Hypothalamic Factor Research Articles

A Critical Point of Male Gonad Development: Neuroendocrine Correlates of Accelerated Testicular Growth in Rats during Early Life

Testis growth during early life is important for future male fertility and shows acceleration during the first months of life in humans. This acceleration coincides with the peak in gonadotropic hormones in the blood, while the role of hypothalamic factors remains vague. Using neonatal rats to assess this issue, we found that day 9 of life is likely critical for testis development in rats. Before this day, testicular growth was proportional to body weight gain, but after that the testes showed accelerated growth. Hypothalamic kisspeptin and its receptor mRNA levels begin to elevate 2 days later, at day 11. A significant increase in the mRNA levels for gonadotropin-releasing hormone (GnRH) receptors in the hypothalamus between days 5 and 7 was followed by a 3-fold decrease in GnRH mRNA levels in this brain region during the next 2 days. Starting from day 9, hypothalamic GnRH mRNA levels increased significantly and positively correlated with accelerated testicular growth. Triptorelin, an agonist of GnRH, at a dose that had no effect on testicular growth during “proportional” period, increased testis weights during the period of accelerated growth. The insensitivity of testicular growth to GnRH during “proportional” period was supported by inability of a 2.5-fold siRNA knockdown of GnRH expression in the hypothalamus of the 7-day-old animals to produce any effect on their testis weights. GnRH receptor blockade with cetrorelix was also without effect on testis weights during “proportional” period but the same doses of this GnRH antagonist significantly inhibited “accelerated” testicular growth. GnRH receptor mRNA levels in the pituitary as well as plasma LH concentrations were higher during “accelerated” period of testicular growth than during “proportional” period. In general, our data defined two distinct periods in rat testicular development that are primarily characterized by different responses to GnRH signaling.

Comment gérer l’arrêt d’une corticothérapie ?

A prolonged treatment with anti-inflammatory corticosteroids induces an inhibition of ACTH secretion from pituitary corticotroph cells. An abrupt interruption of such a treatment potentially leads to the risk of an acute adrenal failure, in particular in stressing situations. The inertia in reactivation of the secretion of the stimulating hypothalamic factors (CRH and AVP) and consecutively of ACTH can be responsible for an inability to adapt the secretion of glucocorticoids in response to stress. A short-time treatment (<3 weeks) with anti-inflammatory corticoids does not expose to this risk. On the contrary, a more prolonged treatment, especially with high daily doses, needs to perform an evaluation of the level of corticotroph secretion. This evaluation should be done before to consider that either stopping the treatment is out of risk or if the initiation of a substitutive treatment with hydrocortisone is required. The measurement of morning plasma cortisol level already provides a significant information. As to whether that is needed, a dynamic evaluation can be performed. Among the available tests, the Synacthen(®)test, easy to perform and using at best 1μg of β1-24 ACTH, appears the most finely informative to answer this question and to choose the most adapted follow-up.

Changes in apoptotic factors in hypothalamus and hippocampus after acute and subchronic stress induction during conditioned place preference paradigm.

The hypothalamus (HYP) and hippocampus (HIP) are important regions involved in stress responses. These areas are also associated with reward processing. In this study, the effects of acute and subchronic stress on the changes in apoptotic factors (Bax/Bcl-2 ratio, caspase-3 activation and PARP degradation) in the HYP and HIP during conditioned place preference (CPP) paradigm were evaluated. Male Wistar rats were divided into two saline- and morphine-treated supergroups. Each supergroup contained control, acute stress (AS) and subchronic stress (SS) groups. In all groups, CPP paradigm was done and thereinafter alterations of apoptotic factors were measured by western blot. The results revealed that in the HYP, all mentioned factors increased significantly in saline- or morphine-treated animals during AS and SS. On the other hand, in the HIP, Bax/Bcl-2 ratio in saline-treated animals increased significantly during AS and SS, while in morphine-treated animals this ratio did not have any significant alteration during AS and was decreased during SS compared with morphine-control group. Caspase-3 and PARP increased during AS and SS in saline- or morphine-treated animals. For example, caspase-3 increased during AS and SS in morphine-treated animals by 2.4 folds and PARP (89 KDa) increased by 3.1 and 3.5 folds, respectively. Interestingly, the increase of apoptotic factors in morphine-treated animals was more considerable than that of saline-treated animals. These results strongly implied that AS and SS trigger apoptotic events in the HYP and HIP of saline- and/or morphine-treated animals as well as morphine reinforces the effect of stress on the induction of apoptosis.

