Pituitary Gland

Growing evidence of cell-to-cell transmission of neurodegenerative disease (ND)-associated proteins (NDAPs) (ie, tau, A␤, and ␣-synuclein) suggests possible similarities to the infectious prion protein (PrP sc ) in spongiform encephalopathies. There are limited data on the potential human-to-human transmission of NDAPs associated with Alzheimer disease (AD) and other non-PrP sc ND. Objective: To examine evidence for human-to-human transmission of AD, Parkinson disease (PD), and related NDAPs in cadaveric human growth hormone (c-hGH) recipients. Design: We conducted a detailed immunohistochemical analysis of pathological NDAPs other than PrP sc in human pituitary glands. We also searched for ND in recipients of pituitary-derived c-hGH by reviewing the National Hormone and Pituitary Program (NHPP) cohort database and medical literature. Setting: University-based academic center and agencies of the US Department of Health and Human Services. Participants: Thirty-four routine autopsy subjects (10 non-ND controls and 24 patients with ND) and a US cohort of c-hGH recipients in the NHPP. Main Outcome Measures: Detectable NDAPs in hu-man pituitary sections and death certificate reports of non-PrP sc ND in the NHPP database. Results: We found mild amounts of pathological tau, A␤, and ␣-synuclein deposits in the adeno/neurohypophysis of patients with ND and control patients. No cases of AD or PD were identified, and 3 deaths attributed to amyotrophic lateral sclerosis (ALS) were found among US NHPP c-hGH recipients, including 2 of the 796 decedents in the originally confirmed NHPP c-hGH cohort database. Conclusions and Relevance: Despite the likely frequent exposure of c-hGH recipients to NDAPs, and their markedly elevated risk of PrP sc -related disease, this population of NHPP c-hGH recipients does not appear to be at increased risk of AD or PD. We discovered 3 ALS cases of unclear significance among US c-hGH recipients despite the absence of pathological deposits of ALS-associated proteins (TDP-43, FUS, and ubiquilin) in human pituitary glands. In this unique in vivo model of human-to-human transmission, we found no evidence to support concerns that NDAPs underlying AD and PD transmit disease in humans despite evidence of their cell-to-cell transmission in model systems of these disorders. Further monitoring is required to confirm these conclusions.

To evaluate a possible role for altered cortisol metabolism in mediating the immunoparesis associated with progressive tuberculosis (TB), we have studied the hypothalamic-pituitary-adrenal axis, and the activities of the 11 ␤ -hydroxysteroid dehydrogenases (11-HSDs) that interconvert active cortisol and inactive cortisone. In active pulmonary tuberculosis (PTB), the ratio of cortisol/cortisone metabolites in 24-h urine showed a shift towards active cortisol (ratio, 1.19 Ϯ 0.1, n ϭ 16 versus 0. 89 Ϯ 0.05 in cured pulmonary tuberculosis (CTB), n ϭ 13, p Ͻ 0. 01; and 0.78 Ϯ 0.04 healthy volunteers (HV), n ϭ 11, p Ͻ 0.005). Conversion of cortisone (administered as 25 mg orally) to cortisol in peripheral plasma was higher in PTB (peak 1,157 Ϯ 55 nM, n ϭ 14 versus 862 Ϯ 50 nM in CTB, n ϭ 10, p Ͻ 0.005, and 882 Ϯ 73 nM in HV, n ϭ 10; p Ͻ 0.005). Cortisol/cortisone ratio was increased in bronchoalveolar lavage fluid in PTB (7.73 Ϯ 1.48, mean Ϯ SE, n ϭ 13) compared with HV (4.05 Ϯ 0.38, n ϭ 11, p Ͻ 0.05) but was not different in plasma (PTB, 3.25 Ϯ 0.68; HV, 4.01 Ϯ 0.92). Responses of plasma cortisol to dexamethasone, CRH stimulation, and multidose ACTH stimulation were not different. These data suggest that in pulmonary tuberculosis, central control of glucocorticoid production is normal but that peripheral metabolism, in particular in the lung, is deviated in favor of the active metabolite cortisol. This offers a possible mechanism to explain the immunoparesis observed in progressive pulmonary tuberculosis.

