[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.

[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.

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.

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.

[Effect of 131I incorporation on the status of the reproductive system in male rats and the dose-dependent effect]. / Vliianie inkorporatsii 131I na sostoianie reproduktivnoi sistemy samtsov krys dozozavisimogo éffekta.

Radioactive 131I was injected in single doses 9.25, 37, and 92.5 kBq to prepubertal (30-day-old) male rats. Iodine incorporation in doses 37 and 92.5 kBq resulted in some functional changes in the reproductive system of mature rats: blood testosterone level increased, its hypothalamic aromatization intensified, and biologically active LH level in the blood dropped. Incorporation of 9.25 kBq of 131I had no effect on male reproductive system. A possibility of direct injury to rat testicles by 131I incorporation is suggested.

[Effect of 6-hydroxydopamine administration to newborn female rats and sex differentiation of the brain]. / Effecty vvedeniia 6-gidroksidofamina novorozhdennym krysiatam-samkam i polovaia differentsiatsiia mozga.

Remote effects of neonatal 6-hydroxydopamine (6-OHDA) combined with testosterone propionate (TP) and alone were compared to ultrastructure of catecholaminergic terminals of the median eminence and hypothalamic catecholamine (CA) content in the critical period of sexual differentiation of the brain. It is suggested that inability of 6-OHDA to prevent TP-induced anovulatory sterility is connected with the preserved hypothalamic CA levels and a lack of significant degenerative changes in CA-ergic terminals in the median eminence.

Augmentation of the sterilizing effect of neonatal androgenization with tropolone, a catechol-O-methyltransferase inhibitor, in female rats.

The influence of tropolone, a catechol-O-methyltransferase (COMT) inhibitor, on the sterilizing effect of neonatal testosterone propionate (TP) has been studied in Wistar female rats. Tropolone-induced changes in COMT activity and noradrenaline (NA) and dopamine (DA) contents in the hypothalamus have been evaluated. Inhibition of COMT activity was maximal 3 h after a single injection of 0.6 mg tropolone on postnatal day 5. An increase in DA level was observed 6 h after drug injection, whereas the NA content was elevated 24 h after tropolone administration. A sexual dimorphism in hypothalamic NA content in rats was found on postnatal day 10: it was higher in males than in females. The rise of catecholamines in the hypothalamus of 10-day-old female rats induced by COMT inhibition with tropolone (0.3 mg on postnatal days 5 and 7) was unable to masculinize developing neuroendocrine regions responsible for sexual cyclicity. At the same time, combined administration of tropolone (0.1 mg daily on postnatal days 4-10) and TP (0.025 mg on day 4) enhanced the sterilizing effect of the androgen. An anovulatory sterility appeared in all experimental animals. It is suggested that a cooperative interaction occurs between catecholamines and sex steroids as determinants of brain sexual differentiation.

[Increase of noradrenaline contents in the hypothalamus of neonatal female rats under the effects of 4-hydroxyestradiol-17beta]. / Povyshenie soderzhaniia noradrenalina v gipotalamuse novorozhdennykh krys-samok pod vozdeistviem 4-gidroksiéstradiola-17beta.

Catecholamine content was studied in hypothalamus of neonatal Wistar female rats treated with 4-hydroxyestradiol-17 (4-OH-E2) in a dose of 10 mg for 1-5 days of life. 4-OH-E2 induced a reliable increase in hypothalamic noradrenaline level in 24 h after the last injection, but not on the 7th, 10th or 12th postnatal days. There was no change in dopamine level. We have postulated a relationship between the increase in hypothalamic noradrenaline content induced by 4-OH-E2 and defeminization effects of 4-OH-E2 on the developing brain of female rats.

Prevention of the anovulatory syndrome and testosterone-induced rise in catecholamine level in the hypothalamus of newborn rats with steroid aromatase inhibitors.

Testosterone propionate administration in a dose of 50 micrograms on the 5th day of the postnatal life did not change hypothalamic noradrenaline and dopamine levels in female rats on the 7th, 8th, 12th days of life but increased it significantly in 10-day-old animals. This rise was completely prevented by steroid aromatase inhibitors (4-androstene-3,16,17-trione, 0.5 mg or 1,4,6-androstatriene-3,17-dione, 1 mg per animal) on the 5th or 7th days of life. Aromatase inhibitors reduced the anovulatory syndrome occurrence in neonatally androgenized rats from 93% to 15-17%. The data obtained prove the importance of testosterone conversion into estrogen for sexual brain differentiation. They support authors' hypothesis that testosterone-induced rise of hypothalamic catecholamine content in newborn female rats is evoked by the estrogen metabolites of testosterone.

[Effect of steroid aromatase inhibitors on the catecholamine content of the hypothalamus of neonatally androgenized rats]. / Vliianie ingibitorov aromatazy steroidov na soderzhanie katekholaminov v gipotalamuse neonatal'no androgenizirovannykh krys.

