Characterizing the postnatal hypothalamic-pituitary-adrenal axis response of in utero heat stressed pigs at 10 and 15 weeks of age.

In utero heat stress alters postnatal physiological and behavioral stress responses in pigs. However, the mechanisms underlying these alterations have not been determined. The study objective was to characterize the postnatal hypothalamic-pituitary-adrenal axis response of in utero heat-stressed pigs. Pigs were subjected to a dexamethasone suppression test followed by a corticotrophin releasing hormone challenge at 10 and 15 weeks of age. Following the challenge, hypothalamic, pituitary, and adrenal tissues were collected from all pigs for mRNA abundance analyses. At 10 weeks of age, in utero heat-stressed pigs had a reduced (P < 0.05) cortisol response to the corticotrophin releasing hormone challenge versus controls. Additionally, the cortisol response tended to be greater overall (P < 0.10) in 15 versus 10-week-old pigs in response to the dexamethasone suppression test. The cortisol response tended to be reduced overall (P < 0.10) in 15 versus 10-week-old pigs in response to the corticotrophin releasing hormone challenge. Hypothalamic corticotropin releasing hormone mRNA abundance tended to be greater (P < 0.10) in in utero heat-stressed versus control pigs at 15-weeks of age. In summary, in utero heat stress altered some aspects of the hypothalamic-pituitary-adrenal axis related to corticotropin releasing hormone signaling, and age influenced this response.

Genetic aspects of hypothalamic and pituitary gland development.

Hypothalamo-pituitary development during embryogenesis is a highly complex process involving the interaction of a network of spatiotemporally regulated signaling molecules and transcription factors. Mutations in any of the genes encoding these components can lead to congenital hypopituitarism, which is often associated with a wide spectrum of defects affecting craniofacial/midline development. In turn, these defects can be incompatible with life, or lead to disorders encompassing holoprosencephaly (HPE) and cleft palate, and septo-optic dysplasia (SOD). In recent years, there has been increasing evidence of an overlapping genotype between this spectrum of disorders and Kallmann syndrome (KS), defined as the association of hypogonadotropic hypogonadism (HH) and anosmia. This is consistent with the known phenotypic overlap between these disorders and opens a new avenue of identifying novel genetic causes of the hypopituitarism spectrum. This chapter reviews the genetic and molecular events leading to the successful development of the hypothalamo-pituitary axis during embryogenesis, and focuses on genes in which variations/mutations occur, leading to congenital hypopituitarism and associated defects.

Maternal supplementation with fishmeal protects against late gestation endotoxin-induced fetal programming of the ovine hypothalamic-pituitary-adrenal axis.

Adverse uterine environments caused by maternal stress (such as bacterial endotoxin) can alter programming of the fetal hypothalamic-pituitary-adrenal axis (HPAA) rendering offspring susceptible to various adulthood diseases. Thus, protection against this type of stress may be critical for ensuring offspring health. The present study was designed to determine if maternal supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFAs) during pregnancy helps to protect against stress-induced fetal programming. Briefly, 53 ewes were fed a diet supplemented with fishmeal (FM) or soybean meal (SM) from day 100 of gestation (gd100) through lactation. On gd135, half the ewes from each dietary group were challenged with either 1.2 µg/kg Escherichia coli lipopolysaccharide (LPS) endotoxin, or saline as the control. The offspring's cortisol response to weaning stress was assessed 50 days postpartum by measuring serum cortisol concentrations 0, 6 and 24 h post weaning. Twenty-four hours post-weaning, lambs were subjected to an adrenocorticotropic hormone (ACTH) challenge (0.5 µg/kg) and serum cortisol concentrations were measured 0, 0.25, 0.5, 1 and 2 h post injection. At 5.5 months of age, offspring were also challenged with 400 ng/kg of LPS, and serum cortisol concentrations were measured 0, 2, 4 and 6 h post challenge. Interestingly, female offspring born to FM+LPS mothers had a greater cortisol response to weaning and endotoxin challenge compared with the other treatments, while female offspring born to SM+LPS mothers had a faster cortisol response to the ACTH stressor. Additionally, males born to FM+LPS mothers had a greater cortisol response to the ACTH challenge than the other treatments. Overall, FM supplementation during gestation combined with LPS challenge alters HPAA responsiveness of the offspring into adulthood.

