Showing papers on "Testosterone published in 2001"

A Mechanism for Androgen Receptor-mediated Prostate Cancer Recurrence after Androgen Deprivation Therapy

Abstract: The development and growth of prostate cancer depends on the androgen receptor and its high-affinity binding of dihydrotestosterone, which derives from testosterone. Most prostate tumors regress after therapy to prevent testosterone production by the testes, but the tumors eventually recur and cause death. A critical question is whether the androgen receptor mediates recurrent tumor growth after androgen deprivation therapy. Here we report that a majority of recurrent prostate cancers express high levels of the androgen receptor and two nuclear receptor coactivators, transcriptional intermediary factor 2 and steroid receptor coactivator 1. Overexpression of these coactivators increases androgen receptor transactivation at physiological concentrations of adrenal androgen. Furthermore, we provide a molecular basis for this activation and suggest a general mechanism for recurrent prostate cancer growth.

A role for estrogen receptor β in the regulation of growth of the ventral prostate

Abstract: In normal rats and mice, immunostaining with specific antibodies revealed that nuclei of most prostatic epithelial cells harbor estrogen receptor beta (ERbeta). In rat ventral prostate, 530- and 549-aa isoforms of the receptor were identified. These sediment in the 4S region of low-salt sucrose gradients, indicating that prostatic ERbeta does not contain the same protein chaperones that are associated with ERalpha. Estradiol (E(2)) binding and ERbeta immunoreactivity coincide on the gradient, with no indication of ERalpha. In prostates from mice in which the ERbeta gene has been inactivated (BERKO), androgen receptor (AR) levels are elevated, and the tissue contains multiple hyperplastic foci. Most epithelial cells express the proliferation antigen Ki-67. In contrast, prostatic epithelium from wild-type littermates is single layered with no hyperplasia, and very few cells express Ki-67. Rat ventral prostate contains an estrogenic component, which comigrates on HPLC with the testosterone metabolite 5alpha-androstane-3beta,17beta-diol (3betaAdiol). This compound, which competes with E(2) for binding to ERbeta and elicits an estrogenic response in the aorta but not in the pituitary, decreases the AR content in prostates of wild-type mice but does not affect the elevated levels seen in ERbeta knockout (BERKO) mice. Thus ERbeta, probably as a complex with 3betaAdiol, is involved in regulating the AR content of the rodent prostate and in restraining epithelial growth. These findings suggest that ligands specific for ERbeta may be useful in the prevention and/or clinical management of prostatic hyperplasia and neoplasia.

Description and evaluation of a short‐term reproduction test with the fathead minnow (Pimephales promelas)

Abstract: Due to the time and expense associated with full life-cycle testing, most current toxicity tests with fish do not explicitly consider reproductive output as an endpoint but, rather, focus on early life-stage survival and development. However, some classes of chemicals could adversely impact reproduction at concentrations below those that affect development. Further, estimates of the effects of toxic compounds on reproductive output can be critical to the ecological risk assessment process. In this manuscript, we describe a short-term reproduction test with the fathead minnow (Pimephales promelas) and evaluate the test using two model reproductive toxicants, methoxychlor (an estrogenic compound) and methyltestosterone (an androgenic chemical). The test is initiated with reproductively mature animals and is comprised of a pre-exposure phase of 14 to 21 d, followed by a chemical exposure of up to 21 d. During and at completion of the test, several endpoints related to reproductive fitness and endocrine function are assessed. Both chemicals evaluated in our study caused a significant decrease in fecundity of the fish at nominal concentrations of 5.0 μg/L (methoxychlor) and 0.2 mg/L (methyltestosterone). Methoxychlor decreased plasma concentrations of one or more steroids (testosterone, 11-ketotestosterone, β-estradiol) in both sexes and caused a significant induction of plasma vitellogenin in males, a response consistent with activation of the estrogen receptor by the pesticide (or its metabolites). Methyltestosterone decreased plasma concentrations of sex steroids and adversely affected gonadal status (as evaluated by relative weight and histopathology) in both sexes. The androgenic nature of methyltestosterone was clearly expressed as masculinization of exposed females via formation of nuptial tubercles, structures normally present only in reproductively active males. The chemical also caused a significant induction of plasma vitellogenin in both males and females; this unexpected estrogenic response was most likely due to aromatization of the androgen to a form capable of binding to the estrogen receptor. These studies demonstrate the utility of this short-term assay for identifying chemicals that exert reproductive toxicity through alterations in endocrine systems controlled by estrogens and androgens.

