[CHANGES IN THE BRAIN TESTOSTERONE METABOLISM AND SEXUAL BEHAVIOR IN MALE RATS PRENATALLY EXPOSED TO METHYLDOPA AND STRESS].

The changes of aromatase and 5α-reductase activities were studied in preoptic area (POA) and medial basal hypothalamus of 10-days-old and sexual behavior in 3-month-old male offsprings of rats exposed daily to noradrenaline antagonist methyldopa (400 mg/kg per os) 30 minutes prior to 1-hour immobilization during the last week of pregnancy (from 15th to 21st day). Prenatal stress caused aromatase activity lowering in the POA of developing brain and feminization (appearance of lordosis) and demasculinization of sexual behavior (prolongation of latent periods to the first mounting and first intromission as well as of the first ejaculation and postejaculation refractory period) in young male offspring. Oral methyldopa used prior to pregnant females stressing prevented early effect of prenatal stress on aromatase activity in the POA and normalized the male sexual behavior in young male rats by shortening both latent period to the first ejaculation and postejaculation refractory period, and an increase of numbers of ejaculation. The data obtained indicate that brain noradrenergic system plays significant role in the mechanisms of metabolic- and behavioral disturbances developing in male rats exposed to prenatal stress.

[Morphofunctional state of reproductive system of ageing male rats in case of using nanocerium].

The influence of nanocrystalline cerium dioxide (NCD, 1 and 100 mg/kg per os daily for 10 days) on morphofuctional state of reproductive system was investigated in ageing male rats. It has been established that activation of hormone-producing testicular Leydig's cells, as well as of secretory and proliferative processes in prostate, underlies the stimulating effect of NCD at a dose 1 mg/kg on hormonal function of testis and spermatogenesis of ageing male rats. NCD used at a dose 100 mg/kg had no significant effect on the assessed indices of morphofuctional state of reproductive system.

[Peculiarities of sexual behavior of female rats with hyperandrogenia in pubertal and postpubertal periods].

The parameters of female and male sexual behavior in 3- and 6- month old female rats which were exposed to an androgen excess (subcutaneous implantation of Silastic capsules containing 5 mg of crystalline testosterone) from the beginning of pubertal period (at the age of 35 days), or within postpubertal period (at the age of 4 months). Hyperandrogenia in pubertal period had no effect on female sexual behavior formation, but it led to appearance of male behavior components in 100% of animals. In female rats which were implanted with testosterone capsules in postpubertal period, sexual disturbances were more pronounced and were characterized by masculinization and defeminization, which was due to a higher degree of androgenic saturation. The data obtained suggest a leading role of hyperandrogenemia in the pathogenesis of sexual behavior disturbances in female rats in different periods of individual development.

[The dynamics of hormonal changes in female rats exposed to chronic stress and androgen excess during pubescence].

The dynamics of blood plasma corticosterone, testosterone and androstenedione levels and their reaction to acute stress (30 min immobilization) in 35-, 40- and 45-day old female rats exposed to chronic stress (daily 30-min immobilization from 35th to 45th day of life) and/or to excess of exogenous androgens (implantation of capsules with testosterone to 33-day old animals) during pubescence was studied. Both control and experimental females in all age groups responded to acute stress by significant elevation of blood plasma corticosterone levels. At the end of the chronic stress session, the extent of adrenals activation in response to acute dosed stress was lowered in androgenized 45-day old females and increased gradually in stressed ones. After acute stress, the blood plasma testosterone level decreased in control 35-day old females and rose - in androgenized females against 10-fold rising of basal hormonal level. In 40-day old control females as well as in androgenized ones exposed to chronic stress during 5 days, the acute dosed stress did not result in significant changes of blood plasma testosterone and elevated blood plasma androstenedione. Stressed 40-day old females with increased basal androstenedione secretion did not respond to acute stress by the hormone level changes while blood plasma testosterone declined significantly. At the end ofpubescence (on the 45th day of life), acute stress did not affect the blood plasma testosterone level in control and androgenized animals, while decreased it in stressed females and increased - in androgenized rats exposed to chronic stress against elevated basal level of the hormone. The conclusion is made about possible functional relationship between the changes in hormonal homeostasis during pubescence and development of reproductive system in mature animals.