Insulin-like growth factor-I regulates LH release by modulation of kisspeptin and NMDA-mediated neurotransmission in young and middle-aged female rats.

This study investigated potential mechanisms by which age and IGF-I receptor (IGF-Ir) signaling in the neuroendocrine hypothalamus affect estradiol-positive feedback effects on GnRH neuronal activation and on kisspeptin and N-methyl-D-aspartate (NMDA)-induced LH release and on the abundance of NMDA receptor subunits Nr1 and Nr2b and Kiss1r transcript and protein in the hypothalamus of young and middle-aged female rats. We infused vehicle, IGF-I, or JB-1, a selective antagonist of IGF-Ir, into the third ventricle of ovariectomized female rats primed with estradiol or vehicle and injected with vehicle, kisspeptin (3 or 30 nmol/kg), or NMDA (15 or 30 mg/kg). Regardless of dose, NMDA and kisspeptin resulted in significantly more LH release, GnRH/c-Fos colabeling, and c-Fos immunoreative cells in young than in middle-aged females. Estradiol priming significantly increased Kiss1r, Nr1, and Nr2b receptor transcript and protein abundance in young but not middle-aged female hypothalamus. JB-1 attenuated kisspeptin and NMDA-induced LH release, numbers of GnRH/c-Fos and c-Fos cells, and Kiss1r, Nr1, and Nr2b transcript and protein abundance in young females to levels observed in middle-aged females. IGF-I significantly enhanced NMDA and kisspeptin-induced LH release in middle-aged females without increasing numbers of GnRH/c-Fos or c-Fos immunoreactive cells. IGF-I infusion in middle-aged females also increased Kiss1r, Nr1, and Nr2b protein and transcript to levels that were equivalent to young estradiol-primed females. These findings indicate that age-related changes in estradiol-regulated responsiveness to excitatory input from glutamate and kisspeptin reflect reduced IGF-Ir signaling.

Role of neuropeptide Y in regulating hypothalamus-pituitary-gonad axis in the rats treated with electro-acupuncture.

Neuropeptide Y (NPY) is an important regulator of reproductive axis, which mainly plays some roles in regulating secretion of gonadotropin-releasing hormone (GnRH) in hypothalamus. In previous studies, we found that the repeated low frequency electro-acupuncture (EA) down-regulated hypothalamus-pituitary-gonad (HPG) axis of common rats and rabbits during puberty. In this study, we investigated the role of NPY in regulating the reproductive axis of common rats at different developmental stages and rats treated with the repeated EA. Low frequency EA (3 Hz) was performed at acupoints (treatment groups) or non-acupoints (control groups) for 20 min daily for 10 days in Sprague-Dawley (SD) rats at four developmental stages, which were juvenile stage, early puberty stage, later puberty stage and adult stage. NPY expression in the hypothalamus were determined using RT-PCR and real-time quantitative PCR (qPCR) after 10 days-treatments. The results showed that NPY expression in the early pubertal group (EPG) was significantly depressed after repeated EA (P<0.05). Compared with the results of GnRH expression and body weights, the change of NPY expression was similar with the fluctuation of GnRH expression after EA and the increase of body weights of rats was not influenced by the depression of NPY expression after EA during early puberty. The results demonstrated that repeated low frequency EA was an effective method on down-regulating not only the GnRH expression but also the NPY expression in the hypothalamus without reducing body weights of rats during early puberty.

Different effects by sex on hypothalamic-pituitary axis of prepubertal offspring rats produced by in utero and lactational exposure to di-(2-ethylhexyl) phthalate (DEHP).