Enhanced responsiveness of the pituitary gland to GnRH is a fundamental step required for secretion of the proestrous LH surge, and is achieved primarily by the actions of ovarian steroid hormones on the gonadotropes. The mechanisms involved are still unclear but the CAMP second messenger pathway can mediate some of these activities. The present study was undertaken to determine the effects of in vitro cholera toxin (CTX, increases CAMP) pretreatment of pituitary cells from proestrous and diestrous 1 rats relative to their LH secretory response to GnRH using a reverse hemolytic plaque assay. The number of gonadotropes that secrete LH in the group treated with CTX increased at low doses of GnRH and also in the absence of the peptide, but decreased at high doses, showing a dual effect: stimulation of some gonadotropes and inhibition of others. The inhibition was achieved within 3 h of pretreatment in proestrous cells but it was not seen until 20 h in diestrous 1 cells. This suggests the existence of at least two subpopulations of gonadotropes, one of which is stimulated by CAMP and another which is inhibited.

Enhanced responsiveness of the pituitary gland to GnRH is a fundamental step required for secretion of the proestrous LH surge, and is achieved primarily by the actions of ovarian steroid hormones on the gonadotropes. The mechanisms involved are still unclear but the CAMP second messenger pathway can mediate some of these activities. The present study was undertaken to determine the effects of in vitro cholera toxin (CTX, increases CAMP) pretreatment of pituitary cells from proestrous and diestrous 1 rats relative to their LH secretory response to GnRH using a reverse hemolytic plaque assay. The number of gonadotropes that secrete LH in the group treated with CTX increased at low doses of GnRH and also in the absence of the peptide, but decreased at high doses, showing a dual effect: stimulation of some gonadotropes and inhibition of others. The inhibition was achieved within 3 h of pretreatment in proestrous cells but it was not seen until 20 h in diestrous 1 cells. This suggests the existence of at least two subpopulations of gonadotropes, one of which is stimulated by CAMP and another which is inhibited.

Preembedding visualization of exocytosis by tannic acid treatment and postembedding immunocytochemical identification of cell types were combined to demonstrate the release of secretory products by exocytosis of characterized cell types. Treatment with tannic acid was carried out by perfusion with Ringer containing tannic acid, followed by fixation, dehydration and embedding. For electron microscopical immunocytochemistry protein A-gold was used as marker. In this study, exocytotic release was demonstrated for prolactin by cells in the pars distalis, and for oxytocin by axon terminals in the pars nervosa of the pituitary gland of the rat.

