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.

Changes in thyroid histomorphology and thyroglobulin immunostaining upon exposure to thiourea in Triturus newts.

Amphibians are useful bioindicators for monitoring aquatic health and the influence of xenobiotics such as endocrine disrupting chemicals. Because aquatic ecosystems experience the majority of global pollution, aquatic organisms are most exposed and vulnerable to endocrine disruptors. Furthermore, penetration of endocrine disruptors into aquatic organisms especially in amphibians is even easier because of more permeable skin, resulting in high bioavailability and bioaccumulation of chemicals. One of the most potent endocrine disruptors is thiourea, which chemically blocks the synthesis of thyroid hormones and prevents metamorphosis in amphibians. We investigated the influence of thiourea on histomorphology of the thyroid gland in Triturus newts at the metamorphic stage, when thyroid hormone concentrations should reach their maximum level. Chronic exposure to thiourea induced hypertrophy and hyperplasia of follicular cells as well as a significant reduction of interstitial tissue. The intensity of the thyroglobulin immunostaining signal significantly decreases upon chronic exposure to thiourea. Successful cross-reactivity of human primary antibody in immunochemical detection of thyroglobulin in Urodela confirms potential homology in thyroglobulin structure throughout the vertebrates.

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.

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.

Maternal Dexamethasone Exposure Induces Sex-Specific Changes in Histomorphology and Redox Homeostasis of Rat Placenta.

As the mediator between the mother and fetus, the placenta allows the most appropriate environment and optimal fetal growth. The placenta of one sex sometimes has a greater ability over the other to respond to and protect against possible maternal insults. Here, we characterized sex differences in the placenta's morphological features and antioxidant status following dexamethasone (Dx) exposure. Pregnant rats were exposed to Dx or saline. The placenta was histologically and stereologically analyzed. The activity of the antioxidant enzymes, lipid peroxides (TBARS), superoxide anion and nitric oxide (NO) was measured. The decrease in placental zone volumes was more pronounced (p < 0.05) in female placentas. The volume density of PCNA-immunopositive nuclei was reduced (p < 0.05) in both sexes. The reduced (p < 0.05) antioxidant enzyme activities, enhanced TBARS and NO concentration indicate that Dx exposure triggered oxidative stress in the placenta of both fetal sexes, albeit stronger in the placenta of female fetuses. In conclusion, maternal Dx treatment reduced the size and volume of placental zones, altered placental histomorphology, decreased cell proliferation and triggered oxidative stress; however, the placentas of female fetuses exerted more significant responses to the treatment effects. The reduced placental size most probably reduced the transport of nutrients and oxygen, thus resulting in the reduced weight of fetuses, similar in both sexes. The lesser ability of the male placenta to detect and react to maternal exposure to environmental challenges may lead to long-standing health effects.

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.

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.

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.

An Extremely Low Frequency Magnetic Field and Global Cerebral Ischemia Affect Pituitary ACTH and TSH Cells in Gerbils.

The neuroendocrine system can be modulated by a magnetic field and cerebral ischemia as external and internal stressors, respectively. This study deals with the separate or combined effects of an extremely low frequency (ELF) magnetic field (50 Hz, average magnetic field of 0.5 mT) for 7 days and global cerebral ischemia for 10 min on the morpho-functional features of pituitary adrenocorticotrophic (ACTH) and thyrotrophic (TSH) cells in 3-month-old gerbils. To determine the immediate and delayed effects of the applied stressors, measurements were made on the 7th and 14th days after the onset of the experiment. The ELF magnetic field and 10-min global cerebral ischemia, separately and particularly in combination, decreased (P < 0.05) the volume density of ACTH cells, while only in combination were intracellular ACTH content and plasma ACTH concentration increased (P < 0.05) on day 7. The ELF magnetic field elevated serum TSH concentration on day 7 and intracellular TSHß content on day 14 (P < 0.05). Also, 10-min global cerebral ischemia alone increased serum TSH concentration (P < 0.05), while in combination with the ELF magnetic field it elevated (P < 0.05) intracellular TSHß content on day 14. In conclusion, an ELF magnetic field and/or 10-min global cerebral ischemia can induce immediate and delayed stimulation of ACTH and TSH synthesis and secretion. Bioelectromagnetics. 2020;41:91-103. © 2019 Bioelectromagnetics Society.

Daidzein upregulates anti-aging protein Klotho and NaPi 2a cotransporter in a rat model of the andropause.