This study investigated the effect of pre and perinatal exposure to di-(2-ethylhexyl) phthalate (DEHP) on the neuroendocrine parameters that regulate reproduction in prepubertal male and female rats. DEHP at doses of 3 and 30mg/kgbw/day was administered orally in the drinking water to dam rats since pregnancy onset until the moment of pups sacrifice at 15 days of age. In these animals gonadotropin serum level and the hypothalamic contents of the amino acids aspartate, glutamate and gamma-aminobutyric acid were determined. No changes in gonadotropin levels and amino acid neurotransmitters were detected at the low dose in both sexes. However, DEHP administered at high dose (30mg/kgbw/day) to dams produced a significant decrease in the inhibitory neurotransmitter GABA and an increase in the stimulatory neurotransmitter aspartate in prepubertal male offspring rats. These modifications were accompanied by gonadotropin serum levels increase. On the contrary, in treated female rats this chemical increased both, aspartate and GABA, which exert a characteristic stimulatory action on gonadotropin in 15-day-old normal females. This study provides new data about changes produced by DEHP on the hypothalamic amino acid neurotransmitters involved in the neuroendocrine reproductive regulation, in prepubertal male and female rat offspring from dams exposed during gestational and lactational periods. These alterations induced by DEHP exposure could be related to the gonadotropin modifications also described in this work, and with changes in the production of sexual hormones previously reported by other authors.

Endogenously elevated androgens alter the developmental programming of the hypothalamic-pituitary axis in male mice.

Transgenic male mice that express human chorionic gonadotropin (hCG) α and ß subunits constitutively hypersecrete hCG and produce elevated levels of androgens. The aim of this study was to characterize the hypothalamic-pituitary function of these transgenic (hCGαß+) males by focusing on FSH regulation. Serum FSH levels and pituitary mRNA expression of Fshb, Lhb, Cga, Gnrhr and Esr1 were reduced, whereas Fst expression was increased in prepubertal hCGαß+ males as compared with wild-type. In the hypothalamus, Cyp19a1 expression, GnRH concentration and ex-vivo GnRH pulsatility were elevated in prepubertal hCGαß+ mice, whereas Kiss1 expression was decreased prepubertally and Gad67 expression was elevated neonatally. The effect of androgens on the developmental programming of the hypothalamic-pituitary axis of hCGαß+ males was evaluated by perinatal and prepubertal antiandrogen (flutamide) administration. Our studies identified a critical window between gestational day 18 and postnatal day 14, during which chronically elevated androgens and/or their locally produced metabolites activate the hypothalamus and concomitantly shut-down the gonadotropin axis.

Developmental changes in neural corticosteroid receptor binding capacity in altricial nestlings.

Altricial nestlings typically do not show an adrenocortical response during the early post-hatch period. This may be a result of an immature hypothalamic-pituitary-adrenal axis, or an enhanced control of the axis by negative feedback. To examine whether the dampened adrenocortical response is due to higher receptor densities in hypothalamus and hippocampus, the major sites for negative feedback and tonic inhibition, we explored the ontogenetic changes in glucocorticoid (GR) and mineralocorticoid receptor (MR) binding capacities in the brain of white-crowned sparrow nestlings. During the 10-day nestling period, MR binding capacity decreased with age, whereas GR capacity was not affected. In addition, this overall decline in MR levels was driven entirely by a decline in cerebellar MR. No age-related changes were observed in hippocampal or hypothalamic areas. Our findings suggest that enhanced negative feedback does not play a major role in the attenuated adrenocortical responses seen in white-crowned sparrow nestlings.

Expression of neuropeptide Y and agouti-related peptide in the hypothalamic arcuate nucleus of newborn neurogenin3 null mutant mice.