Growth retardation in children with thalassaemia major is multifactorial. We studied the growth hormone (GH) response to provocation by clonidine and glucagon, measured the circulating concentrations of insulin, insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP3), and ferritin, and evaluated the spontaneous nocturnal (12 h) GH secretion in prepubertal patients with thalassaemia and age-matched children with constitutional short stature (CSS) (height SDS < ¹2, but normal GH response to provocation). The anatomy of the hypothalamic pituitary area was studied in patients with abnormal GH secretion using MRI scanning. Children with thalassaemia had significantly lower peak GH response to provocation by clonidine and glucagon (8:8 Ϯ 2:3 mg/l and 8:2 Ϯ 3:1 mg/l respectively) than did controls ð17:6 Ϯ 2:7 mg/l and 15:7 Ϯ 3:7 mg/l respectively). They had significantly decreased circulating concentrations of IGF-I and IGFBP3 (68:5 Ϯ 19 ng/ml and 1:22 Ϯ 0:27 mg/l respectively) compared to controls (153 Ϯ 42 ng/ml and 2:16 Ϯ 0:37 mg/l respectively). Seven of the thalassaemic children had a GH peak response of < 7 mg/l after provocation. Those with a normal GH response after provocation also had significantly lower IGF-I and IGFBP3 concentrations than controls. Analysis of their spontaneous nocturnal GH secretion revealed lower mean (2:9 Ϯ 1:77 mg/l) and integrated (2:53 Ϯ 1:6 mg/l) concentrations compared to controls (4:9 Ϯ 0:29 mg/l and 5:6 Ϯ 0:52 mg/l respectively). Five of them had mean nocturnal GH concentration < 2 mg/l and four had maximum nocturnal peak below 10 mg/l. These data denoted defective spontaneous GH secretion in some of these patients. MRI studies revealed complete empty sella ðn ¼ 2Þ, marked diminution of the pituitary size ðn ¼ 4Þ, thinning of the pituitary stalk (n ¼ 3Þ with its posterior displacement ðn ¼ 2Þ, and evidence of iron deposition in the pituitary gland and midbrain ðn ¼ 7Þ in those patients with defective GH secretion ðn ¼ 9Þ. Serum ferritin concentration was correlated significantly with the circulating IGF-I (r ¼ ¹0:47; p < 0:01Þ and IGFBP3 (r ¼ ¹0:43; p < 0:01Þ concentrations. These data prove a high prevalence of defective GH secretion in thalassaemic children associated with structural abnormality of their pituitary gland.

Monthly surveys of the plasma prolactin level in Bufojaponicus at two localities, one in Tokyo and the other in Saitama Prefecture, revealed that the level was highest during the month of breeding in early spring with an additional peak recognized in autumn. The level was lowest during the winter torpid period before breeding and during the spring torpid period after breeding. The pituitary prolactin content observed in Tokyo also showed an annual cycle similar to the plasma prolactin, except that the content in winter was higher than that in summer. A further precise survey of the plasma prolactin level before and during the breeding period revealed that the level in male toads migrating toward the pond for breeding was as low as the level in torpid toads, and also that the level was elevated in only about 50% of migrating female toads. In the pond, almost all female and male toads showed high plasma prolactin levels. Soon after the females finished breeding and returned to land, the level declined to the baseline without exception. In contrast, many males retained high levels on land. The present results indicate that prolactin is not a water drive factor, at least in B.japonicus. Prolactin may, however, play a role in toad osmoregulation in water. There is a possibility that the high prolactin level in some of the migrating female toads is related to oviductal secretion, as some female toads ovulate during migration.

The maternal environment affects fetal development and may permanently affect the physiology of the adult. Fetal growth hormone (GH) secretion is increased by maternal undernutrition but the physiological mechanisms responsible for this increase are unknown. We have recently found evidence suggesting that the GHRH component of the fetal neuroendocrine GH axis may be perturbed by undernutrition. This study sought to determine the effect of maternal undernutrition on immunocytochemically detectable GHRH neurons and the expression of GHRH receptors by somatotropes in the pituitary gland. Ewes were grouped (n = 12 per group) randomly into control (fed 100% of requirements) or nutrient restricted (fed 50% of requirements) from days 28 to 78 of gestation, corresponding to the period from implantation to the end of placentation. At day 78, half the ewes were killed and the fetal brains were perfused. The remaining ewes were re-alimented to 100% of nutritional requirements and killed at day 135. There was no effect of nutrition restriction or age on the number of GHRH neurons. Similarly, the mean density and percentage of somatotropes expressing GHRH receptors was not significantly different between treatment groups at either age. This study found no effect, as determined by immunocytochemistry, of nutrient restriction on the GHRH component of the fetal neuroendocrine GH axis. It remains to be established if the release of GHRH and responsiveness of somatotropes to GHRH in the fetus are affected by undernutrition.