In a rat model of the andropause we aimed to examine the influence of daidzein, soy isoflavone, on the structure and function of parathyroid glands (PTG) and the expression levels of some of the crucial regulators of Ca2+ and Pi homeostasis in the kidney, and to compare these effects with the effects of estradiol, serving as a positive control. Middle-aged (16-month-old) male Wistar rats were divided into the following groups: sham-operated (SO), orchidectomized (Orx), orchidectomized and estradiol-treated (Orx+E; 0.625mg/kg b.w./day, s.c.) as well as orchidectomized and daidzein-treated (Orx+D; 30mg/kg b.w./day, s.c.) group. Every treated group had a corresponding control group. PTH serum concentration was decreased in Orx+E and Orx+D groups by 10% and 21% (p<0.05) respectively, in comparison with the Orx. PTG volume was decreased in Orx+E group by 16% (p<0.05), when compared to the Orx. In Orx+E group expression of NaPi 2a was lower (p<0.05), while NaPi 2a abundance in Orx+D animals was increased (p<0.05), when compared to Orx. Expression of PTH1R was increased (p<0.05) in Orx+E group, while in Orx+D animals the same parameter was decreased (p<0.05), in comparison with Orx. Klotho expression was elevated (p<0.05) in Orx+D rats, in regard to Orx. Orx+D induced reduction in Ca2+/creatinine and Pi/creatinine ratio in urine by 32% and 16% (p<0.05) respectively, in comparison with Orx. In conclusion, presented results indicate the more coherent beneficial effects of daidzein compared to estradiol, on disturbed Ca2+ and Pi homeostasis, and presumably on bone health, in the aging male rats.

Morphofunctional parameters of rat somatotrophes after acute and repeated immobilization or restraint stress.

It is well known that stress changes levels of pituitary hormones in the bloodstream and in the pituitary itself. However, almost nothing is known about the impact of stress on histological and stereological parameters of the growth hormone producing cells (somatotrophs-GH cells). The aim of the present study was to investigate the effect of: acute and repeated immobilization; acute and repeated restraint on histological and morphofunctional parameters of somatotrophs in adult Wistar rats. Changes in the pituitary gland volume; the volume density and volume of somatotrophs following acute and repeated immobilization (IMO, R-IMO); acute and repeated restraint (R, R-R) were evaluated using a stereological system (newCAST), while growth hormone level within pituitary was determined by Western blot. Our results demonstrated the decrease (p < 0.05) of the pituitary volume (17%, 19%) in the IMO and R groups, respectively, and the increase in the R-R group. The volume density of GH cells decreased (p < 0.05) in the R-IMO (7%), R (26%) and R-R (18%) group in comparison to the control value. The pituitary GH content was increased (p < 0.05) after the IMO (2-fold), R (2.5-fold) and R-R (2.1-fold) as compared to the control group. These results point out that acute and repeated immobilization and/or restraint lead not only to changes in GH hormone concentration, but also modify the morphological aspects of GH cells within the rat pituitary.

Somatopause, weaknesses of the therapeutic approaches and the cautious optimism based on experimental ageing studies with soy isoflavones.

The pathological phenomenon of somatopause, noticeable in hypogonadal ageing subjects, is based on the growth hormone (GH) production and secretion decrease along with the fall in GH binding protein and insulin-like growth factor 1 (IGF-1) levels, causing different musculoskeletal, metabolic and mental issues. From the perspective of safety and efficacy, GH treatment is considered to be highly controversial, while some other therapeutic approaches (application of IGF-1, GH secretagogues, gonadal steroids, cholinesterase-inhibitors or various combinations) exhibit more or less pronounced weaknesses in this respect. Soy isoflavones, phytochemicals that have already demonstrated the health benefits in treated elderly, at least experimentally reveal their potential for the somatopausal symptoms remediation. Namely, genistein enhanced GHRH-stimulated cAMP accumulation and GH release in rat anterior pituitary cells; refreshed and stimulated the somatotropic system (hypothalamic nuclei and pituitary GH cells) function in a rat model of the mild andropause, and stimulated the GH output in ovariectomized ewes as well as the amplitude of GH pulses in the rams. Daidzein, on the other hand, increased body mass, trabecular bone mass and decreased bone turnover in the animal model of severe andropause, while both isoflavones demonstrated blood cholesterol-lowering effect in the same model. These data, which necessarily need to be preclinically and clinically filtered, hint some cautious optimism and call for further innovative designing of balanced soy isoflavone-based therapeutics.