Acute Confusional Syndrome and Hypopituitarism Produced by a Giant Aneurysm of Internal Carotid Artery

T he syndrome of pituitary insufficiency secondary to aneurysms of the internal carotid artery is uncommon, and the prevalence has been estimated in 0.17%. The first description was published by Mitchell in 1889, cited by Dussault et al. A 74-year-old woman presented with a 3-day history of progressive weakness and dizziness, nausea, and increasing confusion. Her medical history was only relevant for systemic hypertension. The examination revealed a conscious patient, disoriented, not obeying commands (Glasgow Coma Scale of 13/15), and having equal pupils, with no cranial nerves or motor limbs deficits. The remainder of the physical examination disclosed no abnormality in an afebrile, well-nourished, and wellhydrated patient. Serum and hematologic analyses showed a sodium level of 131 mmol/L and potassium of 3.7 mmol/L. Lumbar puncture and urinalysis were nonspecific. A brain computed tomography without contrast showed an eroded sella in its left half. Magnetic resonance imaging of the brain revealed an intraand left parasellar lesion, isointense on T1-weighted images and hypointense on T2-weighted images (Figure 1). Magnetic resonance angiography showed a 2.2 3 2.5 cm left cavernous internal carotid artery aneurysm. Cerebral angiography (Figure 2) showed a left carotid cavernous aneurysm with intrasellar extension. Basal endocrine studies showed hyperprolactinemia with decreased levels of thyrotropin, free T4, corticotropin, serum cortisol, insulin-like growth factor 1, follicle stimulating hormone, and luteinizing hormone. She started corticosteroids and levothyroxine. Conservative treatment was decided, and the patient was discharged home with replacement endocrine therapy for life. The pathogenesis of pituitary dysfunction induced by sellar and parasellar aneurysms remains uncertain. Two pathogenetic possibilities are postulated, and often, a combination of them is present. On one hand, compression and destruction of pituitary tissue by an expanding mass lesion might explain itself a decrease in the production of all pituitary hormones, including prolactin. On the other, compression of pituitary stalk or hypothalamic tissue compromising the delivery of hypothalamic factors would also explain hypopituitarism, inducing hyperprolactinemia as in our case and the majority of cases previously published.

Stress responsiveness of the hypothalamic-pituitary-adrenal axis: age-related features of the vasopressinergic regulation.

The hypothalamic–pituitary–adrenal (HPA) axis plays a key role in adaptation to environmental stresses. Parvicellular neurons of the hypothalamic paraventricular nucleus secrete corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) into pituitary portal system; CRH and AVP stimulate adrenocorticotropic hormone (ACTH) release through specific G-protein-coupled membrane receptors on pituitary corticotrophs, CRHR1 for CRH and V1b for AVP; the adrenal gland cortex secretes glucocorticoids in response to ACTH. The glucocorticoids activate specific receptors in brain and peripheral tissues thereby triggering the necessary metabolic, immune, neuromodulatory, and behavioral changes to resist stress. While importance of CRH, as a key hypothalamic factor of HPA axis regulation in basal and stress conditions in most species, is generally recognized, role of AVP remains to be clarified. This review focuses on the role of AVP in the regulation of stress responsiveness of the HPA axis with emphasis on the effects of aging on vasopressinergic regulation of HPA axis stress responsiveness. Under most of the known stressors, AVP is necessary for acute ACTH secretion but in a context-specific manner. The current data on the AVP role in regulation of HPA responsiveness to chronic stress in adulthood are rather contradictory. The importance of the vasopressinergic regulation of the HPA stress responsiveness is greatest during fetal development, in neonatal period, and in the lactating adult. Aging associated with increased variability in several parameters of HPA function including basal state, responsiveness to stressors, and special testing. Reports on the possible role of the AVP/V1b receptor system in the increase of HPA axis hyperactivity with aging are contradictory and requires further research. Many contradictory results may be due to age and species differences in the HPA function of rodents and primates.

