages. Radioimmunoassay was used to determine 17beta-estradiol, progesterone, and testosterone concentrations in both serum and yolk. When yolk and serum concentrations were compared, the yolk had significantly higher concentrations of both estradiol and progesterone during post-ovulation and early pregnancy. Yolk concentrations of testosterone were significantly less than serum at pre-ovulation, but there were no differences after that stage. When yolk concentrations were compared between stages, significantly higher concentrations of estradiol were present in ovulatory, post-ovulatory, and pre-implantation stages, while progesterone was significantly higher in post-ovulatory, early pregnancy, and pre-implantation stages and testosterone was higher in pre-ovulation. Most of these results are consistent with the published findings in birds and reptiles. Further, in the bonnethead shark, they suggest that yolk transfer of hormones is adequate for sexual differentiation in embryonic development and that estradiol probably has a significant developmental role.
    General and Comparative Endocrinology 05/2004; 136(2):241-7. DOI:10.1016/j.ygcen.2003.12.018 · 2.67 Impact Factor
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    ABSTRACT: An elevated plasma total homocysteine (tHcy) level is associated with an increased risk of vascular disease. Some studies have shown associations between tHcy level and small-vessel disease of the brain on magnetic resonance imaging (MRI). In the Cardiovascular Health Study, 622 elderly participants without a history of transient ischemic attack or stroke had results for tHcy level and cranial MRI. We sought associations between tHcy level and MRI findings of ventricular grade, sulcal grade, white matter grade, and infarcts. We controlled for other factors, including levels of creatinine, folate, and vitamins B(6) and B(12) and methylenetetrahydrofolate reductase genotype. After controlling for age and sex, tHcy level was not associated with the individual MRI findings. Further adjustments for other factors and other blood tests had little effect on these findings. The only significant finding was a linear trend across quintiles of tHcy level and a pattern of MRI findings combining infarcts and high white matter grade. The linear trend remained significant after controlling for other risk factors and atherosclerotic markers (top quintile vs bottom quintile odds ratio, 3.3; 95% confidence interval, 0.96-11.20; P =.04 for linear trend) but was slightly diminished after further controlling for creatinine, folate, and vitamins B(6) and B(12) (odds ratio, 3.2; 95% confidence interval, 0.81-13.10; P =.07 for linear trend). We were unable to confirm the results of previous studies with respect to tHcy level and individual MRI findings, although an association was seen for an MRI pattern combining infarcts and high white matter grade.
    JAMA Neurology 02/2004; 61(1):67-72. DOI:10.1001/archneur.61.1.67 · 7.01 Impact Factor
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    ABSTRACT: The interplay between the fetus and mother may play a key role in the regulation of primate pregnancy and parturition. This study was designed to test the hypothesis that fetectomy alters maternal pituitary-adrenal function. Between 117 and 122 days of gestation (term = 167 days), six rhesus macaques underwent surgery for catheter implantation. At surgery the fetuses were removed while the membranes and placenta were left in situ. Six additional intact catheterized pregnant animals served as controls. Animals were maintained under a 12L:12D cycle with lights-on from 0700 to 1900 h. Beginning at least 1 wk after surgery, maternal arterial blood samples were collected at 3-h intervals for 24 h for hormone and catecholamine analysis. This sampling protocol was repeated at weekly intervals until cesarean delivery at 151-157 days of gestation. Following fetectomy, plasma ACTH, dehydroepiandrosterone sulfate (DHEAS), and cortisol levels were significantly lower (36%, 35%, and 44%, respectively) compared with control animals (P;lt 0.05). Despite a significant reduction in overall levels, the rhythm in maternal plasma cortisol was maintained following fetectomy. Plasma dopamine and norepinephrine were also depressed (P;lt 0.05), whereas epinephrine remained unaffected. Our data clearly demonstrate the role of the fetus in the regulation of the maternal pituitary-adrenal axis during gestation. This interaction plays a significant role in the regulation of maternal endocrine function that may influence the initiation of labor.