Mice deficient in neurogenin 3 (Ngn3) fail to generate pancreatic endocrine cells and intestinal endocrine cells. Hypothalamic neuropeptides implicated in the control of energy homeostasis might also be affected in Ngn3 homozygous null mutant mice. We investigated the expression of two prominent orexigenic neuropeptides, neuropeptide Y (NPY) and agouti-related protein (AgRP), in the hypothalamic arcuate nucleus of newborn wild-type and Ngn3 null mutant mice. Immunohistochemical analysis demonstrated that, in Ngn3 null mutants, the number of NPY-immunoreactive neurons and nerve fibers was markedly increased in the arcuate nucleus, and the nerve fibers were widely distributed in the hypothalamic area, including the paraventricular and dorsomedial nuclei. Little increase of AgRP immunoreactivity was detected in the arcuate nucleus of mutant mice. In situ hybridization analysis confirmed the increased population of the NPY neurons in the arcuate nucleus of the mutants. The NPY mRNA level, as estimated by laser capture microdissection and real-time quantitative polymerase chain reaction, was 371% higher in Ngn3 null mutants than in wild-type mice. AgRP mRNA levels did not differ significantly between the null mutants and wild-type mice. Thus, up-regulation of the hypothalamic NPY system is probably a feature characteristic of Ngn3 null mice.

Significance of neonatal testicular sex steroids to defeminize anteroventral periventricular kisspeptin neurons and the GnRH/LH surge system in male rats.

The brain mechanism regulating gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) release is sexually differentiated in rodents. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) have been suggested to be sexually dimorphic and involved in the GnRH/LH surge generation. The present study aimed to determine the significance of neonatal testicular androgen to defeminize AVPV kisspeptin expression and the GnRH/LH surge-generating system. To this end, we tested whether neonatal castration feminizes AVPV kisspeptin neurons and the LH surge-generating system in male rats and whether neonatal estradiol benzoate (EB) treatment suppresses the kisspeptin expression and the LH surge in female rats. Immunohistochemistry, in situ hybridization, and quantitative real-time RT-PCR were performed to investigate kisspeptin and Kiss1 mRNA expressions. Male rats were castrated immediately after birth, and females were treated with EB on postnatal Day 5. Neonatal castration caused an increase in AVPV kisspeptin expression at peptide and mRNA levels in the genetically male rats, and the animals showed surge-like LH release in the presence of the preovulatory level of estradiol (E2) at adulthood. On the other hand, neonatal EB treatment decreased the number of AVPV kisspeptin neurons and caused an absence of E2-induced LH surge in female rats. Semiquantitative RT-PCR analysis showed that neonatal steroidal manipulation affects Kiss1 expression but does not significantly affect gene expressions of neuropeptides (neurotensin and galanin) and enzymes or transporter for neurotransmitters (gamma-aminobutyric acid, glutamate, and dopamine) in the AVPV, suggesting that the manipulation specifically affects Kiss1 expressions. Taken together, our present results provide physiological evidence that neonatal testicular androgen causes the reduction of AVPV kisspeptin expression and failure of LH surge in genetically male rats. Thus, it is plausible that perinatal testicular androgen causes defeminization of the AVPV kisspeptin system, resulting in the loss of the surge system in male rats.

Development of the ACTH and corticosterone response to acute hypoxia in the neonatal rat.

Acute episodes of severe hypoxia are among the most common stressors in neonates. An understanding of the development of the physiological response to acute hypoxia will help improve clinical interventions. The present study measured ACTH and corticosterone responses to acute, severe hypoxia (8% inspired O(2) for 4 h) in neonatal rats at postnatal days (PD) 2, 5, and 8. Expression of specific hypothalamic, anterior pituitary, and adrenocortical mRNAs was assessed by real-time PCR, and expression of specific proteins in isolated adrenal mitochondria from adrenal zona fascisulata/reticularis was assessed by immunoblot analyses. Oxygen saturation, heart rate, and body temperature were also measured. Exposure to 8% O(2) for as little as 1 h elicited an increase in plasma corticosterone in all age groups studied, with PD2 pups showing the greatest response ( approximately 3 times greater than PD8 pups). Interestingly, the ACTH response to hypoxia was absent in PD2 pups, while plasma ACTH nearly tripled in PD8 pups. Analysis of adrenal mRNA expression revealed a hypoxia-induced increase in Ldlr mRNA at PD2, while both Ldlr and Star mRNA were increased at PD8. Acute hypoxia decreased arterial O(2) saturation (SPo(2)) to approximately 80% and also decreased body temperature by 5-6 degrees C. The hypoxic thermal response may contribute to the ACTH and corticosterone response to decreases in oxygen. The present data describe a developmentally regulated, differential corticosterone response to acute hypoxia, shifting from ACTH independence in early life (PD2) to ACTH dependence less than 1 wk later (PD8).

