Lemon extract reduces the hepatic oxidative stress and persulfidation levels by upregulating the Nrf2 and Trx1 expression in old rats.

Citrus flavanones are recognized as promising bioactives within the concept of healthy aging. Thus, the present study investigated the effects of a nutritionally relevant dose of lemon extract (LE) on liver redox regulation and persulfidation levels in 24-month-old Wistar rats. LE (40 mg/kg b.m.) was administered orally once daily for 4 weeks. Control groups received either vehicle (sunflower oil) or remained intact. The applied methodology considered qPCR, Western blot, protein persulfidation levels evaluation, histochemistry in line with immunofluorescence, liver biochemical assays (glutathione, total -SH groups and malonaldehyde; MDA), liver enzymes in serum and in silico analysis to explore the potential interaction/binding between the proteins studied in the paper. Our results showed that LE increased glutathione peroxidase (GPx), reductase (GR), glutamate-cysteine ligase catalytic and modifier subunit, respectively, as well as Nrf2 gene expressions, but decreased the expression of superoxide dismutase 2 (SOD2). Upon LE application, protein expression showed upregulation of NRF2, SOD2, GPx, GR, and thioredoxin 1 (Trx1). LE significantly decreased the protein persulfidation levels and concentration of MDA, a marker of oxidative damage in the cell. Histological analysis showed a normal liver histoarchitecture without pathological changes, aligning with the normal serum level of hepatic enzymes. Obtained results showed that LE, by modulating hepatic redox regulators Nrf2 and Trx1, diminishes oxidative stress and alters the persulfidation levels, suggesting a considerable beneficial antioxidant potential of lemon flavanones in the old-aged liver.

Differences in Cholesterol Metabolism, Hepato-Intestinal Aging, and Hepatic Endocrine Milieu in Rats as Affected by the Sex and Age.

Age and sex influence serum cholesterol levels, but the underlying mechanisms remain unclear. To investigate further, we measured cholesterol, precursors (surrogate synthesis markers), degradation products (oxysterols and bile acid precursors) in serum, the liver, jejunum, and ileum, as well as serum plant sterols (intestinal absorption markers) in male and female Wistar rats (4 and 24 months old). The analysis of histomorphometric and oxidative stress parameters (superoxide dismutase, catalase, glutathione-related enzyme activities, lipid peroxide, and protein carbonyl concentrations) in the liver and jejunum offered further insights into the age- and sex-related differences. The hepatic gene expression analysis included AR, ERα, and sex-specific growth hormone-regulated (Cyp2c11 and Cyp2c12) and thyroid-responsive (Dio1, Tbg, and Spot 14) genes by qPCR. We observed age-related changes in both sexes, with greater prominence in females. Aged females had significantly higher serum cholesterol (p < 0.05), jejunum cholesterol (p < 0.05), and serum plant sterols (p < 0.05). They exhibited poorer hepato-intestinal health compared with males, which was characterized by mild liver dysfunction (hydropic degeneration, increased serum ALT, p < 0.05, and decreased activity of some antioxidant defense enzymes, p < 0.05), mononuclear inflammation in the jejunal lamina propria, and age-related decreases in jejunal catalase and glutathione peroxidase activity (p < 0.05). Aged females showed increased levels of 27-hydroxycholesterol (p < 0.05) and upregulated ERα gene expression (p < 0.05) in the liver. Our study suggests that the more significant age-related increase in serum cholesterol in females is associated with poorer hepato-intestinal health and increased jejunal cholesterol absorption. The local increase in 27-hydroxycholesterol during aging might reduce the hepatoprotective effects of endogenous estrogen in the female liver.

Biologia Futura: does the aging process contribute to the relativity of time?