[Effect of chronic stress during puberty on the reproductive system of female rats with experimental hyperandrogenicity].

Effects of chronic stress (daily 30-min immobilization) on 35-45 days of life and its combination with androgenization (implantation of testosterone-containing capsules on 33rd day of life) on reproductive system of 2.5 month old female rats were studied. The term of sexual maturation, estrous cycles regularity and structure, blood plasma levels of testosterone, progesterone and androstenedione as well as ovarian histology were examined. Androgenization resulted in the blood plasma testosterone level increase and the androstenedione level decrease, development of oligo- or anovulatory condition characterized by disorders or discontinuation in estrous cyclicity. We also detected abrupt reduction or absence of postovulatory luteal bodies, cysts formation and ovarian interstitial tissue overgrowth. All experimental animals had normal blood plasma corticosterone level. Stressed rats had no considerable changes in reproductive system except of some cyclicity disorders. Stressed against androgenization rats demonstrated delayed pubescence, an increased number of ovarian cysts along with attenuation ofandrogenization-caused negative effects on the sexual cyclicity.

[Enhancing effect of androgen receptor antagonist on gonadotropic inductors of ovulation in rats with polycystic ovaries].

Hormonal indices, phase pattern of estrous cycles, and histological structure of the ovaries were studied in female rats with polycystic ovaries caused by subcutaneous implantation of Silastic capsules with testosterone after consecutive treatment with non-steroid antiandrogen, flutamide (flutafarm), urinary FSH (menopur) and HCG (choragon). It was shown that while the plasma testosterone level was increased, administration of the drugs in subtherapeutical doses interrupted persistent diestrus, renewed estrous cycle, gonadal and uterine weights, induced appearance of postovulatory luteal bodies and restored fertility. Therefore, antiandrogen potentiation of pharmnnaco-dynamic effect of the gonadotropins with regard to their ability to ovulation induction was found out.

Prenatal dexamethasone prevents early and long-lasting neuroendocrine and behavioral effects of maternal stress on male offspring.

The hypothesis on the mediating role of hypothalamic-pituitary-adrenocortical (HPA) hormone secretion in neuroendocrine, neurochemical and behavioral alterations generated by prenatal stress in male rat offspring was tested in this study with dexamethasone (Dex) used for suppression of HIPA stress responses. Pregnant dams were being restrained daily for 1 h over the last week of gestation. In male offspring this resulted in attenuation of sex-specific pattern of the protein fractions (on the 5th postnatal day), steroid aromatase activity (on the 10th postnatal day) in the brain preoptic area, and in a decrease of male copulatory behavior, hypothalamic noradrenaline and plasma corticosterone responses to an acute stress, an increase in HPA responses to noradrenergic stimulation and other effects in adulthood. All those changes were prevented with prenatal Dex in a dose of 0.1 mg/kg b.w. injected 30 min prior to restraining pregnant dams. As such, HPA hormone secretion mediates alterations of programming of brain development induced by prenatal stress.

[Peculiarities of stress-reactivity of hypothalamo-pituitary-adrenal system in prenatally stressed rats exposed to dexamethasone].

The protective effect of dexamethasone, a synthetic agonist of glucocorticoids, on the functional activity of hypothalamo-pituitary-adrenal system (HPAS) in adult offspring in both genders whose mothers were subject to immobilization stress in last trimester of pregnancy, has been studied. Dexamethasone treatment prior to stressing pregnant rats prevented the manifestations of injuring effect of prenatal stress on HPAS activity in adult male offspring. The post-stressor changes in hypothalamic noradrenaline content and corticosterone level in blood plasma, as well as GABAA and GABA, receptors activity, did not differ from normal indices. In prenatally stressed female rats no preventive effect of dexamethasone has been reported. The results of investigations suggest the pathogenetic role of increased production of glucocorticoids in mediating the mechanisms of prenatal stress effects in gender-related functional disorders of HPAS. They demonstrate the possibility of pharmacological prevention of some congenital forms of neuroendocrine pathology and determine the necessity of a gender approach when developing preventive strategies.