    Biology of Reproduction 12/2001; 65(5):1616-21. · 3.45 Impact Factor
  • Journal of Neuroendocrinology 09/2001; 12(9):899-909. DOI:10.1046/j.1365-2826.2000.00549.x · 3.51 Impact Factor
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    ABSTRACT: To determine the effects of a saw palmetto herbal blend (SPHB) compared with finasteride on prostatic tissue androgen levels and to evaluate needle biopsies as a source of tissue for such determinations. Prostate levels of testosterone and dihydrotestosterone (DHT) were measured on 5 to 10-mg biopsy specimens (18-gauge needle cores) in three groups of men with symptomatic benign prostatic hyperplasia: 15 men receiving chronic finasteride therapy versus 7 untreated controls; 4 men undergoing prostate adenomectomy to determine sampling variability (10 specimens each); and 40 men participating in a 6-month randomized trial of SPHB versus placebo, before and after treatment. Prostatic tissue DHT levels were found to be several times higher than the levels of testosterone (5.01 versus 1.51 ng/g), that ratio becoming reversed (1.05 versus 3.63 ng/g) with chronic finasteride therapy. The finasteride effect was statistically significant for both androgens (P <0.01), and little overlap of individual values between finasteride-treated and control patients was seen. In the randomized trial, tissue DHT levels were reduced by 32% from 6.49 to 4.40 ng/g in the SPHB group (P <0.005), with no significant change in the placebo group. For control versus finasteride-treated men, the tissue androgen values obtained with needle biopsy specimens were similar-both for absolute values and the percentage of change-to those previously reported using surgically excised volumes of prostatic tissue. The quantification of prostatic androgens by assay of needle biopsies is thus feasible and offers the possibility of serial studies in individual patients. The SPHB-induced suppression of prostatic DHT levels, modest but significant in a randomized trial, lends an element of support to the hypothesis that inhibition of the enzyme 5-alpha reductase is a mechanism of action of this substance.
    Urology 06/2001; 57(5):999-1005. DOI:10.1016/S0090-4295(00)01052-9 · 2.13 Impact Factor
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    ABSTRACT: Folic acid is presently the mainstay of treatment for most subjects with elevated plasma homocyst(e)ine concentrations [Plasma or serum homocyst(e)ine, or total homocysteine, refers to the sum of the sulfhydryl amino acid homocysteine and the homocysteinyl moieties of the disulfides homocystine and homocystein-cysteine, whether free or bound to plasma proteins.] Changes in homocyst(e)ine in response to folic acid supplementation are characterized by considerable interindividual variation. The purpose of this study was to identify factors that contribute to heterogeneity in short-term responses to folic acid supplementation. The effects of folic acid supplementation (1 or 2 mg per day) for 3 wk on plasma homocyst(e)ine concentrations were assessed in 304 men and women. Overall, folic acid supplementation increased mean plasma folate 31.5±98.0 nmol/L and decreased mean plasma homocyst(e)ine concentrations 1.2±2.4 μmol/L. There was evidence of substantial interindividual variation in the homocyst(e)ine response from −18.5 to +7.1 μmol/L, including an increase in homocyst(e)ine in 20% of subjects (mean increase 1.5±1.4 μmol/L). Basal homocyst(e)ine, age, male gender, cigarette smoking, use of multivitamins, methylene tetrahydrofolate reductase, and cystathionine β-synthase polymorphisms accounted for 47.6% of the interindividual variability in the change in homocyst(e)ine after folic acid supplementation, but about 50% of variability in response to folic acid was not explained by the variables we studied.