In his Theory of relativity, Einstein determined that the time is relative to the reference frame of the observer. Under specific conditions, there is a difference in the elapsed time between two clocks, known as time dilation. A similar relativistic effect could be attributed to the brain operating at different frequencies, e.g., while it is slow and during the thought process. Time flow and the aging process are causally linked. Herein, we introduce physical relativity into the mind/thought context and elaborate changed perception of the time flow (the impression of the time acceleration) with aging. The phenomenology of time is observed in the context of physical and biological clock, as well as by introducing the category of 'mind time.' Mental processing impairment is crucial for the "aging-caused relativity of time," while adjusting of its' perception seems to be a matter of body/mind rest, mental hygiene and physical activity of the aging subject. We also provide a brief overview of the perception of time flow in some disease states that coincide with aging. Our main idea has a perspective for future development in the interdisciplinary synergy of philosophy, physical-mathematical elaboration, experimental biology and clinical investigations.

Age-Related Changes in Calcitonin-Producing Thyroid C-Cells of Male Wistar Rats.

Thyroid C-cells secrete the hormone calcitonin (CT) which acts as an inhibitor of bone resorption. Our aim was to examine the age-related changes in the structure and function of CT-producing C-cells, using histomorphometric, ultrastructural, and biochemical analyses. We used young adult (3-months-old), middle-aged (16-months-old), and old (24-months-old) male rats. The peroxidase-antiperoxidase method was applied for localization of CT. Stereological analysis was performed using the newCAST stereological software package. Serum samples were analyzed for the determination of CT, testosterone (T), calcium (Ca2+), and phosphorus (P). We found a significant increase in the volume density (Vv) of C-cells in both older groups (p < 0.05). The percentage of smaller volume range C-cells increased (p < 0.0001), while the proportion of greater volume range C-cells decreased (p < 0.05) with ageing. Ultrastructural analysis revealed a larger number of secretory granules in older rats. Serum CT increased (p < 0.001), while serum T and P were reduced (p < 0.01) in older rats. Serum Ca2+ was lower (p < 0.0001) in middle-aged rats compared to young adults. We revealed a 20% incidence of C-cell hyperplasia in older rats and one case of medullary thyroid carcinoma in an old rat. Our findings indicate that the ageing process causes significant histomorphometric changes at the thyroid C-cell level.

Systematic analysis of nutrigenomic effects of polyphenols related to cardiometabolic health in humans - Evidence from untargeted mRNA and miRNA studies.

Cardiovascular and metabolic disorders present major causes of mortality in the ageing population. Polyphenols present in human diets possess cardiometabolic protective properties, however their underlying molecular mechanisms in humans are still not well identified. Even though preclinical and in vitro studies advocate that these bioactives can modulate gene expression, most studies were performed using targeted approaches. With the objective to decipher the molecular mechanisms underlying polyphenols cardiometabolic preventive properties in humans, we performed integrative multi-omic bioinformatic analyses of published studies which reported improvements of cardiometabolic risk factors following polyphenol intake, together with genomic analyses performed using untargeted approach. We identified 5 studies within our criteria and nearly 5000 differentially expressed genes, both mRNAs and miRNAs, in peripheral blood cells. Integrative bioinformatic analyses (e.g. pathway and gene network analyses, identification of transcription factors, correlation of gene expression profiles with those associated with diseases and drug intake) revealed that these genes are involved in the processes such as cell adhesion and mobility, immune system, metabolism, or cell signaling. We also identified 27 miRNAs known to regulate processes such as cell cytoskeleton, chemotaxis, cell signaling, or cell metabolism. Gene expression profiles negatively correlated with expression profiles of cardiovascular disease patients, while a positive correlation was observed with gene expression profiles following intake of drugs against cardiometabolic disorders. These analyses further advocate for health protective effects of these bioactives against age-associated diseases. In conclusion, polyphenols can exert multi-genomic modifications in humans and use of untargeted methods coupled with bioinformatic analyses represent the best approach to decipher molecular mechanisms underlying healthy-ageing effects of these bioactives.

Vitamin D3 Treatment Alters Thyroid Functional Morphology in Orchidectomized Rat Model of Osteoporosis.