Targeted disruption of luteinizing hormone/ human chorionic gonadotropin receptor gene

Abstract: LH/hCG receptors were disrupted by gene targeting in embryonic stem cells. The disruption resulted in infertility in both sexes. The gonads contained no receptor mRNA or receptor protein. Serum LH levels were greatly elevated, and FSH levels were moderately elevated in both sexes; estradiol and progesterone levels decreased but were not totally suppressed in females; testosterone levels were dramatically decreased and estradiol levels moderately elevated in males. The external and internal genitalia were grossly underdeveloped in both sexes. Abnormalities included ambiguous vaginal opening, abdominal testes, micropenis, dramatically decreased weights of the gonads and reproductive tract, arrested follicular growth beyond antral stage, disarray of seminiferous tubules, diminished number and hypotrophy of Leydig cells, and spermatogenic arrest beyond the round spermatid stage. LH/hCG receptor gene disruption had no effect on FSH receptor mRNA levels in ovaries and testes, progesterone receptor (PR) levels in ovaries and androgen receptor (AR) levels in testes. However, it caused a dramatic decrease in StAR and estrogen receptor-alpha (ERalpha) mRNA levels and an increase in ERbeta mRNA levels in both ovaries and testes. Estradiol and progesterone replacement therapy in females and testosterone replacement in males, to determine whether phenotype and biochemical changes were a consequence of decreased gonadal steroid levels or due to a loss of LH signaling, revealed complete restoration of some and partial restoration of others. Nevertheless, the animals remained infertile. It is anticipated that the LH receptor knockout animals will increase our current understanding of gonadal and nongonadal actions of LH and hCG.

Effects of phthalate esters on the developing reproductive tract of male rats

Abstract: Phthalate esters are a large group of chemical agents used predominantly as plasticizers and solvents. Certain members of this chemical class have been shown to cause reproductive and developmental toxicity. Recent attention has focused on the potential of these agents to interfere with male reproductive development through a postulated antiandrogenic mechanism. Observations have focused on di-n-butyl phthalate (DBP), di-(2-ethylhexyl) phthalate (DEHP) and butyl benzylphthalate, with most information relating to dose-response relationships obtained for DBP. Neither DBP, DEHP nor their major metabolites interacted with human or rodent androgen receptors (AR) in transcriptional activation assays. DBP was administered during the critical window of development of the male reproductive system, after which the resulting offspring were examined until adulthood. DBP elicited marked effects on the developing male reproductive tract, including malformations of the epididymis and vas deferens, and hypospadias. Retention of thoracic nipples/areolae and reductions in anogenital distance were also noted. Surprisingly, Leydig cell adenomas were induced in some male offspring at 100 days of age. All these events occurred in the absence of any toxicity in the pregnant dam. Examination of testes from fetal rats indicated markedly reduced testosterone levels and increased Leydig cell numbers after DBP administration to the dams. Leydig cells were positive for AR and 3-betahydroxysteroid dehydrogenase.

Testosterone Acts Directly on CD4+ T Lymphocytes to Increase IL-10 Production

Abstract: Males are less susceptible than females to experimental autoimmune encephalomyelitis and many other autoimmune diseases. Gender differences in cytokine production have been observed in splenocytes of experimental autoimmune encephalomyelitis mice stimulated with myelin proteins and may underlie gender differences in susceptibility. As these differences should not be limited to responses specific for myelin proteins, gender differences in cytokine production upon stimulation with Ab to CD3 were examined, and the mechanisms were delineated. Splenocytes from male mice stimulated with Ab to CD3 produced more IL-10 and IL-4 and less IL-12 than those from female mice. Furthermore, splenocytes from dihydrotestosterone (DHT)-treated female mice produced more IL-10 and less IL-12 than those from placebo-treated female mice, whereas there was no difference in IL-4. IL-12 knockout mice were then used to determine whether changes in IL-10 production were mediated directly by testosterone vs indirectly by changes in IL-12. The results of these experiments favored the first hypothesis, because DHT treatment of female IL-12 knockout mice increased IL-10 production. To begin to delineate the mechanism by which DHT may be acting, the cellular source of IL-10 was determined. At both the RNA and protein levels, IL-10 was produced primarily by CD4+ T lymphocytes. CD4+ T lymphocytes were then shown to express the androgen receptor, raising the possibility that testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. In vitro experiments demonstrated increased IL-10 production following treatment of CD4+ T lymphocytes with DHT. Thus, testosterone can act directly via androgen receptors on CD4+ T lymphocytes to increase IL-10 gene expression.