Regulation of the cell proliferation and migration as extra-pituitary functions of GnRH

GnRH was originally identified as a hypothalamic factor which promotes gonadotropin release from the pituitary and was named gonadotropin-releasing hormone (GnRH). However, broad tissue distributions of GnRH and the GnRH receptor in various extrapituitary tissues and organs have been revealed and it has been suggested that GnRH has extrapituitary effects such as neuromodulation, immunomodulation, and regulation of follicular atresia and ovulation. Although a number of studies have been performed on these effects, little is known about the molecular mechanisms and physiological settings in which GnRH exerts its activities in extrapituitary organs or tissues. Our recent studies had demonstrated that GnRH is able to regulate both cell proliferation and cell migration at much lower concentration than that in the peripheral circulation by using human carcinoma cell lines. Moreover, stimulating activity of GnRH on the developing chick embryonic GnRH neurons was also demonstrated and strongly suggests possible involvement of GnRH in some of extrapituitary functions. This mini-review intends to provide solid evidence of GnRH activity in the regulation of cell proliferation and migration and its physiological relevance in extra-pituitary functions. Recent other research, including that in various invertebrates, provides new insight into the evolutionary scenarios of GnRH signaling systems, and GnRH functions. Both proliferating and migrating activities are important fundamental cellular activities and could provide an important clue into understanding what the driving force behind the evolution of the GnRH signaling system was.

Interactions of Growth Hormone, Insulin-Like Growth Factor-1, and Ghrelin with the Blood-Brain Barrier

Growth hormone (GH) therapy is associated with improved neurobehavior, leading to the question whether GH crosses the blood-brain barrier (BBB) from blood after its release there from the pituitary, or whether GH exerts CNS effects by secondary mediators, particularly insulin-like growth factor (IGF)-1. GH release from the pituitary is controlled not only by hypothalamic factors, but also by ghrelin that is mainly produced in the stomach and uses its unique structure to interact with the BBB. This review summarizes studies of the permeation of GH, IGF-1, and ghrelin across the BBB, and discusses them in the context of neuroendocrine regulation. Exogenous GH has a half-life of approximately 3.8-7.6 min in mouse blood and shows a slow non-saturable permeation across the BBB, with 26.8 % remaining intact in the brain 20 min after intravenous delivery. IGF-1 crosses the BBB by saturable transport mediated by its receptors, and its interactions with the BBB are greatly affected by serum binding proteins. The interactions of ghrelin with the BBB appear to be dependent on species and show directionality. The BBB provides regulatory compartmentalization to fine-tune the CNS actions of GH and its related hormones.

A novel GH secretagogue, A233, exhibits enhanced growth activity and innate immune system stimulation in teleosts fish

In teleosts fish, secretion of GH is regulated by several hypothalamic factors that are influenced by the physiological state of the animal. There is an interaction between immune and endocrine systems through hormones and cytokines. GH in fish is involved in many physiological processes that are not overtly growth related, such as saltwater osmoregulation, antifreeze synthesis, and the regulation of sexual maturation and immune functions. This study was conducted to characterize a decapeptide compound A233 (GKFDLSPEHQ) designed by molecular modeling to evaluate its function as a GH secretagogue (GHS). In pituitary cell culture, the peptide A233 induces GH secretion and it is also able to increase superoxide production in tilapia head-kidney leukocyte cultures. This effect is blocked by preincubation with the GHS receptor antagonist [d-Lys(3)]-GHRP6. Immunoneutralization of GH by addition of anti-tilapia GH monoclonal antibody blocked the stimulatory effect of A233 on superoxide production. These experiments propose a GH-mediated mechanism for the action of A233. The in vivo biological action of the decapeptide was also demonstrated for growth stimulation in goldfish and tilapia larvae (P<0.001). Superoxide dismutase levels, antiprotease activity, and lectin titer were enhanced in tilapia larvae treated with this novel molecule. The decapeptide A233 designed by molecular modeling is able to function as a GHS in teleosts and enhance parameters of the innate immune system in the fish larvae.

Abstract 2427: The stress response controls the interorgan glutathione/interleukin-6 cycling activity: A systemic signaling mechanism promoting metastases growth.