[Calcium-dependent mechanisms of stress disorders and noradrenergic responses of the hypothalamo-pituitary-adrenal system in neonatally androgenized female rats].

The effects of neonatal administration ofverapamil, a calcium L-type channel blocker, on the stress and noradrenergic responses of hypothalamo-pituitary-adrenal (HPA) axis in adult female rats with anovulatory syndrome induced by neonatal androgenization have been studied. There was no adrenocortical response to an acute stress nor noradrenaline infusion in the 3rd brain ventricle in females with persistent estrus. Verapamil pretreatment completely restored the adrenocortical responses to normal level. No changes were found in studied parameters following treatment with verapamil alone. These results demonstrate possible involvement of calcium signalling in pathogenesis of the disorders of HPA function in adult female rats, induced by neonatal androgenization.

[Sex characteristics of neuroendocrine effects of prenatal exposure to exogenous glucocorticoids].

The effects of hydrocortisone acetate treatment of rats during the last gestational week on neurochemical and morphological characteristics of the brain in early postnatal and mature offspring were studied. Disappearance of sexual differences both in aromatase and 5alpha-reductase activities and noradrenaline concentration in the preoptic area in 10-day old rats was found. Meanwhile a sexual dimorphism in serotonin metabolism emerged. In adult offspring, the prenatal exposure to glucocorticoids resulted in disappearance of sexual differences in neurocytes' nuclei volume in medial preoptic and suprachiasmatic nuclei. The adrenocortical reaction to noradrenaline infusion to the 3rd brain ventricle was absent in the experimental males and intensified in females. In males, adrenocortical reaction to restraint decreased while post-stress changes in hypothalamic noradrenaline concentration and hippocampal glutamate decarboxylase activity were not observed. In the similar experiments in females both the augmentation of adrenocortical reaction and inhibition of GABA-ergic system were revealed. The results obtained indicate the modifying effect of prenatal exposure to glucocorticoids on sexual dimorphism of neuroendocrine system.

Early postnatal effects of prenatal exposure to glucocorticoids on testosterone metabolism and biogenic monoamines in discrete neuroendocrine regions of the rat brain.

We investigated the effects of hydrocortisone acetate and dexamethasone administered to pregnant rats during the last gestational week on sexual differentiation of testosterone metabolism and biogenic monoamine contents and turnover in the discrete brain regions in 10-day-old offspring. In the preoptic area, sex-dependent differences in aromatase activity were attenuated by prenatal glucocorticoids. Prenatal dexamethasone but not hydrocortisone acetate caused the inversion of sexual dimorphism of 5alpha-reductase activity in the preoptic area. In the brain preoptic area of the male pups prenatally exposed to hydrocortisone acetate, a decrease in noradrenaline turnover was found. Dopamine turnover in the preoptic area and 5-hydroxytryptamine metabolism in the preoptic area and medial basal hypothalamus increased in females as a result of hydrocortisone acetate treatment. Our results indicate that excess glucocorticoids in prenatal life modifies the basic neurochemical and neurophysiological mechanisms of sexual brain differentiation and might contribute to behavioral and reproductive disorders in adulthood.

Participation of endogenous opioids in pathogenesis of early neuroendocrine manifestations of prenatal stress syndrome.

We studied sex dimorphism in the content of norepinephrine and activity of enzymes involved in testosterone metabolism in the preoptic hypothalamic area of 10-day-old rats. Prenatal stress eliminated sex-related differences in these indices. These disturbances were absent in rats subjected to prenatal stress under conditions of opioid receptor blockade with naltrexone. These data attests to the important role of opioids in the pathogenesis of prenatal stress syndrome.