Objective: This study aims to clarify the relative position of the normal important structures and anatomical spaces formed by the structures passed through during the transfrontal pituitary surgery, and discuss how to avoid some eloquent structures. Methods: A total of 120 cases of magnetic resonance imaging images from normal adult brains were selected as the object of study and divided into male and female groups. The important adjacent structures of the pituitary passed through during the transfrontal pituitary surgery were marked on the reconstructed images. In all planes of the spaces passing through successively during the pituitary surgery, the morphological parameters such as the size, boundary, structure, and spatial extent of the spaces were measured. Results: The size, boundary, structure, and spatial extent of the space between the 2 optic nerves, the space between the optic nerves and the pituitary stalk, and the space between the tuber cinereum and the interal carotid artery in the plane of the pituitary stalk were measured, the anterior part and the posterior part in male were shorter than those in female (P ¼ 0.021; P ¼ 0.029); no statistically significant difference was found in the measurements of the lengths and angles of these spaces. Conclusions: The authors' findings provide the surgeons with the detailed anatomical data and help to provide a morphological basis for intraoperative protection of the pituitary and vital adjacent structures and surgical approach.

We report on the isolation of a murine homeobox-containing gene, Six6 (Optx2), that shows extended identity in its coding region with Six3, the only member of the mammalian Six gene family known to be expressed in the optic primordium. Phylogenetic analysis demonstrates that Six6 and Six3 belong to a separate group of homeobox-genes that are closely related to the recently identi®ed Drosophila optix. Earliest Six6 expression was detected in the ¯oor of the diencephalic portion of the primitive forebrain, a region predicted to give rise to the neurohypophysis and to the hypothalamus. Later on, Six6 mRNA was found in the primordial tissues giving rise to the mature pituitary: the Rathke's pouch and the infundibular recess. In the optic primordium, Six6 demarcates the presumptive ventral optic stalk and the ventral portion of the future neural retina. In the developing eye, Six6 expression was detected in the neural retina, the optic chiasma and optic stalk, but not in the lens. When compared to Six6, Six3 expression pattern was highly similar, but with a generally broader transcripts distribution in the brain and in the visual system. We ®nally show that Six6 does not require Pax6 for its expression in the optic primordium, suggesting that Six6 acts on a parallel and/or independent pathway with Pax6 in the genetic cascade governing early development of the eye.

The brain's unimaginably complex operations are expressed in just two types of output: muscle activity and hormone release. These are the means by which the brain acts beyond its bony casing. Muscle-mediated actions (such as speaking, writing, pupillary reflexes) send signals to the outside world that may convey thoughts, emotions or evidence of neurological disorder. The outputs of the brain as a hormone secreting gland are usually less evident. Their discovery required several paradigm shifts in our understanding of anatomy. The first occurred in 1655. Exactly 300 years later, Geoffrey Harris' monograph Neural control of the pituitary gland launched the scientific discipline that is now known as neuroendocrinology. His hypotheses have stood the test of time to a remarkable degree. A key part of his vision concerned the two-way 'interplay between the central nervous system and endocrine glands'. Over the past 60 years, the importance of this reciprocity and the degree to which cerebral functions are influenced by the endocrine environment have become increasingly clear.

The brain&#39;s unimaginably complex operations are expressed in just two types of output: muscle activity and hormone release. These are the means by which the brain acts beyond its bony casing. Muscle-mediated actions (such as speaking, writing, pupillary reflexes) send signals to the outside world that may convey thoughts, emotions or evidence of neurological disorder. The outputs of the brain as a hormone secreting gland are usually less evident. Their discovery required several paradigm shifts in our understanding of anatomy. The first occurred in 1655. Exactly 300 years later, Geoffrey Harris&#39; monographNeural control of the pituitary glandlaunched the scientific discipline that is now known as neuroendocrinology. His hypotheses have stood the test of time to a remarkable degree. A key part of his vision concerned the two-way ‘interplay between the central nervous system and endocrine glands’. Over the past 60 years, the importance of this reciprocity and the degree to whic...