Abstract B16 melanoma F10 (B16-F10) cells with high glutathione (GSH) content show very high metastatic activity in vivo. An intertissue flow of GSH, where the liver is the main reservoir, increases GSH content in metastatic cells and promote their growth. We studied possible tumor-derived molecular signals that could activate GSH release from hepatocytes. GSH efflux increases in hepatocytes isolated from mice bearing liver or lung metastases, thus suggesting a systemic mechanism. Fractionation of serum-free conditioned medium from cultured B16-F10 cells and monoclonal antibody-induced neutralization techniques facilitated identification of interleukin (IL)-6 as a tumor-derived molecule promoting GSH efflux in hepatocytes. IL-6 activates GSH release through a methionine-sensitive/organic anion transporter polypeptide 1- and multidrug resistance protein 1-independent channel located on the sinusoidal site of hepatocytes. Specific siRNAs were used to knock down key factors in the main signaling pathways activated by IL-6, which revealed a STAT3-dependent mechanism. Our results show that IL-6 (mainly of tumor origin) facilitates GSH release from hepatocytes and its interorgan transport to metastatic growing foci. Metastatic tumor activated the hypothalamic-pituitary-adrenal axis, thus increasing expression of hypothalamic corticotropin releasing factor and plasma levels of adrenocorticotropin hormone, corticosterone, and cathecolamines. Corticosterone and norepinephrine increased IL-6 expression and synthesis in metastatic cells, thus promoting the interorgan GSH/IL-6 cycling activity. Our results suggest possible mechanisms of cross-talk between metastases and the central nervous system of the host. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2427. doi:1538-7445.AM2012-2427

Oxytocin: An Emerging Regulator of Prolactin Secretion in the Female Rat

In the female rat, a complex interplay of both stimulatory and inhibitory hypothalamic factors controls the secretion of prolactin. Prolactin regulates a large number of physiological processes from immunity to stress. Here, we have chosen to focus on the control of prolactin secretion in the female rat in response to suckling, mating and ovarian steroids. In all three of these states, dopamine, released from neurones in the mediobasal hypothalamus, is a potent inhibitory signal regulating prolactin secretion. Early research has determined that the relief of dopaminergic tone is not sufficent to account for the full surge of prolactin secretion observed in response to the suckling stimulus, launching a search for possible prolactin-releasing factors. This research has subsequently broadened to include searching for prolactin-releasing factors controlling prolactin secretion after mating or ovarian steroids. A great deal of literature has suggested that this prolactin-releasing factor may include oxytocin. Oxytocin receptors are present on lactotrophs. These oxytocin receptors respond to exogenous oxytocin and antagonism of endogenous oxytocin inhibits lactotroph activity. In addition, the pattern of oxytocin neuronal activity and oxytocin release correlate with the release of prolactin. Here, we suggest not only that oxytocin is stimulating prolactin secretion, but also that prolactin secretion is controlled by a complex network of positive (oxytocin) and negative (dopamine) feedback loops. We discuss the available literature and attempt to describe the circuitry we believe may be responsible for controlling prolactin secretion.

Adaptive and Innate Immunity and Acute Illness

The adaptive immune system (ADIM) involves the bone marrow that produce bone marrow derived (B) lymphocytes, and also release precursor cells for thymus derived (T) lymphocytes. B cell produce antibodies and regulate antibody formation, T cells mediate cellular immunity by killer T cells, and T cells mediating delayed type hypersensitivity. During an ADIM response, T and B lymphocytes proliferate, and their receptors undergo somatic mutation and clonal selection in order to generate highly specific antigen receptors. Seven to ten days needed for an adaptive immune response to develop. Antigen presenting cells (APC) initiate the ADIM response. Innate immunity (INIM) protects us for life. Innate antigen receptors are germ line coded, constant and polyspecific. The bone marrow produces monocyte/macrophages which recognize antigen, CD5+ B lymphocytes producing polyreactive natural antibodies, and polymorhonuclear granulocytes which are phagocytic cells. Natural killer, NK and NKT cells, and suppres- sor/regulatory T (Ts/r) cells are thymus derived. Cytokines are produced by monocytee/macrophages, NK, NKT Ts/r cells. The liver produces acute phase proteins (APP). Complement, properdin, defensins, scavenger receptors, enzymes and numerous other substances function as APP. The INIM system is capable of instantaneous defense at any time even under adverse conditions it will protect the host. During homeostasis both the adaptive and innate immune systems are regulated by vasopressin (VP) and everything works in harmony. During acute illness immune derived cytokines induce the acute phase response (APR), which is an emergency defense reaction against life threatening insults. During APR the INIM system is stimulated rapidly (maximum ∼1000 times, within 24-48 hours) and take over host defense as the ADIM system is not capable for a rapid response, and it is suppressed. Major endocrine, metabolic, and immune alterations take place. The HPA axis, sympathetic nervous system, glucocorticoids, catecholamines, pro-inflammatory cytokines, the brain, liver and white blood cells mediate APR. Fever and catabolism are hallmarks of APR. APR is the last effort by the organism to survive a life threatening event. In the overwhelming majority, febrile illness will be followed by recovery, which indicates the efficiency of this reaction. As a rule acute febrile illness will subside and chronic inflammatory disease will follow. During chronic inflammation VP becomes the hypothalamic regulator of immune and inflammatory process. Recovery will follow in most instances. The neuroendocrine, metabolic and immune abnormalities will be normalized and VP will serve as the hypothalamic factor regulating bodily functions during homeostasis. In cases when chronic stress does not subside, the INIM system will remain activated, and because of the excess energy requirement of this system cachexia may develop, which may be a lethal condition.