High‐grade prostate cancer is associated with low serum testosterone levels

Abstract: BACKGROUND The aim of this study was to assess whether low serum testosterone levels in men with newly diagnosed prostate cancer have an association to the endocrine status, prostate-specific antigen (PSA) levels, Gleason score, and androgen receptor expression. METHODS Besides a full clinical work-up, the following hormones were quantified in men with newly diagnosed prostate cancer by serum analysis: total testosterone, human luteinising hormone (hLH), human follicle stimulating hormone (hFSH), estradiol, and dehydroepiandrostendione (DHEA). In a subgroup of men, androgen receptor expression was determined immunohistochemically. RESULTS One hundred and fifty six patients (65.7 ± 8.5 yrs) with a mean PSA of 29.8 ng/ml (median: 7.4 ng/ml) were analysed. Fifty-two patients (33%) had a partial androgen deficiency (serum testosterone <3.0 ng/ml). These men had lower hLH (3.3 vs. 5.9 mIU/ml), hFSH (6.2 vs. 8.4 mIU/ml), and estradiol (18.8 vs. 29.1 pg/ml) serum levels. Mean Gleason score was higher (7.4 vs. 6.2) in men with a low serum testosterone, PSA-levels were lower (25.3 vs. 31.9 ng/ml). Mean testosterone levels decreased from 4.1 ± 1.7 ng/ml in patients with Gleason scores ≤ 5 to 2.8 ± 2.7 ng/ml with Gleason scores ≥ 8. Androgen receptor expression was higher in patients with low serum testosterone. CONCLUSIONS Patients with high Gleason score prostate cancer have lower testosterone and estradiol serum levels. The fact that gonadotropins were lower in parallel suggests a tumor-mediated suppression of the hypothalamic-pituitary-gonadal hormone axis particularly in men with high Gleason score tumours. Prostate 47:52–58, 2001. © 2001 Wiley-Liss, Inc.

Testosterone‐mediated neuroprotection through the androgen receptor in human primary neurons

Abstract: Estrogen is an active neuroprotectant and is presently investigated as a potential therapy against Alzheimer’s disease for women. To determine if male hormones could also be neuroprotective, we investigated the effect of testosterone, methyltestosterone, and epitestosterone at physiological concentrations on primary cultures of human neurons induced to undergo apoptosis by serum deprivation. Serum deprivation significantly induces neuronal apoptosis in a protracted fashion. As expected, physiological concentrations of 17-bestradiol and transcriptionally inactive 17-a-estradiol protect neurons against apoptosis. Similar to 17-b-estradiol, physiological concentrations of testosterone are also neuroprotective. Androgen receptors are present at 8 ^ 2 fmol/mg protein in the neuron cultures. The non-aromatizable androgen, mibolerone, is also neuroprotective and aromatase inhibitor, 4-androsten-4-OL-3,17-dione, does not prevent testosteronemediated neuroprotection. In contrast, anti-androgen, flutamide, eliminates testosterone-mediated neuroprotection. Testosterone analog, methyltestosterone, showed androgen receptordependent neuroprotection that was delayed in time indicating that a metabolite may be the active agent. The endogenous anti-androgen, epitestosterone, also showed a slight neuroprotective effect but not through the androgen receptor. These results indicate that androgens induce neuroprotection directly through the androgen receptor. These data suggest that androgens may also be of therapeutic value against Alzheimer’s disease in aging males.

Modulation of Rat Leydig Cell Steroidogenic Function by Di(2-Ethylhexyl)Phthalate

Abstract: Exposure of rodents to phthalates is associated with developmental and reproductive anomalies, and there is concern that these compounds may be causing adverse effects on human reproductive health. Testosterone (T), secreted almost exclusively by Leydig cells in the testis, is the primary steroid hormone that maintains male fertility. Leydig cell T biosynthesis is regulated by the pituitary gonadotropin LH. Herein, experiments were conducted to investigate the ability of di(2-ethylhexyl)phthalate (DEHP) to affect Leydig cell androgen biosynthesis. Pregnant dams were gavaged with 100 mg(-1) kg(-1) day(-1) DEHP from Gestation Days 12 to 21. Serum T and LH levels were significantly reduced in male offspring, compared to control, at 21 and 35 days of age. However, these inhibitory effects were no longer apparent at 90 days. In a second set of experiments, prepubertal rats, from 21 or 35 days of age, were gavaged with 0, 1, 10, 100, or 200 mg(-1) kg(-1) day(-1) DEHP for 14 days. This exposure paradigm affected Leydig cell steroidogenesis. For example, exposure of rats to 200 mg(-1) kg(-1) day(-1) DEHP caused a 77% decrease in the activity of the steroidogenic enzyme 17beta-hydroxysteroid dehydrogenase, and reduced Leydig cell T production to 50% of control. Paradoxically, extending the period of DEHP exposure to 28 days (Postnatal Days 21-48) resulted in significant increases in Leydig cell T production capacity and in serum LH levels. The no-observed-effect-level and lowest-observed-effect-level were determined to be 1 mg(-1) kg(-1) day(-1) and 10 mg(-1) kg(-1) day(-1), respectively. In contrast to observations in prepubertal rats, exposure of young adult rats by gavage to 0, 1, 10, 100, or 200 mg(-1) kg(-1) day(-1) DEHP for 28 days (Postnatal Days 62-89) induced no detectable changes in androgen biosynthesis. In conclusion, data from this study show that DEHP effects on Leydig cell steroidogenesis are influenced by the stage of development at exposure and may occur through modulation of T-biosynthetic enzyme activity and serum LH levels.