The neuroendocrine events during the ovine growth-promoted maturation: the developmental importance of hypophysiotrophic action of somatostatin in ewes.

The comparison of hypothalamic somatostatin (SRIH)-neuronal systems, hypophyseal somatotroph populations and growth hormone (GH) blood plasma patterns among developmental stages, from infancy until puberty, may help to describe the nature of the hypothalamo-hypophyseal mechanisms underlying the changes in GH on the systemic level leading to the somatic, that is growth and sexual maturity in sheep. The aim of this study was to elucidate (i) developmental importance of hypophysiotrophic action of SRIH, (ii) precise time of maturation of this action and (iii) photoperiodic regulation of the postnatal ontogeny in ewes. The central and peripheral activity of the SRIH-GH axis is described through a sequence of histomorphological and functional changes in Merino ewes born after the summer solstice. The actual time of puberty of these animals was delayed until the following breeding season, when the sheep were 14-month old. Histomorphometric examinations have been made in 21 infantile (preweanling, 12-week old), prepubertal (15- and 22-week old), peripubertal (30- and 52-week old) and pubertal (63-week old) ovary-intact sheep. Functional examinations of the GH plasma levels were determined every 1-2 weeks during the period from the 12th to 63rd week of age. The highest GH level was observed at the 13th week of age, on the beginning of the breeding season. The fluctuations in the GH level just after the winter and summer solstice were detected as the one and only deviation from a rule of uniformly low GH concentrations observed until puberty. The age of the fall in serum GH levels corresponded with the postweaning period and the beginning of the phase of the lower daily live-weight gains (growth rate). Thus, the development of GH secretion was finished before the 15th week of age, that is together with the ending of the transitional infantile/prepubertal period, whereas the maturational processing within the hypothalamo-hypophyseal unit prolonged after the 15th week of age until 22 weeks of age and concerned the role of SRIH as the hypophysiotrophic factor regulating somatic maturation, i.e. attenuating growth. Altogether, the pattern of GH secretion during weaning is important for the shift between infancy and prepuberty depended upon an intensive growth and defined as growth maturation. The maturation of the SRIH-GH axis is finished by 22 weeks of age, independently of photoperiodic influences, whereas the neuroendocrine mechanisms to integrate somatic, that is growth and sexual maturation, are seasonal in nature in the ewe. Our observations confirm the hypothesis of the inherent endogenous rhythm controlling somatic maturation in the sheep.

Kisspeptin in reproduction.

Although the functions of kisspeptin originally were believed to be restricted to metastasis suppression, a novel role for this protein was discovered in 2003. Loss-of-function mutations in its receptor, GPR54, were found to cause absence of puberty and hypogonadotropic hypogonadism in humans. Mice with targeted deletions of GPR54 also have a hypogonadotropic phenotype, confirming the important role of this ligand-receptor family in the control of puberty and reproductive function. Since these discoveries, the peptide products of the KISS1 gene have been shown to be powerful stimulators of the gonadotropic axis. This review examines the role of kisspeptins and GPR54 in reproductive function.

An essential role for the hematopoietic transcription factor Ikaros in hypothalamic-pituitary-mediated somatic growth.