Structurally conserved C-RFa revealed prolactin releasing activity in vitro and gene expression changes in pituitary of seasonally acclimatized carp

Here we show the cloning and characterization of a novel homolog of prepro C-RFa cDNA from Cyprinus carpio. The deduced preprohormone precursor of 115 amino acids leads to a mature bioactive peptide of 20 amino acids with identical sequence to other teleost C-RFa. Modeling of the mature C-RFa peptide highlighted significant similarity to homologous human PrRP20, specifically the conserved amphipathic system defined by the C-terminal alpha-helix. Clearly, the synthetic C-RFa peptide stimulated prolactin release from primary cultured fish pituitary cells. For the first time, significant variation was shown in C-RFa mRNA and protein levels in the hypothalamus and pituitary between summer- and winter-acclimatized carp. Furthermore, C-RFa protein distribution in carp central nervous tissue was visualized by immunodetection in fibers and cells in hypothalamus, olfactory tract, cerebellum and pituitary stalk. In conclusion, we demonstrated the structure conservation of C-RFa in teleosts and mammals and immunopositive cells and fibers for C-RFa in brain areas. Finally, the increase of C-RFa expression suggests the participation of this hypothalamic factor in the mechanism of modulation in PRL expression in carp.

DNA polymorphisms of the KiSS1 3′ Untranslated region interfere with the folding of a G-rich sequence into G-quadruplex

KISS1R and its ligand, the kisspeptins, are key hypothalamic factors that regulate GnRH hypothalamic secretion and therefore the pubertal timing. During studies analysing KiSS1 as a candidate gene in pubertal onset disorders, two SNP and one nucleotide insertion were observed in a 23 nucleotides G-rich sequence located 65 nucleotides downstream of the stop codon. The polymorphisms formed four haplotypes. Biophysical experiments revealed the ability of this G-rich sequence to fold into G-quadruplex structures and demonstrated that the three DNA polymorphisms did not perturb the folding into G-quadruplex but affected G-quadruplex conformation. A functional luciferase reporter-based assay revealed functional differences between 3′UTR haplotypes. These data show that polymorphisms in a G-rich sequence of the 3′UTR of KISS1, able to fold into G-quadruplex structures, can modulate gene expression. They highlight the potential role of this G-quadruplex in the regulation of KISS1 expression and in the timing of pubertal onset.

Ovulation, Implantation and Placentation in Females with Obesity and Metabolic Disorders: Life in the Balance

Obesity due to endocrine and metabolic disorders causing dysfunctions of appetite-regulating pathways and energy balance is an increasingly concerning issue. Such form of obesity is mainly caused by the failure of elevated levels of the hormone leptin (LEP) to suppress feeding and mediate weight loss; the syndrome, caused by disruptions of signal transduction processes at the level of leptin receptors (LEPR), has been named as leptin resistance. Alterations in genes coding for LEPR and other hypothalamic factors in obese individuals have been related to low rates of pregnancies and deliveries. Fertility depends mainly on the success of processes involving ovulation, fertilization, implantation, placentation and embryo development; processes that seem to be affected in obese females. However, mechanistical research in human beings is very difficult to undertake, especially in reproductive issues, for both technical and ethical reasons. Thus, investigation is usually taken on animal models. Most of the studies have been carried out in mice, in which mutations in LEP and LEPR genes cause severe obese phenotypes (Leprob/ob and Leprdb/db mouse); in addition, such genotypes are infertile. However, total loss of LEPR function by monogenic disorders in humans, unlike mice, are really scarce. Functional alterations by LEPR gene polymorphisms are more common; the same has been found in the swine, an animal model very close to human. This review outlines, from results of translational animal research and clinical studies, the factors, mechanisms and pathways involved in the reproductive failures of individuals with metabolic disorders during the critical period from ovulation to completion of placentation and early-embryo development.