Phytoestrogens can produce inhibitory effects on gonadotropin secretion in both animals and humans. The aims of this study were 2-fold: 1) to determine in vivo whether genistein and coumestrol act on the GnRH pulse generator to suppress hypothalamic multiunit electrical activity volleys and associated LH pulses and/or on the pituitary to suppress the LH response to GnRH; and 2) to examine the effect of these phytoestrogens on GnRH-induced pituitary LH release in vitro and to determine whether estrogen receptors are involved. Wistar rats were ovariectomized and chronically implanted with recording electrodes and/or indwelling cardiac catheters, and blood samples were taken every 5 min for 7-11 h. Intravenous infusion of coumestrol (1.6-mg bolus followed by 2.4 mg/h for 8.5 h) resulted in a profound inhibition of pulsatile LH secretion, a 50% reduction in the frequency of hypothalamic multiunit electrical activity volleys, and a complete suppression of the LH response to exogenous GnRH. In contrast, both genistein (1.6-mg bolus followed by 2.4 mg/h for 8.5 h) and vehicle were without effect on pulsatile LH secretion. Coumestrol (10 Ϫ5 M; over 2 or 4 h) suppressed GnRH-induced pituitary LH release in vitro, an effect blocked by the antiestrogen ICI 182,780. It is concluded that coumestrol acts centrally to reduce the frequency of the hypothalamic GnRH pulse generator. In addition, the inhibitory effects of coumestrol on LH pulses occur at the level of the pituitary by reducing responsiveness to GnRH via an estrogen receptor-mediated process. (Endocrinology 142: 1202(Endocrinology 142: -1208(Endocrinology 142: , 2001) )

Reproduction is of significant economic importance in dairy cattle. Improved understanding of mechanisms that control estrous behavior and other reproduction traits could help in developing strategies to improve and/or monitor these traits. The objective of this study was to predict and rank genes and processes in brain areas and pituitary involved in reproductive traits in cattle using information derived from three different data sources: gene expression, protein-protein interactions, and literature. We identified 59, 89, 53, 23, and 71 genes in bovine amygdala, dorsal hypothalamus, hippocampus, pituitary, and ventral hypothalamus, respectively, potentially involved in processes underlying estrus and estrous behavior. Functional annotation of the candidate genes points to a number of tissue-specific processes of which the “neurotransmitter/ion channel/synapse” process in the amygdala, “steroid hormone receptor activity/ion binding” in the pituitary, “extracellular region” in the v...

Studies of genetically engineered flies and mice have revealed the role that orthologs of the human LIM homeobox LHX4 have in the control of motor-neuron-identity assignment and in pituitary development. Remarkably, these mouse strains, which bear a targeted modification of Lhx4 in the heterozygous state, are asymptomatic, whereas homozygous animals die shortly after birth. Nevertheless, we have isolated the human LHX4 gene, as well as the corresponding cDNA sequence, to test whether it could be involved in developmental defects of the human pituitary region. LHX4, which encodes a protein 99% identical to its murine counterpart, consists of six coding exons and spans 145 kb of the q25 region of chromosome 1. We report a family with an LHX4 germline splice-site mutation that results in a disease phenotype characterized by short stature and by pituitary and hindbrain (i.e., cerebellar) defects in combination with abnormalities of the sella turcica of the central skull base. This intronic mutation, which segregates in a dominant and fully penetrant manner over three generations, abolishes normal LHX4 splicing and activates two exonic cryptic splice sites, thereby predicting two different proteins deleted in their homeodomain sequence. These findings, which elucidate the molecular basis of a complex Mendelian disorder, reveal the fundamental pleiotropic role played by a single factor that tightly coordinates brain development and skull shaping during head morphogenesis.