Vitamin D plays an essential role in prevention and treatment of osteoporosis. Thyroid hormones, in addition to vitamin D, significantly contribute to regulation of bone remodeling cycle and health. There is currently no data about a possible connection between vitamin D treatment and the thyroid in the context of osteoporosis. Middle-aged Wistar rats were divided into: sham operated (SO), orchidectomized (Orx), and cholecalciferol-treated orchidectomized (Orx + Vit. D3; 5 µg/kg b.m./day during three weeks) groups (n = 6/group). Concentration of 25(OH)D in serum of the Orx + Vit. D3 group increased 4 and 3.2 times (p < 0.0001) respectively, compared to Orx and SO group. T4, TSH, and calcitonin in serum remained unaltered. Vit. D3 treatment induced changes in thyroid functional morphology that indicate increased utilization of stored colloid and release of thyroid hormones in comparison with hormone synthesis, to maintain hormonal balance. Increased expression of nuclear VDR (p < 0.05) points to direct, TSH independent action of Vit. D on thyrocytes. Strong CYP24A1 immunostaining in C cells suggests its prominent expression in response to Vit. D in this cell subpopulation in orchidectomized rat model of osteoporosis. The indirect effect of Vit. D on bone, through fine regulation of thyroid function, is small.

Genistein regulates calcium and phosphate homeostasis without activation of MEK 1/2 signalling pathway in an animal model of the andropause.

Soy isoflavone genistein interplays with numerous physiological or pathophysiological processes during ageing. However, its protective role and underlying mechanisms of action in the regulation of calcium (Ca2+) and phosphate (Pi) homeostasis in an animal model of the andropause are yet to be fully clarified. Wistar male rats (16-month-old) were divided into sham-operated, orchidectomized, orchidectomized estradiol-treated (0.625 mg/kg b.m./day) and orchidectomized genistein-treated (30 mg/kg b.m./day) groups. Treatments were administered subcutaneously for 3 weeks, while the controls received vehicle alone. Estradiol treatment increased the expression level of fibroblast growth factor receptor (FGFR) and parathyroid hormone 1 receptor (PTH1R), and activated mitogen - activated protein kinase kinase 1/2 (MEK 1/2) signaling pathway in the kidneys. Genistein application induced a prominent gene and protein expression of Klotho and downregulated the expression of FGFR and PTH1R in the kidney of andropausal rats. Activation of protein kinase B (Akt) signalling pathway was observed, while MEK 1/2 signaling pathway wasn't altered after genistein treatment. The increase of 25 (OH) vitamin D in the serum and decrease in Ca2+ urine content was observed after genistein application. Our findings strongly suggest genistein as a potent biocompound with beneficial effects on the regulation of Ca2+ and Pi homeostasis, especially during aging process when the balance of mineral metabolism is impaired. These novel data provide closer insights into the physiological roles of genistein in the regulation of mineral homeostasis.

Systematic Bioinformatic Analyses of Nutrigenomic Modifications by Polyphenols Associated with Cardiometabolic Health in Humans-Evidence from Targeted Nutrigenomic Studies.

Cardiometabolic disorders are among the leading causes of mortality in the human population. Dietary polyphenols exert beneficial effects on cardiometabolic health in humans. Molecular mechanisms, however, are not completely understood. Aiming to conduct in-depth integrative bioinformatic analyses to elucidate molecular mechanisms underlying the protective effects of polyphenols on cardiometabolic health, we first conducted a systematic literature search to identify human intervention studies with polyphenols that demonstrate improvement of cardiometabolic risk factors in parallel with significant nutrigenomic effects. Applying the predefined inclusion criteria, we identified 58 differentially expressed genes at mRNA level and 5 miRNAs, analyzed in peripheral blood cells with RT-PCR methods. Subsequent integrative bioinformatic analyses demonstrated that polyphenols modulate genes that are mainly involved in the processes such as inflammation, lipid metabolism, and endothelial function. We also identified 37 transcription factors that are involved in the regulation of polyphenol modulated genes, including RELA/NFKB1, STAT1, JUN, or SIRT1. Integrative bioinformatic analysis of mRNA and miRNA-target pathways demonstrated several common enriched pathways that include MAPK signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway, focal adhesion, or PPAR signaling pathway. These bioinformatic analyses represent a valuable source of information for the identification of molecular mechanisms underlying the beneficial health effects of polyphenols and potential target genes for future nutrigenetic studies.