Ikaros transcription factors play critical functions in the control of lymphohematopoiesis and immune regulation. Family members contain multiple zinc fingers that mediate DNA binding and homooligomerization or heterooligomerization. Ikaros is abundantly expressed in pituitary mammosomatotrophs, where it deacetylates histone 3 sites on the proximal growth hormone (GH) promoter to silence gene expression. Ikaros-null mice display stunted growth with reduced circulating levels of the GH target factor insulin-like growth factor I (IGF-I). Ikaros-deficient mice have small anterior pituitary glands with a disproportionately reduced somatotroph population. Systemic administration of GH results in increased IGF-I levels and enhanced somatic growth. In contrast, reconstitution with WT lymphocytes was not sufficient to rescue the stunted growth phenotype of Ikaros-deficient mice. Ikaros was identified in mouse hypothalamic arcuate nuclei, where it colocalized with GH-releasing hormone (GHRH); in contrast, Ikaros-null mice lack GHRH immunoreactivity in the hypothalamus. Overexpression of Ikaros enhanced GHRH promoter activity and induced endogenous GHRH gene expression. These findings unmask a wider role for Ikaros in the neuroendocrine system, highlighting a critical contribution to the development of the hypothalamic-pituitary somatotrophic axis.

Neuroendocrine hypothesis of aging: the role of corticoadrenal steroids.

The age-related modifications of neuroendocrine secretions normally capable of integrative activity in the whole body might partly promote and amplify many aging phenomena. The quantitative and qualitative changes of hypothalamus-pituitary-adrenal axis are a significant example. The dampening of cortisol and dehydroepiandrosterone (DHEA) circadian fluctuation and the progressive decrease of DHEA/cortisol ratio are at the basis of multiple clinical implications: the shift from anabolic to catabolic status, the activation of atherosclerosis progression, the deterioration of immune competence, the impairment of cognitive and affective performances and the glico- and lipometabolic disorders. The hypothesis of a DHEA supplementation strategy comes out from these premises.

Postnatal regulation by monoamines of vasopressin expression in the neuroendocrine hypothalamus of MAO-A-deficient mice.

We studied the influence of noradrenaline (NA) and serotonin (5-HT) on arginine-vasopressin (AVP) expression in the mouse neuroendocrine hypothalamus during the postnatal period. We used 11-day-old transgenic Tg8 mice knock-out for the monoamine oxidase A gene, which are characterized by increased amounts of NA (two-fold) and 5-HT (nine-fold) in the brain compared with wild-type littermates. AVP expression, determined by enzyme immunoassay and in situ hybridization, was increased in the suprachiasmatic nucleus (SCN), decreased in the supraoptic nucleus (SON), and unchanged in the paraventricular nucleus of Tg8 mice compared with wild-types. Inhibiting NA synthesis by injecting alpha-methylparatyrosine to Tg8 mice, AVP levels were decreased in the SCN but increased in the SON. Moreover, the administration of parachlorophenylalanine, a 5-HT synthesis inhibitor, was associated with increased AVP contents in the SCN only. Together, these data show a marked region-specific sensitivity of AVP expression to NA and 5-HT during the postnatal period in the mouse hypothalamus.

Maternal glucocorticoid treatment programs HPA regulation in adult offspring: sex-specific effects.

Pregnant guinea pigs were treated with dexamethasone (1 mg/kg) or vehicle on days 40--41, days 50--51, and days 60--61 of gestation. Adult offspring were split into two groups. Group 1 guinea pigs were catheterized, and the hypothalamo-pituitary-adrenal (HPA) axis was tested in basal and activated states. Group 2 guinea pigs were euthanized with no further manipulation. In male offspring, prenatal dexamethasone exposure resulted in a significant reduction in brain-to-body weight ratio. Dexamethasone-exposed male offspring exhibited reduced basal and activated plasma cortisol levels, which was associated with elevated hippocampal mineralocorticoid receptor (MR) mRNA and increased plasma testosterone. In females exposed to glucocorticoids in utero, basal and stimulated plasma cortisol levels were higher in the follicular and early luteal phases of the cycle, but this effect was reversed in the late luteal phase, indicating a significant interaction of sex steroids. In female offspring (at estrus), glucocorticoid receptor mRNA levels were lower in the paraventricular nucleus and pars distalis but higher in the hippocampus in animals exposed to dexamethasone in utero. Hippocampal MR mRNA levels were significantly lower (approximately 50%) than in controls. In conclusion, repeated antenatal glucocorticoid treatment programs HPA function in a sex-specific manner, and these changes are associated with modification of corticosteroid receptor expression in the adult brain and pituitary.