SummaryAn analysis of the gonadotrophin response to an intravenous injection of LH‐RH (50 μg) has been undertaken in 41 patients with secondary amenorrhoea. Thirtyfive of the patients were free of any recognizable pathology to account for their amenorrhoea and apparently had a dysfunction of the hypothalamic‐pituitary axis. In these patients, the gonadotrophin response to LH‐RH was highly variable. There was in general a correlation between baseline plasma LH or FSH levels and their respective increments. There was no correlation, however, between basal oestrogen levels and gonadotrophin increments except in the case of those patients whose basal levels of plasma FSH were higher than those of LH and in those patients whose body weight was less than the ideal for the population. It appears that the gonadotrophin response to a single injection of LH‐RH in the majority of patients with secondary amenorrhoea of unknown origin is too variable to be of use either as a diagnostic or progno...

That light and melatonin rhythms provide both clock and calendar information in humans and numerous other species is beyond dispute; this holds true for all stages of life, including the very early ones. Experimental evidence elucidates that exposure to light and melatonin titres are keys for the very development of circadian and seasonal rhythms. As evinced by a 2011 publication in Nature Neuroscience such awareness could impact considerably on the design and conduct of experimental studies as well as their subsequent analyses, interpretations and comparisons. Therefore "when and how experimental animals were bred, developed and raised" may be critical when experimenting with animals generally, and not just rodents. As long as the suggested imprinting of circadian system stability via light cues is not falsified, the perinatal season or perinatal experimental light:dark [L:D] conditions that an animal was kept under should be routinely recorded, published and considered in analysing and interpreting study data.

Molecular regulation of the hypothalamic-pituitary-gonadal (HPG) axis plays an essential role in the fine tuning of seasonal estrus in Capra hircus. Noncoding RNAs (ncRNAs) are emerging as key regulators in sexual development and mammalian reproduction. In order to identify ncRNAs and to assess their expression patterns, along the HPG axis, we sequenced ncRNA libraries from hypothalamus, pituitary and ovary of three goats. Among the medium length noncoding RNAs (mncRNAs) identified, small nucleolar RNAs (snoRNAs) and transfer RNAs (tRNAs) were found to be more abundant in ovary and hypothalamus, respectively. The observed GC content was representative for different classes of ncRNAs, allowing the identification of a tRNA-derived RNA fragments (tRFs) subclass, which had a peak distribution around 32-38% GC content in the hypothalamus. Differences observed among organs confirmed the specificity of microRNA (miRNA) profiles for each organ system. Data on ncRNAs in organs constituting t...

Mercury, a ubiquitous toxic element, is known to alter expression of sex steroids and to impair reproduction across vertebrates but the mechanisms underlying these effects are not clearly identified. We examined whether contamination by mercury predicts the probability to skip reproduction in black-legged kittiwakes (Rissa tridactyla) from Svalbard. We also manipulated the endocrine system to investigate the mechanism underlying this relationship. During the pre-laying period, we injected exogenous GnRH (gonadotropin-releasing hormone) to test the ability of the pituitary to release luteinizing hormone (LH, a key hormone for the release of sex steroids and hence breeding) in relation to mercury burden. Birds that skipped reproduction had significantly higher mercury concentration in blood than breeders. Endocrine profiles of these birds also varied based on breeding status (breeders versus non-breeders), mercury contamination and sex. Specifically, in skippers (birds that did not breed), baseline LH decreased with increasing mercury concentration in males, whereas it increased in females. GnRH-induced LH levels increased with increasing mercury concentration in both sexes. These results suggest that mercury contamination may disrupt GnRH input to the pituitary. Thus, high mercury concentration could affect the ability of long-lived birds to modulate their reproductive effort (skipping or breeding) according to ongoing environmental changes in the Arctic, thereby impacting population dynamics.