Impaired aerobic exercise adaptation in children and adolescents with craniopharyngioma is associated with hypothalamic involvement

Many patients treated for craniopharyngioma (CP) complain of a relative incapacity for physical activity. Whether this is due to an objective decrease in adaptation to exercise is unclear. We assessed exercise tolerance in children with surgically treated CP and appropriate pituitary hormone replacement therapy compared with healthy controls and we examined the potential relationships with hypothalamic involvement, GH replacement, and the catecholamine deficiency frequently observed in these subjects. Seventeen subjects (12 males and five females) with CP and 22 healthy controls (14 males and eight females) aged 15.3±2.5 years (7.3-18 years) underwent a standardized cycle ergometer test. Maximum aerobic capacity was expressed as the ratio of VO(2max) to fat-free mass (VO(2max)/FFM), a measure independent of age and fat mass in children. VO(2max)/FFM was 20% lower in children with CP compared with controls (P<0.05), even after adjustment for gender. Children with hypothalamic involvement (n=10) had a higher percentage of fat mass (P<0.05) than those without hypothalamic involvement (n=7) and lower VO(2max)/FFM (P<0.05), whereas children without hypothalamic involvement had VO(2max)/FFM close to that of controls (P>0.05). GH treatment was associated with a significant positive effect on aerobic capacity (P<0.05) only in the absence of hypothalamic involvement. No relationship was found between exercise capacity parameters and daily urine epinephrine excretion or epinephrine peak response to insulin-induced hypoglycemia. Children with CP have a decrease in aerobic capacity mainly related to hypothalamic involvement. The hypothalamic factors altering aerobic capacity remain to be determined.

Effects of Herba Epimedii and Fructus Ligustri lucidi on the transcription factors in hypothalamus of aged rats

To comparatively analyze the difference in the expression of 54 transcription factors in the hypothalamus using protein chips following the medication of Chinese drugs for Shen-tonification, Herba Epimedii, and Fructus Ligustri lucidi (FL) to aged rats. Wistar rats, aged 15 months of SPF grade, were randomized into three groups, three males and three females in each group. They were medicated with Herba Epimedii decoction (HED, 0.14 g/kg), Fructus Ligustri lucidi decoction (FLD, 0.12 g/kg), and distilled water, respectively, twice a day for 15 days. The rats were sacrificed at the morning of the 16th day 1 h after medication, and their hypothalamus was taken and made into homogenate under an ice-bath for detecting the expression of transcription factors with chip technique. The expressions of signal transduction and transcription activation factor-6 (Stat-6) and androgen receptor (AR) were up-regulated, and those of pre-B transcription factor1 (Pbx-1), stat-1 and AP-2 were down-regulated in both HED and FLD treated groups, but these changes occurred mainly in female rats in the former while mainly in males in the latter. Chinese drugs for Shen-tonification could impact the expression of transcription factors in the hypothalamus of aged rats, dominantly on the neuro-endocrine factors responsible for the growth and development. The effects of drugs for tonifying Shen-yang and for tonifying Shen-yin are different, which is probably one of the pharmacological mechanisms of the Shen-tonifying drugs.