Bioavailable Estradiol May Be an Important Determinant of Osteoporosis in Men: The MINOS Study

Abstract: During recent years, experimental data, case reports, and epidemiological studies have suggested an important role for estradiol in bone metabolism in men. In a cohort of 596 men, aged 51–85 yr, we measured bone mineral density (BMD) of the lumbar spine, hip, total body, and forearm; serum levels of sex steroid hormones [total and free testosterone, total estradiol (17βE2), bioavailable estradiol (bio-17βE2), androstenedione, and sex hormone-binding globulin]; and markers of bone turnover [serum osteocalcin, bone alkaline phosphatase, N-terminal extension propeptide of type I collagen, and β-isomerized C-terminal telopeptide of collagen type I (βCTX)], as well as urinary excretion of βCTX and deoxypyridinoline (DPyr). An age-related decrease was found for bio-17βE2 (r = −0.16; P < 0.001), free testosterone (r = −0.25; P < 0.001), free testosterone index (r = −0.32; P< 0.001), and androstenedione (r = −0.22; P< 0.001), but not for total 17βE2 or total testosterone. 17βE2 and bio-17βE2, but not other hormon...

Brain aromatase is neuroprotective.

Abstract: The expression of aromatase, the enzyme that catalyzes the biosynthesis of estrogens from precursor androgens, is increased in the brain after injury, suggesting that aromatase may be involved in neuroprotection. In the present study, the effect of inactivating aromatase has been assessed in a model of neurodegeneration induced by the systemic administration of neurotoxins. Domoic acid, at a dose that is not neurotoxic in intact male mice, induced significant neuronal loss in the hilus of the hippocampal formation of mice with reduced levels of aromatase substrates as a result of gonadectomy. Furthermore, the aromatase substrate testosterone, as well as its metabolite estradiol, the product of aromatase, were able to protect hilar neurons from domoic acid. In contrast, dihydrotestosterone, the 5 alpha-reduced metabolite of testosterone and a nonaromatizable androgen, was not. These findings suggest that aromatization of testosterone to estradiol may be involved in the neuroprotective action of testosterone in this experimental model. In addition, aromatase knock-out mice showed significant neuronal loss after injection of a low dose of domoic acid, while control littermates did not, indicating that aromatase deficiency increases the vulnerability of hilar neurons to neurotoxic degeneration. The effect of aromatase on neuroprotection was also tested in male rats treated systemically with the specific aromatase inhibitor fadrozole and injected with kainic acid, a well characterized neurotoxin for hilar neurons in the rat. Fadrozole enhanced the neurodegenerative effect of kainic acid in intact male rats and this effect was counterbalanced by the administration of estradiol. Furthermore, the neuroprotective effect of testosterone against kainic acid in castrated male rats was blocked by fadrozole. These findings suggest that neuroprotection by aromatase is due to the formation of estradiol from its precursor testosterone. Finally, a role for local cerebral aromatase in neuroprotection is indicated by the fact that intracerebral administration of fadrozole enhanced kainic acid induced neurodegeneration in the hippocampus of intact male rats. These findings indicate that aromatase deficiency decreases the threshold for neurodegeneration and that local cerebral aromatase is neuroprotective. Brain aromatase may therefore represent a new target for therapeutic approaches to neurodegenerative diseases.

Effects of butylparaben on the male reproductive system in rats.

Abstract: Parabens are a group of compounds widely used as preservatives in foodstuffs, cosmetics, toiletries and pharmaceuticals. These compounds are known to exert a weak estrogenic activity, with butylparaben showing the most potent activity among methyl-, ethyl- and propyl esters in in vitro recombinant yeast assay and in in vivo uterotrophic assay. To account for potential reproductive effects in male animals, butylparaben was administered to 3-week-old Wistar rats divided in groups of eight subjects, at doses of 0.00%, 0.01%, 0.10% and 1.00% with the animal's diet. After 8 weeks, the rats were killed by decapitation and the weights of the testes, epididymides, prostates, seminal vesicles and preputial glands were recorded. The absolute and relative weights of epididymides were decreased in a dose-dependent manner and the decrease was statistically significant at 0.10% and above. The cauda epididymal sperm reserve of all treated groups was significantly decreased. The sperm count of the group receiving the highest dose was 58.2% of control values. The daily sperm production (DSP) in the testis was also significantly lower in all treated groups when compared to controls. Serum testosterone concentration was lowered dose-dependently and was significant at 0.1% or more. The daily intake of butylparaben that caused these disruptions is similar to the lower level of acceptable daily intake (ADI) for parabens in the European Community (EC) and in Japan. The results of the present experiments show for the first time that exposure of a postweaning mammal to butylparaben had an adverse effect on the secretion of testosterone and in the functions of the male reproductive system.