Early and long-term neuroendocrine effects of prenatal stress in male and female rats.

The effects of maternal stress, termed prenatal stress (PNS) on the neuroendocrine regulation of reproduction and the stress reactivity of offspring were studied in rats. PNS prevented the formation of sexual dimorphism in catecholamine levels, aromatase activity, and androgen 5alpha-reductase activity in the preoptic area of the brain and the mediobasal hypothalamus in 10-day-old rats. The morphological correlate of the functional lesions induced by PNS consisted of the elimination of gender-related differences in the volumes of neuron nuclei in the suprachiasmatic nucleus. Prenatal stress altered the stress and adrenergic reactivities of the hypothalamo-hypophyseal-adrenal system in mature males and females. The long-term effects of PNS were regarded as a consequence of the disruption of the hormone-neurotransmitter imprinting of the neuroendocrine system.

[The perinatal stress modification of the reactivity of the hypothalamo-hypophyseal-adrenal system]. / Perynatal'na stresova modyfikatsiia reaktyvnosti hipotalamo-hipofizarno-nadnyrkovoï systemy.

The literature data and the results of authors research work concerning long-term effects of prenatal stress and of early postnatal handling on the hypothalamic-pituitary-adrenal stress response are reviewed in the article. Functional state of that system, and the role of hormones, biogenic monoamines and glucocorticoid receptors of the brain in pathogenesis of its alteration are discussed. Special reference is made to gender- and age-related effects of pre- and postnatal stress. The body of evidences supports basic states of the brain hormone-neurotransmitter imprinting during early ontogenesis.

[Physical endurance in rats exposed prenatally to stress of exogenous glucocorticoids]. / Fizichna vitrivalist' shchuriv, iaki zaznali prenatal'nogo vplivu stresu abo ekzogennikh gliukokortikoidiv.

Gender- and age-related peculiarities of the influence of prenatal stress or exogenous glucocorticoids on physical endurance in rats were found in the experiments using fatigue test. Normal adult females were of greater endurance than males. Prenatal stress resulted in increased physical fatigue mainly in females while sexual differences were reversed. Hydrocortisone acetate administration to pregnant rats prevented sexual dimorphism in physical fatigue development in adult animals due to increase of physical endurance in males and its decrease in females. In aging rats disappearance of both sexual differences and prenatal stress effects took place against a background of fast physical fatigue development.

Prenatal stress and glucocorticoid effects on the developing gender-related brain.

Hormonal and neurotransmitter environment of nondifferentiated cells in the developing brain determines many of gender-specific behavioural and neuroendocrine functions. Early postnatal and long-term effects of maternal stress or prenatal glucocorticoid on sex-related peculiarities of the brain morphology, biogenic monoamine turnover, testosterone metabolism, hypothalamic noradrenaline (NA) and adrenocortical responses to an acute stress were studied in Wistar rat offsprings. Maternal stress (1 h immobilization daily for gestational days 15-21) prevented development of sexual dimorphism in neuronal cell nuclei volumes in suprachiazmatic nucleus (SCN) in 10 day old pups. That was associated with a disappearance of male female differences in NA and 5-hydroxytryptamine turnover in the preoptic area (POA) and dopamine (DA) turnover in the mediobasal hypothalamus (MBH) by decreasing them in male pups. Hydrocortisone acetate (5 mg daily during the last week of pregnancy) produced changes in NA turnover in the POA of males and females which were quite similar to those after maternal stress. Changes in aromatase and 5alpha-reductase activities in the POA of male pups were quite opposite as affected by maternal stress or prenatal glucocorticoid. Sexual differences in 5alpha-reductase activity in the MBH appeared due to its increase in prenatally stressed male pups. In contrast to adult males, in adult females maternal stress did not restrict hypothalamic NA and blood plasma corticosterone response to acute stress (1 h immobilization). Our findings on morphology and functions of gender-related developing brain areas stand in correlation with modifying effects of maternal stress and prenatal glucocorticoid on behavior and neuroendocrine regulations.

