Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth.

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.

Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer.

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.

Characteristics and regulation of the ovarian cycle in vervet monkeys (Chlorocebus aethiops).

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.

Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial.

Context: 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.

Objective: To determine the effects of TRT on prostate tissue of aging men with low serum testosterone levels.

Design, Setting, And Participants: 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.

Prostatic tissue testosterone and dihydrotestosterone in African-American and white men.

Objectives: 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.

Methods: 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.

Persistent intraprostatic androgen concentrations after medical castration in healthy men.

Context: 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.

Effect of medical castration on CD4+ CD25+ T cells, CD8+ T cell IFN-gamma expression, and NK cells: a physiological role for testosterone and/or its metabolites.

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.

Gonadotropin-releasing hormone antagonist (Cetrorelix) therapy fails to protect nonhuman primates (Macaca arctoides) from radiation-induced spermatogenic failure.

Treatment of men of reproductive age with radiation or alkylating agents often produces prolonged azoospermia. We previously demonstrated that suppression of testosterone (T) with gonadotropin-releasing hormone (GnRH) analogs restored spermatogenesis following atrophy induced by radiation or chemotherapy in rats. This study tested whether GnRH antagonist therapy could reverse radiation-induced testicular injury in primates with a similar protocol.

Sensitivity to stress-induced reproductive dysfunction linked to activity of the serotonin system.

Objective: To use a nonhuman primate model and determine whether individuals sensitive to stress-induced reproductive dysfunction have lower activity of central serotonergic neurons under nonstressed conditions.

Design: The activity of the central serotonergic system was assessed by measuring responsiveness to a fenfluramine challenge (5 mg/kg, IV) in sedated monkeys previously categorized as highly stress resistant (HSR; n = 4; normal menstrual cyclicity through two stress cycles), medium stress resistant (MSR; n = 5; ovulatory in the first stress cycle but anovulatory in the second stress cycle), or low stress resistant (i.e.

A novel mouse model of hypogonadotrophic hypogonadism: N-ethyl-N-nitrosourea-induced gonadotropin-releasing hormone receptor gene mutation.

An autosomal-recessive mutation that causes hypogonadotrophic hypogonadism was isolated during an N-ethyl-N-nitrosourea mutagenesis screen in mice. Affected males had micropenis and small, undescended testes with spermatogenesis arrested at the pachytene stage of meiosis, leading to sterility. Androgen-sensitive organs were small and immature.

Maternal serum and yolk hormone concentrations in the placental viviparous bonnethead shark, Sphyrna tiburo.

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.

Plasma total homocysteine levels and cranial magnetic resonance imaging findings in elderly persons: the Cardiovascular Health Study.

Background: 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).

Design: 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.

The protective effect of 17beta-estradiol on experimental autoimmune encephalomyelitis is mediated through estrogen receptor-alpha.

Low-dose estrogen (E2) treatment significantly inhibits the clinical signs and histopathological lesions of experimental autoimmune encephalomyelitis (EAE), and is being used in clinical trials to treat multiple sclerosis. To assess the role of intracytoplasmic estrogen receptors in mediating suppression of EAE, we studied mice with disrupted estrogen receptor-alpha (Esr1) and -beta (Esr2) genes. We demonstrate that the protective effect of E2 is abrogated in B6.