Androgen replacement therapy in the aging male--a critical evaluation.

Abstract: Recent years have seen an increasing interest in the study of the aging male, with a particular interest in the problem of whether so-called rejuvenating hormones and, more specifically, androgens can improve quality of life, counteract progressive skeletal muscle loss and strength, prevent falls and fractures, prolong independent living, and reduce the dependence on medical care. Almost a decade has elapsed since the first studies on androgen supplementation in elderly men were published (1, 2) and, in the view of the persisting controversies concerning this problem as well as the increasing public interest for rejuvenating hormones, it may be indicated to evaluate critically the clinical relevance of the relative androgen deficiency in elderly males, the diagnostic criteria of androgen deficiency, as well as the risks and benefits of androgen supplementation in elderly men. Male hormone replacement therapy implies, of course, that elderly men have a significant deficit in male hormone. Therefore, the first question to be answered is whether the common occurrence of the age-associated decline of testosterone levels is inherent to the aging process and occurs also in healthy men or whether the observed decline is the consequence of intercurrent disease, obesity, stress, relative physical inactivity, medications, etc. After years of controversy, due to differences in the characteristics of the population studied and variation in the timing of blood sampling (morning or afternoon) or the frequently small number of elderly subjects studied, authors now agree that in healthy men also there is a clear, slow but continuous, age-dependent decline of testosterone (T) levels, which is more pronounced for free T (FT) than for total T, a consequence of the age-associated increase of the levels of sex hormone binding globulin (SHBG); at 75 yr of age mean total T level in the morning is about two thirds of the mean level at 20–30 yr of age, whereas the mean FT and bioactive T (FT plus albumin bound T) level are only 40% of the mean levels in younger males. Moreover, the circadian rhythm of plasma T levels, with higher levels in the morning than in the evening, is generally lost in elderly men (3). However, wide interindividual variations exist due to genetic factors, body mass index, diet, social habits (alcohol, tobacco), and stress, and about 20% of males over 70 yr old have T levels in the upper third of males 20–40 yr of age (4). This is in clear distinction to the situation in postmenopausal women who all have clearly decreased estradiol levels. It is important to mention that this decrease, observed in cross-sectional studies, has now been confirmed by longitudinal studies (5–9). However, the androgen deficiency in elderly men is generally moderate; therefore, some authors have suggested the term partial androgen deficiency in the aging male (PADAM). Others, in analogy with the term menopause in women, use the term andropause, although distinct from women in menopause, elderly men retain their reproductive capacity. Although the decrease in (F)T levels occurs in healthy elderly men, it is evident that sequelae of intercurrent disease (10), medication, environmental, psychosocial, and socioeconomic factors accelerate this age-associated decrease. Recently, the important role of abdominal obesity in the ageassociated decrease of T levels has been stressed (10–12).

Changes in testosterone, cortisol, and estradiol levels in men becoming fathers.

Abstract: Objective To quantify longitudinally steroid hormone (testosterone, cortisol, and estradiol) concentrations in men becoming fathers for the first time ("dads"). Subjects and Methods Volunteer study subjects were recruited from first-trimester prenatal classes in Kingston, Ontario, in February 1999. Twenty-three dads provided saliva samples from recruitment through 3 months after the birth of their children. Fourteen men who were not fathers were recruited from the general population to serve as age-matched controls for season and time of day. Estradiol, testosterone, and cortisol levels were quantified. Results After controlling for effects of time of day and season, dads had lower mean ± SE testosterone (6.5±0.7 vs 10.0±0.9 ng/dL; P P P =.01), and higher estradiol concentrations in those detectable samples (3.81±0.09 pg/mL [13 dads] vs 3.26±0.11 pg/mL [9 controls]; P P =.02), and cortisol concentration was increased in the week before the birth (to a mean of 0.16 µg/dL). In each of 13 dads providing frequent samples, testosterone concentration and variance were low immediately after the birth (no change from previous levels in 5, decrease after prebirth increase in 3, and decrease relative to all other times in 5). Conclusions In this population of Canadian volunteers attending prenatal classes, expectant fathers had lower testosterone and cortisol levels and a higher proportion of samples with detectable estradiol concentrations than control subjects. Individual patterns of testosterone variance relative to the birth and estradiol and cortisol concentrations immediately before the birth may be worthy of further investigation. The physiologic importance of these hormonal changes, if any, is not known. However, they are hormones known to influence maternal behavior.