40 Years of Research on the "Reproductive Brain" of Teleost Fishes

This year marks the 40th anniversary of the first article ever published on the effects of a brain hypothalamic factor on pituitary gonadotrophin in a teleost fish, the carp [1]. Since this pioneer work, one generation of researchers has written more than 1250 papers dedicated to various aspects of the brain control over the reproductive axis of fish. What we have learnt is that, overall, the neuroendocrine circuits controlling the pituitary gonadotropic activity and the main molecular actors involved in this control are highly conserved in vertebrates, indicating that they are at least 450 million years old and, probably, that many of these actors, if not all, were inherited from invertebrates

Transgenic mice expressing the human growth hormone gene provide a model system to study human growth hormone synthesis and secretion in non-tumor-derived pituitary cells: Differential effects of dexamethasone and thyroid hormone

Growth hormone (GH) is regulated by pituitary and hypothalamic factors as well as peripheral endocrine factors including glucocorticoids and thyroid hormone. Studies on human GH are limited largely to the assessment of plasma levels in endocrine disorders. Thus, insight into the regulation of synthesis versus secretion has come mainly from studies done on non-human GH and/or pituitary tumor cells. However, primate and non-primate GH gene loci have differences in their structure and, by extension, regulation. We generated transgenic (171hGH/CS-TG) mice containing the intact hGH1 gene and locus control region, including sequences required for integration-independent and preferential pituitary expression. Here, we show hGH co-localizes with mouse (m) GH in somatotrophs in situ and in primary pituitary cells. Dexamethasone treatment increased hGH and mGH, as well as GH releasing hormone (GHRH) receptor RNA levels, and hGH release was stimulated by GHRH treatment. By contrast, triiodothyronine decreased or had no effect on hGH and mGH production, respectively, and the negative effect on hGH was also seen in the presence of dexamethasone. Thus, 171hGH/CS-TG mouse pituitary cultures represent a model system to investigate hormonal control of hGH synthesis and secretion.

Hypophyseal hormonal response to hypothalamic factors in hypoxia

Exposure to high altitude induces various physiological changes, including activation or inhibition of hormonal systems. In response to activation processes, a desensitization of several pathways has been described, especially in the adrenergic system. In the present study, we aimed to assess if the hypophyseal hormones are also subjected to a hypoxia-induced decrease in their response to hypothalamic factors. Basal levels of hormones and the responses of TSH, thyroid hormones, prolactin, sex hormones and growth hormone to the injection of TRH, GnRH and GHRH were studied in 8 men in normoxia and on prolonged exposure (3–4 days) to an altitude of 4,350 m. Thyroid hormones were elevated at altitude (+16 to +21%), while TSH levels were unchanged, FSH and prolactin decreased while LH was unchanged. Norepinephrine and cortisol were elevated while no change was observed in epinephrine, dopamine, GH, IGF-1 and IGF-BP3. The mean response to hypothalamic factors was similar in both altitudes for all studied hormones, although total T4 was lower in hypoxia during 45 to 60 minutes after injection. The effect of hypoxia on the hypophyseal response to hypothalamic factors was similar among subjects, except for the GH response to GHRH administration. We conclude that prolonged exposure to altitude hypoxia induces contrasted changes in hormonal levels. The hypophyseal response to hypothalamic factors does not appear to be blunted.

Congenital absence of vasopressin and age-dependent changes in ACTH and corticosterone stress responses in rats

The hypothalamic components of the hypothalamo–pituitary–adrenal axis (HPA) are corticotropin-releasing hormone (CRH) and vasopressin. To test the hypothesis that HPA regulation changes with age, we compared ether and bacterial lipopolysaccharide (LPS) injection induced stress reactions in adult and 10-day-old Brattleboro rats, which naturally lack vasopressin owing to mutation of the gene (di/di). The LPS stimulus was used also with V1b receptor antagonist pretreatment (SSR149415). In adult di/di or V1b pretreated rats, we observed normal pituitary and adrenocortical secretory responses, while in all 10-day-old rats stress-induced serum corticosterone increases were marked, but adrenocorticotropin (ACTH) increases were significantly smaller. Compared to control pups the adenohypophysis of the 10-day-old di/di rats responded normally to CRH, but their adrenal glands were hyper-responsive to ACTH, while in adults there was greater secretion at both levels with no difference between the genotypes. The serum transcortin level was higher in adults than pups, with the di/di pups having higher transcortin levels than controls. Hence, using the same stressors in adults and pups with both a genetic model and pharmacological pretreatment, we have shown that the role of vasopressin in ACTH regulation is more important during the neonatal period than in adulthood. Blunted hypophysial sensitivity to CRH and similar adrenal gland sensitivity to ACTH in the pups compared to adults suggest that hypothalamic factors could be responsible for the neonatal stress hyporesponsive period.