    Lipids 01/2001; 36:S27-S32. DOI:10.1007/s11745-001-0678-8 · 2.35 Impact Factor
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    ABSTRACT: Noradrenaline plays a key role in the initiation of ovulation in nonprimate species. A similar noradrenaline role in the primate has not been established experimentally. We utilized the ovariectomized-oestrogen-supplemented (OVX + E) rhesus macaque to examine the effects of intravenous (i.v.) infusion of oestradiol-17beta (E2) on the activity of the brain noradrenaline system. Experiment 1 established the induction of a preovulatory surge-like release of luteinizing hormone in OVX + E monkeys by i.v. infusion of E2 (OVX + E + E2). In experiment 2, a marked increase in hypothalamic microdialysate noradrenaline concentrations occurred after identical E2 infusion into the OVX + E monkeys that were used in experiment 1. In experiment 3, tyrosine hydroxylase (TH) mRNA expression in the locus coeruleus of the brainstem increased at various times after E2 infusion as determined by semiquantitative in situ hybridization. The amount of TH mRNA in OVX + E + E2 animals was higher (P < 0.05) than that in either the OVX + E or OVX monkeys; no difference was found in the latter two groups. Moreover, selected locus coeruleus sections from E2-infused monkeys were examined for the localization of oestrogen receptors (ER) by in situ hybridization. Both ER-alpha and ER-beta mRNAs were expressed in the locus coeruleus, although the expression was greater for ER-alpha than for ER-beta. We conclude that i.v. infusion of E2, which induces a preovulatory surge-like release of LH, stimulates brain noradrenaline activity; this enhanced activity likely involves an ER-mediated process and is reflected by hypothalamic noradrenaline release and locus coeruleus TH mRNA expression. The results support the concept that noradrenaline can influence the E2-stimulated ovulation in nonhuman primates and that the brainstem is one of the components in this neuroendocrine process.
    Journal of Neuroendocrinology 09/2000; 12(9):899-909. · 3.51 Impact Factor
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    ABSTRACT: Elevated total plasma homocysteine (tHcy) is an established risk factor for the development of vascular disease and neural tube defects. Total homocysteine levels can be lowered by folic acid supplements but individual response is highly variable. In this case-control study, involving 142 coronary artery disease (CAD) patients and 102 controls, we have typed six genetic polymorphisms in three homocysteine metabolizing genes and examined their relationship to the incidence of CAD, tHcy levels, and lowering of tHcy levels in response to folic acid supplementation. We found that two single nucleotide polymorphisms in the cystathionine beta synthase (CBS) gene, 699C --> T and 1080T --> C, are associated with decreased risk of CAD and increased responsiveness to the tHcy lowering effects of folic acid. Individuals homozygous for 699T were significantly underrepresented in CAD patients as compared to controls (4.9% vs 17.3%, P = 0.0015), as were individuals homozygous for the 1080C (29.6% vs 44.2%, P = 0.018). Additionally, 699T and 1080C homozygous individuals were the most responsive to folate supplementation. 699T homozygotes lowered tHcy levels 13.6% on average, compared to 4.8% lowering in 699C homozygotes (P = 0.009), while 1080C homozygotes lowered 12.9% compared to just 2.7% for 1080T homozygotes (P = 0.005). The two polymorphisms in CBS are third codon changes and would not be predicted to affect the underlying protein. However, there is strong linkage disequilibrium between these two positions, suggesting that they may also be linked to other as yet unidentified polymorphisms within the CBS gene. These observations suggest that specific CBS alleles are a risk factor for the development of vascular disease and that genetic information could be predictive of individual response to folic acid supplementation.
    Molecular Genetics and Metabolism 06/2000; 70(1):53-60. DOI:10.1006/mgme.2000.2993 · 2.83 Impact Factor
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    ABSTRACT: Serum steroid hormones in the peripheral circulation of the clearnose skate, Raja eglanteria, were measured at the time of capture and at various times throughout the year while the animals were maintained as a captive breeding population. These analyses demonstrate interesting correlations between changes in hormone concentrations and annual reproductive events. Animals were sampled once (78 females, 20 males) or multiple times (15 females). For both groups of females, 17beta-estradiol was detected throughout the year with significant elevations occurring during October and November when ovarian follicles begin to mature (as determined through necropsy examinations), and January and February when maximum mating activity is observed and egg laying begins. Testosterone and dihydrotestosterone concentrations were significantly elevated in females only during January and February. Testosterone elevations were synchronous with longer-term elevations in 17beta-estradiol in females sampled either once or repetitively. Testosterone concentrations in males were significantly elevated during times of maximum breeding activity compared to periods of sexual inactivity. Data from females sampled during five stages of the egg laying process, as defined by the position of palpable egg capsules within the reproductive tract, revealed that 17beta-estradiol was highest when egg capsules were forming in the nidamental gland (stage 2) or uterus (stage 3); testosterone and dihydrotestosterone were maximal when eggs were in the uterus (stage 3) or cloaca (stage 4); and progesterone was significantly elevated immediately after oviposition (stage 5), suggesting a possible role for progesterone in the regulation of sequential laying of egg pairs. J. Exp. Zool. 284:575-585, 1999.