Molecular Determinants of the Cardiometabolic Improvements of Dietary Flavanols Identified by an Integrative Analysis of Nutrigenomic Data from a Systematic Review of Animal Studies.

SCOPE: Flavanols are important polyphenols of the human diet with extensive demonstrations of their beneficial effects on cardiometabolic health. They contribute to preserve health acting on a large range of cellular processes. The underlying mechanisms of action of flavanols are not fully understood but involve a nutrigenomic regulation. METHODS AND RESULTS: To further capture how the intake of dietary flavanols results in the modulation of gene expression, nutrigenomics data in response to dietary flavanols obtained from animal models of cardiometabolic diseases have been collected and submitted to a bioinformatics analysis. This systematic analysis shows that dietary flavanols modulate a large range of genes mainly involved in endocrine function, fatty acid metabolism, and inflammation. Several regulators of the gene expression have been predicted and include transcription factors, miRNAs and epigenetic factors. CONCLUSION: This review highlights the complex and multilevel action of dietary flavanols contributing to their strong potential to preserve cardiometabolic health. The identification of the potential molecular mediators and of the flavanol metabolites driving the nutrigenomic response in the target organs is still a pending question which the answer will contribute to optimize the beneficial health effects of dietary bioactives.

Development of genistein-loaded gold nanoparticles and their antitumor potential against prostate cancer cell lines.

Soy isoflavone genistein (Gen) exerts beneficial effects against prostate cancer cells in vitro and in vivo. However, its use as a chemoprevention/therapeutic agent is largely limited due to its low bioavailability. In this study we synthesized two variants of a new delivery system, genistein-gold nanoparticles conjugates Gen@AuNPs1 and Gen@AuNPs2, by an environmentally friendly method, using a dual role of Gen to reduce Au3+ and stabilize the formed AuNPs, with no additional component. The formation of Gen@AuNPs was confirmed via UV-Vis spectroscopy, FTIR, and Raman spectra measurements. The spherical shape and uniform size of Gen@AuNPs1 and Gen@AuNPs2 (10 ± 2 and 23 ± 3 nm, respectively), were determined by transmission electron microscopy. The nano-conjugates also varied in hydrodynamic diameter (65.0 ± 1.7 and 153.0 ± 2.2 nm) but had similar negative zeta potential (-35.0 ± 2.5 and -37.0 ± 1.6 mV), as measured by dynamic light scattering. The Gen loading was estimated to be 46 and 48%, for Gen@AuNPs1 and Gen@AuNPs2, respectively. The antiproliferative activities of GenAuNPs were confirmed by MTT test in vitro on three malignant prostate carcinoma cell lines (PC3, DU 145, and LNCaP), while selectivity toward malignant phenotype was confirmed using non-cancerous MRC-5 cells. Flow cytometric analysis showed that the inhibition on cell proliferation of more potent Gen@AuNPs1 nano-conjugate is comparable with the effects of free Gen. In conclusion, the obtained results, including physicochemical characterization of newly synthesized AuNPs loaded with Gen, cytotoxicity, and IC50 assessments, indicate their stability and bioactivity as an antioxidant and anti-prostate cancer agent, with low toxicity against human primary cells.

Thyroid Gland Alterations in Old-Aged Wistar Rats: A Comprehensive Stereological, Ultrastructural, Hormonal, and Gene Expression Study.

The aim of the present study was to determine and elaborate on all changes in old-aged (OA) versus young-aged (YA) rat thyroids by using stereological, ultrastructural, hormonal, and gene expression analyses. We used 4- and 24-month-old male Wistar rats in our evaluation, presenting all changes in comparison with YA rats. Results showed that the thyroid parenchyma was characterized by higher absolute volumes of the gland, colloid, epithelium, and interstitium by 135, 135, 140, and 142% (p < 0.05) respectively, while the relative volumes of colloid and glands were unchanged. Ultrastructural analysis revealed less active glands, with smaller amounts of lysosomes, thyroglobulin (Tg) granules, and microvilli in the luminal colloid. Optical density values for thyroid peroxidase (TPO), Tg, and vascular-endothelial growth factor immunostaining remained unchanged; however, TPO and Tg exhibited visually stronger expression in small active follicles. Thyroxine (T4)-Tg, the relative intensity of fluorescence (RIF), serum T4, and the sodium-iodide symporter immunohistochemical and gene expressions decreased by 20, 40, 29, and 31% (p < 0.05), respectively, in OA thyroids. Pituitary thyroid-stimulating hormone (TSH) RIF increased by 44% (p < 0.05), but the TSH serum concentration remained unchanged. In conclusion, the obtained results indicate depression of the thyroid gland synthetic and secretory capacity with advanced age.