Dietary soy-phytoestrogens decrease testosterone levels and prostate weight without altering LH, prostate 5alpha-reductase or testicular steroidogenic acute regulatory peptide levels in adult male Sprague-Dawley rats

Abstract: Nutritional factors, especially phytoestrogens, have been extensively studied for their potential beneficial effects against hormone-dependent and age-related diseases. The present study describes the short-term effects of dietary phytoestrogens on regulatory behaviors (food/water intake, locomotor activity and body weight), prostate weight, prostate 5-reductase enzyme activity, reproductive hormone levels, and testicular steroidogenic acute regulatory peptide (StAR) levels in adult Sprague‐Dawley rats. Animals were fed either a phytoestrogen-rich diet containing 600 µg/g isoflavones (as determined by HPLC) or a phytoestrogen-free diet. After 5 weeks of consuming these diets, plasma phytoestrogen levels were 35 times higher in animals fed the phytoestrogen-rich vs phytoestrogen-free diets. Body and prostate weights were significantly decreased in animals fed the phytoestrogenrich diet vs the phytoestrogen-free fed animals; however, no significant change in prostate 5-reductase enzyme activity was observed between the treatment groups. Locomotor activity levels were higher in the phytoestrogen-rich vs the phytoestrogen-free animals during the course of the treatment interval. Plasma testosterone and androstenedione levels were significantly lower in the animals fed the phytoestrogen-rich diet compared with animals fed the phytoestrogen-free diet. However, there were no significant differences in plasma LH or estradiol levels between the diet groups. Testicular StAR levels were not significantly different between the phytoestrogen-rich vs the phytoestrogen-free fed animals. These results indicated that consumption of dietary phytoestrogens resulting in very high plasma isoflavone levels over a relatively short period can significantly alter body and prostate weight and plasma androgen hormone levels without affecting gonadotropin or testicular StAR levels. The findings of this study identify the biological actions of phytoestrogens on male reproductive endocrinology and provide insights into the protective effects these estrogen mimics exert in male reproductive disorders such as benign prostatic hyperplasia and prostate cancer.

Polymorphisms of the androgen receptor gene and the estrogen receptor beta gene are associated with androgen levels in women.

Abstract: To elucidate the possible role of genetic variation in androgen receptor (AR), estrogen receptor α (ERα), and ERβ on serum androgen levels in premenopausal women, the CAG repeat polymorphism of the AR gene, the TA repeat polymorphism of the ERα gene, and the CA repeat polymorphism of the ERβ gene were studied in a population-based cohort of 270 women. Total testosterone, free testosterone, dehydroepiandrosterone sulfate, androstenedione, 17-hydroxyprogesterone, 3α-androstanediol glucuronide, 17β-estradiol, LH, FSH, and sex steroid hormone-binding globulin (SHBG) were measured in serum samples obtained in the follicular phase of the menstrual cycle. Women with relatively few CAG repeats in the AR gene, resulting in higher transcriptional activity of the receptor, displayed higher levels of serum androgens, but lower levels of LH, than women with longer CAG repeat sequences. The CA repeat of the ERβ gene also was associated with androgen and SHBG levels; women with relatively short repeat regions hence disp...

Testosterone inhibits early atherogenesis by conversion to estradiol: critical role of aromatase.

Abstract: The effects of testosterone on early atherogenesis and the role of aromatase, an enzyme that converts testosterone to estrogens, were assessed in low density lipoprotein receptor-deficient male mice fed a Western diet. Castration of male mice increased the extent of fatty streak lesion formation in the aortic origin compared with testes-intact animals. Administration of anastrazole, a selective aromatase inhibitor, to testes-intact males increased lesion formation to the same extent as that observed with orchidectomized animals. Testosterone supplementation of orchidectomized animals reduced lesion formation when compared with orchidectomized animals receiving the placebo. This attenuating effect of testosterone was not observed when the animals were treated simultaneously with the aromatase inhibitor. The beneficial effects of testosterone on early atherogenesis were not explained by changes in lipid levels. Estradiol administration to orchidectomized males attenuated lesion formation to the same extent as testosterone administration. Aromatase was expressed in the aorta of these animals as assessed by reverse transcription–PCR and immunohistochemistry. These results indicate that testosterone attenuates early atherogenesis most likely by being converted to estrogens by the enzyme aromatase expressed in the vessel wall.

Leptin is associated with increased prostate cancer risk : a nested case-referent study.