    Journal of Experimental Zoology 11/1999; 284(5):575-85. DOI:10.1002/(SICI)1097-010X(19991001)284:53.3.CO;2-9
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    ABSTRACT: The temporal relationships and regulation of events in the primate follicle during the periovulatory interval are poorly understood. This study was designed to elucidate the dynamics of steroid synthesis in the macaque follicle during ovarian stimulation cycles in which serum/follicular fluid aspirates were collected at precise intervals before (0 h) and after (up to 36 h) administration of the ovulatory human chorionic gonadotrophin (HCG) bolus. Serum concentrations of progesterone increased (P < 0.05) within 30 min, and follicular fluid progesterone concentrations were elevated 180-fold within 12 h, of HCG injection, and remained elevated until the time of ovulation. In contrast, 17beta-oestradiol concentrations increased initially, but then declined (P < 0.05) by 36 h post-HCG. Acute incubation of granulosa cells with and without steroidogenic substrates demonstrated that: (i) 3beta-hydroxysteroid dehydrogenase and aromatase activities were present in equivalent amounts before and after HCG; whereas (ii) P450 side-chain cleavage activity increased (P < 0.05) within 12 h of HCG; and (iii) exogenous low-density lipoprotein and cholesterol were not utilized for steroidogenesis. This model should be useful for further studies on ovulation and luteinization in primates, and enable elucidation of the local actions of progesterone and other steroids at specific time points during the periovulatory interval.
    Human Reproduction 04/1999; 14(3):642-9. · 4.59 Impact Factor
  • The Journal of Urology 01/1999; 162(5). DOI:10.1097/00005392-199904020-00450 · 3.75 Impact Factor
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    ABSTRACT: Elevated plasma total homocysteine (tHcy), low B-vitamin intake, and genetic polymorphisms related to tHcy metabolism may play roles in coronary heart disease (CHD). More prospective studies are needed. We used a prospective case-cohort design to determine whether tHcy-related factors are associated with incidence of CHD over an average of 3.3 years of follow-up in a biracial sample of middle-aged men and women. Age-, race-, and field center-adjusted CHD incidence was associated positively (P<0.05) with tHcy in women but not men, and CHD was associated negatively (P<0.05) with plasma folate (women only), plasma pyridoxal 5'-phosphate (both sexes), and vitamin supplementation (women only). However, after accounting for other risk factors, only plasma pyridoxal 5'-phosphate was associated with CHD incidence; the relative risk for the highest versus lowest quintile of pyridoxal 5'-phosphate was 0.28 (95% CI=0.1 to 0.7). There was no association of CHD with the C677T mutation of the methylenetetrahydrofolate reductase gene or with 3 mutations of the cystathionine beta-synthase gene. Our prospective findings add uncertainty to conclusions derived mostly from cross-sectional studies that tHcy is a major, independent, causative risk factor for CHD. Our findings point more strongly to the possibility that vitamin B6 offers independent protection. Randomized trials, some of which are under way, are needed to better clarify the interrelationships of tHcy, B vitamins, and cardiovascular disease.
    Circulation 07/1998; 98(3):204-10. DOI:10.1161/01.CIR.98.3.204 · 14.95 Impact Factor

Publication Stats

4k Citations
401.87 Total Impact Points

Institutions

  • 1993–2010
    • Oregon Health and Science University
      • • Department of Physiology & Pharmacology
      • • Division of Reproductive Sciences
      • • Department of Obstetrics & Gynecology
      Portland, Oregon, United States
  • 1996–2007
    • University of Washington Seattle
      Seattle, Washington, United States
  • 1981–2007
    • Wisconsin National Primate Research Center
      Madison, Wisconsin, United States
  • 2006
    • University of California, Los Angeles
      • Department of Urology
      Los Angeles, CA, United States