Administration of 50 micrograms of testosterone propionate to newborn female rats on the 5th day of life provoked a reliable increase in noradrenaline and dopamine concentrations in the hypothalamus of 10-day-old rats. Neonatal administration of aromatase inhibitors on the 5th and 7th days of life prevented testosterone-induced increase in catecholamine concentrations. The data obtained prove the integration of the processes of testosterone aromatization and catecholamine accumulation in androgen-dependent brain differentiation.

It is possible that noradrenaline is the biogenic monoamine responsible for androgen-dependent sexual brain differentiation.

The effect of neonatal testosterone propionate (TP) treatment and its combination with alpha-methyl-p-tyrosine (alpha MPT) on noradrenaline, dopamine and serotonin contents in the hypothalamus of 7-day-old female rats has been studied. The property of alpha MPT to prevent anovulatory sterility in neonatally androgenized rats earlier established by the authors is related to interfering with a rise of hypothalamic level of noradrenaline induced by TP in the early postnatal period. The experimental data give evidence against the participation of dopamine in sexual differentiation of the brain and indicate the secondary character of serotonin content changes in the hypothalamus in relation to the noradrenaline level. Hence, noradrenaline may participate in androgen-dependent sexual differentiation of the hypothalamus.

New evidences for participation of biogenic monoamines in androgen-dependent sexual differentiation of hypothalamic control of gonadotropin secretion in rats.

Corpora lutea have been found in the ovarian tissue transplanted into the anterior ocular chamber of castrated two-month-old male rats receiving on 3rd through 7th post-natal days alpha-methyl-p-tyrosine or p-chlorophenylalanine. Administration of these agents in combination with testosterone propionate to newborn female rats prevented essentially development of the anovulatory syndrome and maintained a normal picture of vaginal smears, ovarian and uterine structure as well as cyclic changes of adenohypophyseal and blood plasma lutropin contents and normal levels of estradiol and progesterone in the blood plasma except of progesterone level in animals receiving alpha-methyl-p-tyrosine. The preventive effect of the adrenoblocking agents droperidol and propranolol was weak and inconstant. Results suggest participation of catecholamines and serotonin in the androgen-dependent sexual differentiation of the brain in rats.

[Preventive effect of inhibitors of catecholamine synthesis, serotonin and adrenoblockaders on anovulatory syndrome development in neonatally androgenized rats. 2]. / Preventivnoe deistvie ingibitorov sinteza katekholaminov, serotonina i adrenoblokatorov na vozniknovenie anovuliatornogo sindroma u neonatal'no androgenizirovannykh krys. Soobshchenie 2.

Administration to female rats of 250 micrograms of testosterone propionate (TSP) on the 3rd day of postnatal life led to reduction of estradiol, progesterone, and, to a lesser degree, of lutropin in the blood plasma of these animals at the age of 3 months. There was an increase of the lutropin content in the adenohypophysis and of luliberin in the hypothalamus. Combined with TSP administration of alpha-methyl-p-tyrosine, p-chlorphenylalanine or droperidol promoted preservation of cyclic changes in the hypothalamic gonadotropin activity and partially prevented disturbances of estradiol and progesteron secretion caused by neonatal androgenization. The mechanisms of participation of biogenic monoamines in sex differentiation of the hypothalamus are discussed.

[Characteristics of the hypothalamo-hypophyseal regulation and morphological and functional state of the reproductive organs in female rats, androgenized in the neonatal period, depending on the time of the action of testosterone]. / Osobennosti gipotalamo-gipofizarnoi reguliatsii, morfologicheskogo i funktsional'nogo sostoianiia reproduktivnykh organov u neonatal'no androgenizirovannykh samok krys v zavisimosti ot vremeni vozdeistviia testosterona

Testosterone propionate was injected to rats in a dose of 150 microng on the 2nd, 3rd and 4th day or in a dose of 500 microng on the 5th day after birth. Histological picture of the ovaries, vagina and uterus, the content of progesterone and its C20-restored metabolite in the ovaries, the LH-releasing activity of the hypothalamus, and the LH and FSH in the adenohypophysis were studied in these rats at the age of 3-5 months. The effects of the neonatal andronization of rats proved to depend on the time of testosterone action at all the levels of the hypothalamus-hypophysis-ovaries-accessory organs. Early administration of androgen caused more severe injuries of the reproductive system.

[Effect of neonatal androgenization on biogenic monoamines of the hypothalamus and the functional activity of the rat pituitary]. / Vliianie neonatal'noi androgenizatsii na biogennys monoaminy gipotalamusa i funktsional'nuiu aktivnost' gipofiza krys

Injection of testosterone-propionate to female Wistar rats on the 2nd--4th days of birth failed to alter the serotonin level, but produced a sharp fall of the noradrenaline and dopamine levels in the hypothalamus of 3 1/2-month-old animals. This was accompanied by an increase in the prolactin content in the adenohypophysis with the retention of the normal somatotropic activity. The results of these studied indicated the participation of catecholamines in the pathogenesis of the anovular sterility, and elucidated current views on the control of the hypophysial gonadotropic function.