Abstract: A Western lifestyle has been implicated in the pathogenesis of prostate cancer. However, no clear association between obesity and prostate cancer has been shown. Leptin may stimulate prostate growth and angiogenesis, and receptors for leptin are present in the prostate. Leptin may, thus, be associated with increased risk of prostate cancer. One hundred forty-nine men with prostate cancer were identified (together with 298 matched referents) who, before diagnosis, had participated in population-based health surveys in Northern Sweden. Blood pressure, body mass index, and use of tobacco were recorded. Leptin, insulin, insulin-like growth factor I (IGF-I), IGF-I-binding proteins 1-3, testosterone, and sex hormone-binding globulin were analyzed in stored samples. Their influences on prostate cancer were estimated by conditional logistic regression analysis. Prostate cancer specimens were investigated for immunoreactivity for the leptin receptor. Relative risk (95% confidence intervals) estimates of prostate cancer over the quintiles of leptin were 1.0, 2.1 (1.1-4.1), 2.6 (1.4-4.8), 1.4 (0.7-2.7), and 1.6 (0.8-3.2). Adjustments for metabolic variables, testosterone, and IGF-I and its binding proteins did not attenuate this increased risk. Immunoreactivity for the leptin receptor was detected in normal, high-grade prostatic intraepithelial neoplasia lesions and malignant prostatic epithelium. Moderately elevated plasma leptin concentrations are associated with later development of prostate cancer. This may be due to direct effects of leptin on prostatic intraepithelial neoplasia lesions, or to indirect actions through other mechanisms. A critical fat mass related to an interior milieu favorable for prostate cancer development seems to exist, because intermediate but not high leptin levels are related to prostate cancer risk.

Watching fights raises fish hormone levels.

Abstract: Cichlid fish wrestling for dominance induce an androgen surge in male spectators.

The Postmenopausal Ovary Is Not a Major Androgen-Producing Gland

Abstract: It is currently believed that the postmenopausal ovary remains a gonadotropin-driven, androgen-producing gland. However, the adrenal contribution to circulating androgen levels may explain some conflicting results previously reported. In addition, the steroidogenic potential and gonadotropin responsiveness of the postmenopausal ovary have not been recently reassessed. Plasma T, bioavailable T, free T, androstenedione (Adione), and dehydroepiandrosterone sulfate levels were measured in postmenopausal or ovariectomized women with complete adrenal insufficiency, compared with women with intact adrenals. A stimulation human chorionic gonadotropin test (on d 0, 3, and 6) was performed in postmenopausal women with adrenal insufficiency. Dexamethasone was administered for 4 d in postmenopausal women with intact adrenals. Intraovarian T and androstenedione were also measured in homogenates of ovarian tissue from postmenopausal women. Immunocytochemistry was performed on postmenopausal ovaries and premenopausal controls to detect the presence of steroidogenic enzymes (P-450 aromatase, P-450 SCC, 3beta HSD, and P-450 C17) and gonadotropin receptors. Plasma androgen levels were below or close to the limit of the assay in all women with adrenal insufficiency. They were similar in postmenopausal and oophorectomized women with normal adrenals. No hormonal changes were observed after human chorionic gonadotropin injections in women with adrenal insufficiency. In contrast, a dramatic decrease of all steroids was observed after dexamethasone administration in postmenopausal women with intact adrenals. Intraovarian T and androstenedione levels were negligible in postmenopausal ovarian tissue. P-450 aromatase was absent from the 17 ovaries studied, and the enzymes for androgen biosynthesis were either absent (n = 13) or present in very low amounts (n = 4). In all the postmenopausal ovaries, FSH and LH receptors were completely absent. In the absence of adrenal steroids, postmenopausal women have no circulating androgens. This result is consistent with the immunocytochemical studies showing the almost constantly absent steroidogenic enzymes and LH receptors in the postmenopausal ovary. Thus, the climacteric ovary is not a critical source of androgens. The arrest of androgen secretion after menopause may impact significantly on women's health.

Bone loss in men with prostate cancer treated with gonadotropin-releasing hormone agonists.