Compensatory sprouting of uninjured magnocellular neurosecretory axons in the rat neural lobe following unilateral hypothalamic lesion.

Axonal sprouting of intact neurons of the magnocellular neurosecretory system was investigated using a unilateral hypothalamic knife cut of the hypothalamoneurohypophysial tract to partially denervate the rat neural lobe (NL). Densitometric, morphometric, ultrastructural, and metabolic measures were utilized to demonstrate the compensatory response to denervation in this system. Densitometric analysis revealed a transient reduction in the intensity of vasopressin staining in the NL at 10 days postsurgery (PS) with a subsequent recovery by 20 days PS. There was a comparable initial reduction in the cross-sectional area of the NL followed by a more gradual recovery to normal by 90 days PS. Ultrastructural investigation revealed a reduction in total axon number in the NL at 10 days PS similar to the declines in vasopressin immunoreactivity and size of the NL. A subsequent partial recovery of axon number occurred, paralleling the return to normal NL size between 30 and 90 days PS. Hypertrophy of both somata and cell nuclei of magnocellular neurons in the supraoptic and paraventricular hypothalamic nuclei contralateral to the lesion was also apparent during this period. Daily measurements of urine osmolality revealed an initial transient hypoosmolality followed by a chronic hyperosmolality which persisted throughout the 90 day postsurgical period. There was a concomitant chronic decrease in both daily drinking and urine excretion volumes which began immediately following surgery. These results suggest that intact, contralateral magnocellular vasopressinergic efferents undergo compensatory sprouting as a result of partial denervation of the NL in the absence of a functional deficit in vasopressin.

Morphofunctional study of the effects of fetal exposure to cyproterone acetate on the hypothalamo-pituitary-gonadal axis of adult rats.

Fetal exposure to cyproterone acetate (CPA), while allowing, normal sexual morphogenesis, has previously been shown to lead to functional endocrine abnormalities in adult rats of both sexes. Because of this, we examined morphologically and morphometrically the hypothalamic nuclei involved in sexual dimorphism as well as the pituitary lactotropes of rats exposed in utero from day 15 to 20 of gestation to CPA. Male and female offspring was studied at the age of 70-80 days. In both sexes the brain weight was lower (p less than 0.05) in CPA-treated than in control rats. Morphometrical investigations showed that the surface density (Sv) and the volume density (Vv) of the ventromedial nucleus were higher (p less than 0.05) in CPA-treated male than in control rats. By comparing sexes the Sv and Vv of the ventromedial nucleus were higher (p less than 0.01) in CPA-treated male than in corresponding female rats. Also the nuclear surface of the tyrosine hydroxylase-immunoreactive neurons of the arcuate nucleus was higher (p less than 0.05) in CPA-treated male than in female rats. In lactotropes of the pituitary gland the immunoreactive prolactin (PRL) was densitometrically increased (p less than 0.05) in CPA-treated female compared with control rats. By electron microscopy, PRL granules and autophagocytosis appeared to be more abundant in CPA-treated rats of both sexes. These data show that fetal exposure to CPA results in long-term anatomical and physiological alterations of hypothalamic and preoptic nuclei as well as of the pituitary lactotropes. These permanent changes support the functional endocrine abnormalities observed in adult rats.

[The development of neuroendocrine regulation in ontogeny]. / Stanovlenie neiroéndokrinnoi reguliatsii v ontogeneze.

Published and author's data on hypothalamic control over the most important endocrine functions during mammalian ontogenesis were reviewed. The data presented indicates that adenohypophyseotropic protein neurohormones are synthesized and accumulated in hypothalamus long before birth. At the end of the prenatal period most of hypothalamic neurohormones reached the adenohypophysis and were involved in regulation of the tropic hormones secretion. Exceptionally, regulative properties of thyroliberin and somatostatin are only manifested in immature-born animals (rats) in early postnatal period.