Soy isoflavone-caused shunting of the corticosteroidogenesis pathways in andropausal subjects: Top-down impulse for the optimal supplementation design.

In a series of our previous works, we revealed the beneficial effects of applied soy isoflavones (genistein or daidzein) on the wide context of corticosteroidogenesis in vivo, in a rat model of the andropause. Soy isoflavones decreased the circulating levels of pituitary adrenocorticotropic hormone, inhibited aldosterone secretion, as well as corticosterone production and secretion, but stimulated dehydroepiandrosterone secretion, all in andropausal rats. In vitro studies indicate that the mechanism underlying these hormonal changes relies on inhibition of the pituitary tyrosine kinase and adrenocortical 3ß-hydroxysteroid dehydrogenase enzymes by soy isoflavones. Although the clinical studies are in their infancy, the opinion is that genistein and daidzein have therapeutic potential for the safe treatment of ageing-caused androgen deprivation and glucocorticoid excess with related metabolic/hemodynamic issues in males. Our accumulated experience and knowledge in the field of biomedical effects of plant polyphenols have provided a platform for potential recommending the agenda to organize and accelerate experimental research aimed at producing the optimal supplementation. We hypothesize that an in vivo approach should first be exploited in the sequence of investigative steps, followed by in vitro studies and synchronously conducted molecular docking analyses. In vivo research, besides establishing the margin of exposure safety or adjustment of the correct polyphenol dose, enables identification and quantification of the metabolites of applied polyphenols in the blood. Subsequent in vitro exploitation of the metabolites and related docking analyses provide clarification of the molecular mechanisms of action of applied polyphenols. Chemical modification of the polyphenol structure or coupling it with nanoparticles might be the next step in optimizing the design of supplementation. Selected, intact or chemically-modified polyphenol molecules should be included in preclinical studies on a more closely-related species, while clinical studies would finally assess the safety and effectiveness of a polyphenol-based remedial strategy. The final supplement represents a product of an appropriate technological process, conducted in accordance with the recommendations derived from the preceding research.

A Moderate Increase in Ambient Temperature Influences The Structure and Hormonal Secretion of Adrenal Glands in Rats.

OBJECTIVE: As a consequence of global warming, the increase in the average annual temperature is observed, while the living organisms actively adapt to these changes. High environmental temperature initiates numerous physiological, autonomic, and behavioral responses, and activates the stress response. Thus, the aim of the study was to investigate effect of a moderate increase in ambient temperature on the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis by determining histological changes in adrenal glands and hormonal levels in adult male rats. MATERIALS AND METHODS: In this experimental study, the morpho-functional state of adrenal glands was estimated by stereological evaluation of parameters, including the adrenal volume, adrenocortical cell/nuclear size and number, and the volume density of vascular tissues after four days of exposure to a moderate increase in ambient temperature of 35 ± 1˚C. Novelli histochemical and vascular endothelial growth factor (VEGF) immunohistochemical staining provided insight into the adrenal gland vascular network. Additionally, the adrenal levels of aldosterone, corticosterone, and pituitary adrenocorticotropic hormone (ACTH) were determined as crucial indicators of the hypothalamic-pituitaryadrenocortical (HPA) axis activity. RESULTS: Prolonged exposure to a moderate increase in ambient temperature for four days resulted in a significant increase in ACTH level up to 24%, which altered adrenal glands both structurally and functionally. The adrenocortical volume and number of cells in all cortical zones were markedly increased (P<0.05). A statistically significant increase was shown in the level of aldosterone (16%) and corticosterone (25%) in serum levels of individuals. CONCLUSION: Increased activity of the HPA axis reflects the response to a moderate increase in ambient temperature during four days, showing the capacity of the HPA axis to adapt the organism to daily temperature changes.