Abstract: Prostate cancer is the most common visceral malignancy in men. As the tumor is testosterone dependent, a frequent treatment modality involves therapy with GnRH agonists (GnRH-a) resulting in hypogonadism. Because testosterone is essential for the maintenance of bone mass in men, we postulated that GnRH-a therapy would negatively impact skeletal integrity. We compared bone mineral density (BMD), biochemical markers of bone turnover, and body composition in 60 men with prostate cancer (19 men receiving GnRH-a therapy and 41 eugonadal men) and BMD in 197 community-living healthy controls of similar age. BMD was assessed by dual energy x-ray absorptiometry and ultrasound. Biochemical markers of bone turnover, included markers of bone resorption (urinary N-telopeptide) and bone formation markers (bone-specific alkaline phosphatase and osteocalcin). Body composition (total body fat and lean body mass) was assessed by dual energy x-ray absorptiometry. Significantly lower BMD was found at the lateral spine (0.69 +/- 0.17 vs. 0.83 +/- 0.20 g/cm(2); P < 0.01), total hip (0.94 +/- 0.14 vs. 1.05 +/- 0.16 g/cm(2); P < 0.05), and forearm (0.67 +/- 0.11 vs. 0.78 +/- 0.07 g/cm(2); P < 0.01) in men receiving GnRH-a compared with the eugonadal men with prostate cancer. Significant differences were also seen at the total body, finger, and calcaneus (all P < 0.01). BMD values in eugonadal men with prostate cancer and healthy controls were similar. Markers of bone resorption (urinary N-telopeptide) and bone formation (bone-specific alkaline phosphatase) were elevated in men receiving GnRH-a therapy compared with those in eugonadal men with prostate cancer. Men receiving GnRH-a also had a higher percent total body fat (29 +/- 5% vs. 25 +/- 5%; P < 0.01) and lower percent lean body weight (71 +/- 5% vs. 75 +/- 5%; P < 0.01) compared with eugonadal men with prostate cancer. In conclusion, men with prostate cancer receiving androgen deprivation therapy have a significant decrease in bone mass and increase in bone turnover, thus placing them at increased risk of fracture.

Caveolin-1 mediates testosterone-stimulated survival/clonal growth and promotes metastatic activities in prostate cancer cells.

Abstract: Previously, we demonstrated that up-regulation of caveolin-1 (cav-1) was associated with prostate cancer metastasis, biochemical recurrence after radical prostatectomy, and androgen insensitivity. The objective of this study was to characterize the regulation of cav-1 by testosterone (T) and to test the effects of cav-1 on prostate cancer cell survival/clonal growth and metastatic activities. Our results demonstrated that T up-regulated cav-1 protein levels in part through transcriptional regulation and significantly enhanced survival of prostate cancer cell lines ABAC3 and LNCaP after serum starvation (>40% and >60% increased viability, respectively) and in an extended clonogenic assay (approximately 4-fold and 6-fold increase in colonies, respectively). Importantly, antisense cav-1 inhibited the survival effects of T in these assay systems. Modest but not high levels of adenoviral vector-mediated cav-1 expression alone also significantly increased viability (>40%) and clonal growth (10-fold increase in colonies) after serum starvation. Analysis of spontaneous metastasis in stably transfected antisense cav-1 mouse prostate cancer cell clones demonstrated reduction of spontaneous lymph node metastasis incidence (13%), spontaneous lymph node metastasis volume (46%), and experimental lung metastasis incidence (40%) compared with vector control cell clones. Surgical castration further reduced spontaneous lymph node metastasis incidence and volume (18% and 28%, respectively) in antisense cancer cell clones, but not in vector control clones. Our studies demonstrate that cav-1 is a downstream effector of T-mediated prostate cancer cell survival/clonal growth and that modest levels of cav-1 can independently promote prostate cancer cell survival/clonal growth and metastatic activities.

Reducing bioavailable sex hormones through a comprehensive change in diet: the diet and androgens (DIANA) randomized trial.

Abstract: High serum levels of testosterone and estradiol, the bioavailability of which may be increased by Western dietary habits, seem to be important risk factors for postmenopausal breast cancer. We hypothesized that an ad libitum diet low in animal fat and refined carbohydrates and rich in low-glycemic-index foods, monounsaturated and n-3 polyunsaturated fatty acids, and phytoestrogens, might favorably modify the hormonal profile of postmenopausal women. One hundred and four postmenopausal women selected from 312 healthy volunteers on the basis of high serum testosterone levels were randomized to dietary intervention or control. The intervention included intensive dietary counseling and specially prepared group meals twice a week over 4.5 months. Changes in serum levels of testosterone, estradiol, and sex hormone-binding globulin were the main outcome measures. In the intervention group, sex hormone-binding globulin increased significantly (from 36.0 to 45.1 nmol/liter) compared with the control group (25 versus 4%,; P < 0.0001) and serum testosterone decreased (from 0.41 to 0.33 ng/ml; -20 versus -7% in control group; P = 0.0038). Serum estradiol also decreased, but the change was not significant. The dietary intervention group also significantly decreased body weight (4.06 kg versus 0.54 kg in the control group), waist:hip ratio, total cholesterol, fasting glucose level, and area under insulin curve after oral glucose tolerance test. A radical modification in diet designed to reduce insulin resistance and also involving increased phytoestrogen intake decreases the bioavailability of serum sex hormones in hyperandrogenic postmenopausal women. Additional studies are needed to determine whether such effects can reduce the risk of developing breast cancer.