[The sexual dimorphism of the monoaminergic system of the brain: the effects of prenatal stress and neonatal androgenization in rats]. / Polovoi dimorfizm monoaminergicheskoi sistemy mozga: éffekty prenatal'nogo stressa i neonatal'noi androgenizatsii krys.

Prenatal stress and neonatal androgenization manifest themselves by early postnatal changes in sexual differences of catecholamine and indoleamine contents and turnover in the preoptic area and mediobasal hypothalamus in 10-day-old rats. Neonatal androgenization did not prevent the formation of sexual dimorphism of noradrenaline content and turnover in the preoptic area but enhanced sexual differences of dopamine turnover in both these brain areas.

[Recovery of various parameters of the functional state of the reproductive system in thymectomized rats as affected by thymic membrane factor]. / Vosstanovlenie nekotorykh pokazatelei funktsional'nogo sostoianiia reproduktivnoi sistemy u timéktomirovannykh krys pod vliianiem membrannogo faktora timusa.

Ten-month-old male rats thymectomized in early post-puberty were ascertained to have lower plasma luteinizing and testicular hormones and higher testicular steroid dehydrogenase activity. Following 24 hours of administration of a thymocyte membrane structural agent, pituitary gonadotropic and gonadal androgenic functions became normal. There was no agreement between the hormonal parameters and the levels of nucleic acids in the testes and prostate.

Early postnatal changes in sexual dimorphism of catecholamine and indoleamine content in the brain of prenatally stressed rats.

Sexual dimorphism in catecholamine and indoleamine content in the brain preoptic area and mediobasal hypothalamus was studied in 10-day-old rat pups whose mothers had been exposed to the daily 1-h immobilization stress during the last week of pregnancy. Concentration of noradrenaline in the preoptic area and 5-hydroxyindoleacetic acid in the mediobasal hypothalamus of the prenatally stressed male offspring as well as dopamine content in the mediobasal hypothalamus and 5-hydroxyindoleacetic acid content in the preoptic area of the females were increased by 59%, 45%, 34%, 76%, respectively. Dopamine content in the preoptic area of the female pups was decreased. In addition, an increase of 5-hydroxytryptamine metabolism in the female preoptic area has been revealed. As a result of prenatal stress, sex-related differences in noradrenaline and 5-hydroxyindoleacetic acid concentrations in the preoptic area and those in dopamine concentration in the mediobasal hypothalamus disappeared. The suggestion is made that the early changes in sexual dimorphism of the brain catecholamines and 5-hydroxytryptamine metabolism in prenatally stressed rats may be responsible for the development of the long-term disorders of sexual differentiation of the neuroendocrine functions.

Catecholamines in steroid-dependent brain development.

UNLABELLED: Sex-specific peculiarities of catecholamine (CA) content and turnover in neuroendocrine brain areas and their modification with neonatal steroids or prenatal stress (PS) in Wistar rats were studied. No changes in noradrenaline (NA) content and turnover rate were found in the preoptic area (POA), meanwhile dopamine (DA) turnover rates in the POA and mediobasal hypothalamus (MBH) were increased in neonatally androgenized 10-day-old females. Treatment of female neonates with various catecholestrogens increased hypothalamic NA content by 30-95% but only 4-hydroxyestradiol-17 beta induced anovulation. 6-Hydroxydopamine had no significant impact on hypothalamic CA content in neonates and did not prevent testosterone-induced persistent estrous. Maternal stress (restriction for 1 h a day, 15-21st days of pregnancy) resulted in a decrease of hypothalamic NA and blood plasma corticosterone response to acute stress in adult male offspring. Sex differences in CA content in the POA and MBH disappeared in 10-day-old prenatally stressed rats. CONCLUSIONS: (1) sexual brain differentiation needs co-operative actions of sex steroids and CA to be completed; and (2) early changes in CA content and turnover induced by PS or neonatal steroid exposure predetermine long-term alterations of the stress responsiveness, reproductive behaviour and neuroendocrine control of ovulation.