Citrus Flavanones Upregulate Thyrotroph Sirt1 and Differently Affect Thyroid Nrf2 Expressions in Old-Aged Wistar Rats.

A growing population of elderly people consume citrus flavanones, naringenin, and hesperetin in the form of fruits or juices. Flavanones are bioactives with potent antioxidant properties and have potential in slowing down the aging process. Because flavanones exert controversial effects on pituitary-thyroid functioning, our study on the old-aged rat model aimed to elucidate the mechanism by which naringenin and hesperetin affect this axis. Naringenin and hesperetin increased the Sirt1 mRNA level by 91 and 71% (p < 0.05), which was followed by increased Sirt1 expression by 20 and 15% (p < 0.05), respectively. Only naringenin decreased thyroid-stimulating hormone expression by 20% (p < 0.05). Thyroid peroxidase protein expression was upregulated after naringenin or hesperetin by 62 and 43% (p < 0.05), respectively. Naringenin lowered mRNA levels of Tpo, Sod1, Sod2, Cat, and Nrf2 by 50, 32, 45, 35, and 42% (p < 0.05), respectively, and increased Gpx by 54% (p < 0.05), while hesperetin decreased Sod1 and Sod2 mRNA levels by 46 and 55% (p < 0.05), respectively. Naringenin increased the protein expressions of Nrf2 and SOD2 by 58 and 50% (p < 0.05), respectively, and decreased SOD1 expression by 48% (p < 0.05), while hesperetin protein decreased expressions of SOD1 and Nrf2 by 63 and 32% (p < 0.05), respectively. Altogether, our findings suggest that citrus flavanones contribute to restoring the impaired thyroid functioning in the old-aged rats.

Immunohistomorphometric and Hormonal Analysis of the Pituitary Gonadotropic Cells After Application of the Nandrolone Decanoate and Swimming Training in Adult Male Rats.

The aim of the study was to investigate the effects of chronic nandrolone decanoate treatment and/or swimming training on immunohistomorphometric parameters on rat pituitary gonadotropic cells. Male Wistar albino rats, 10 weeks old, were classified into four groups: control (T−N−), nandrolone (T−N+), swimming training (T+N−), and swimming training with nandrolone (T+N+). The T+ groups swam for 4 weeks, 1 h/day, 5 days/week. The N+ groups received nandrolone decanoate (20 mg/kg) once per week for 4 weeks. Pituitary tissue sections were processed and stained for immunohistochemical analysis and immunofluorescence. The volume density of luteinizing hormone (LH) cells was decreased by 48% in T−N+ and for 35% in the T+N+ group. The volume density of follicle-stimulating hormone (FSH) cells was decreased by 39% in T−N+ and for 30% in T+N+ compared to the control. Nandrolone alone, or combined with swimming training, decreased the number of LH/FSH cells compared to the control. The levels of the immunofluorescent signal of LH/FSH cells were increased in all experimental groups. Nandrolone alone decreased the serum level of LH by 17%, whereas swimming training alone increased FSH levels by 11% compared to the control. Serum levels of testosterone were increased in all experimental groups. Nandrolone alone, or combined with swimming training, decreased immunohistomorphometric parameters of gonadotropic cells, whereas the levels of immunofluorescent signal were increased.

The effects of prenatal dexamethasone exposure and fructose challenge on pituitary-adrenocortical activity and anxiety-like behavior in female offspring.

Prenatal glucocorticoid overexposure could largely influence pituitary-adrenal activity and anxiety-like behavior in offspring. Our aim was to study the possible potentiating effect of moderate dose of fructose - common ingredient of today's diet - on prenatal glucocorticoid treatment-induced hypothalamo-pituitary-adrenal (HPA) axis changes. Pregnant female rats were treated with multiple dexamethasone (Dx) doses (3 x 0.5 mg/kg/b.m. Dx; 16th-18th gestational day). Half of female offspring from control and Dx treated dams were supplemented with 10% fructose solution, from weaning till adulthood. Immunohistochemistry, unbiased stereological evaluation and hormonal analysis are used to provide the morpho-functional state of pituitary and adrenal gland. Anxiety-like behavior was assessed using the light/dark box test and the elevated plus maze test. Prenatally Dx exposed females, with or without fructose consumption, had markedly reduced adrenocortical volume (p < 0.05) comparing to controls. Increased basal plasma ACTH level in these females (p < 0.05) maintained corticosterone concentration at control level produced by smaller adrenal glands. In parallel, anxiety-like behavior was shown by both tests used. In conclusion, prenatal Dx exposure cause negative psychophysiological outcome reflected in increased HPA axis activity and anxiety behavior in female offspring, while moderately increased fructose consumption failed to evoke any alteration or to potentiate effects of prenatal Dx exposure.

Pituitary Hyperplasia, Hormonal Changes and Prolactinoma Development in Males Exposed to Estrogens-An Insight From Translational Studies.

Estrogen signaling plays an important role in pituitary development and function. In sensitive rat or mice strains of both sexes, estrogen treatments promote lactotropic cell proliferation and induce the formation of pituitary adenomas (dominantly prolactin or growth-hormone-secreting ones). In male patients receiving estrogen, treatment does not necessarily result in pituitary hyperplasia, hyperprolactinemia or adenoma development. In this review, we comprehensively analyze the mechanisms of estrogen action upon their application in male animal models comparing it with available data in human subjects. Sex-specific molecular targets of estrogen action in lactotropic (PRL) cells are highlighted in the context of their proliferative and secretory activity. In addition, putative effects of estradiol on the cellular/tumor microenvironment and the contribution of postnatal pituitary progenitor/stem cells and transdifferentiation processes to prolactinoma development have been analyzed. Finally, estrogen-induced morphological and hormone-secreting changes in pituitary thyrotropic (TSH) and adrenocorticotropic (ACTH) cells are discussed, as well as the putative role of the thyroid and/or glucocorticoid hormones in prolactinoma development, based on the current scarce literature.

The adrenal cortex after estradiol or daidzein application in a rat model of the andropause: Structural and hormonal study.

INTRODUCTION AND AIM: Daidzein application may represent an effective and less harmful alternative to indicated, classical estrogenization of ageing men. The aim of this study was to perform structural and hormonal analysis of the adrenal cortex, after estradiol or daidzein supplementation in a rat model of the andropause. MATERIAL AND METHODS: Middle-aged Wistar rats were divided into sham operated (SO; n = 8), orchidectomized (Orx; n = 8), estradiol treated orchidectomized (Orx + E; n = 8) and daidzein treated orchidectomized (Orx + D; n = 8) groups. Estradiol (0.625 mg/kg b.m./day) or daidzein (30 mg/kg b.m./day) were administered subcutaneously for three weeks, while the SO and Orx groups received the vehicle alone. Set objectives were achieved using stereology, histochemistry/immunohistochemistry, immunoassays and ultrastructural analysis. RESULTS: Both estradiol and daidzein treatment significantly increased volumes of the zona glomerulosa cell and nuclei, but decreased circulating aldosterone levels. Estradiol markedly increased volumes of the zona fasciculata cell and nuclei in parallel with significant decrease of the adrenal tissue level of corticosterone, while daidzein significantly decreased both the adrenal and circulating levels of corticosterone. Serum DHEA level and volumes of the zona reticularis cell and nuclei significantly increased upon estradiol treatment, whereas daidzein even stronger increased the circulating level of DHEA. Shunting of the corticosteroidogenesis pathways towards adrenal androgens production, after the treatments, corresponded to the ultrastructural findings and zonal capillary network rearrangements. CONCLUSIONS: Given the coherence of its effects and relative safety, daidzein could be the remedy of choice for the treatment of ageing-caused androgen deprivation and the hypothalamo-pituitary-adrenal axis hyperfunction/related metabolic issues in males.