We investigated whether carbofuran CF , a carbamate pesticide, at sub-lethal concentration had any adverse effects on reproductive function of the Indian catfish , Heteropneustes fossilis. 17␤-Estradiol content of serum and ovary of Ž . Ž . Ž pre-spawning P and spawning S fish was reduced after sub-lethal concentration of carbofuran treatment 0.5᎐2 . mgrml, 30 days . After 30 days of CF treatment, the serum and ovarian vitellogenin levels of fish at the P stage were also reduced but remained unaltered in the S stage. The staining intensity of the pituitary gonadotrophs of the pre-spawning fish was significantly higher in CF-treated fish compared to controls suggesting the inability of the pituitary gonadotrophs to release gonadotropin following CF treatment. CF thus acts as an antiestrogenic, endocrine-disrupting agent in fish, possibly targeting the pituitary-gonad axis.

Vanecek, Jiri. Cellular Mechanisms of Melatonin Action. Physiol. Rev. 78: 687–721, 1998. — The pineal hormone melatonin is involved in photic regulations of various kinds, including adaptation to light intensity, daily changes of light and darkness, and seasonal changes of photoperiod lengths. The melatonin effects are mediated by the specific high-affinity receptors localized on plasma membrane and coupled to GTP-binding protein. Two different G proteins coupled to the melatonin receptors have been described, one sensitive to pertussis toxin and the other sensitive to cholera toxin. On the basis of the molecular structure, three subtypes of the melatonin receptors have been described: Mel1A, Mel1B, and Mel1C. The first two subtypes are found in mammals and may be distinguished pharmacologically using selective antagonists. Melatonin receptor regulates several second messengers: cAMP, cGMP, diacylglycerol, inositol trisphosphate, arachidonic acid, and intracellular Ca2+concentration...

Male rats were grafted on Day 21 of age with 'young' (21 days old) or 'adult' (90 days old) pituitary glands and then treated daily with 4 mg bromocriptine/ kg or vehicle. Plasma samples were obtained on Days 21, 25 and 35 and when balano\x=req-\ preputial separation occurred. Both types of grafts advanced the age at which balano\x=req-\ preputial separation occurred and increased prolactin concentrations. Bromocriptine treatment reduced the prolactin values in both grafted groups, but did not block the advancement of puberty in rats treated with 'young' pituitary grafts. These results suggest the existence of two possible mechanisms in precocious puberty induced by pituitary grafts: one is prolactin-dependent (when 'adult' pituitary glands were used) and the other not directly related to prolactin (when 'young' pituitary glands were used).

The LH response to 100 or 1000 ng of LH-RH was studied in adult male rats treated neonatally with 500 pg of estradiol benzoate or olive oil. The dose of 100 ng elicited the same LH increase in both groups, but the estrogenized animals responded more when 1000 ng of LH-RH was injected. These data suggest that the decreased LH response to orchidectomy found in estrogenized animals is not due to a failure in pituitary responsiveness to LH-RH.

Deterioration of reproductive health in human and wildlife species during the past decades has drawn considerable attention to the potential adverse effects of exposure to xenosteroids during sensitive periods of sex development. The hypothalamic-pituitary (HP) unit is a key element in the neuroendocrine system controlling development and function of the reproductive axis; the HP unit being highly sensitive to the organizing effects of endogenous and exogenous sex steroids. To gain knowledge on the molecular mode of action and potential biomarkers of exposure to estrogenic compounds at the HP unit, we screened for differentially expressed genes at the pituitary and hypothalamus of rats after neonatal exposure to estradiol benzoate. Our analyses identified persistent up-regulation of ␣and ␤-globin mRNAs at the pituitary following neonatal estrogenization. This finding was confirmed by combination of RT-PCR analyses and in situ hybridization. Induction of ␣and ␤-globin mRNA expression at the pituitary by neonatal exposure to estrogen was demonstrated as dose-dependent and it was persistently detected up to puberty. In contrast, durable up-regulation of ␣and ␤-globin genes was not detected at the hypothalamus, cortex, cerebellum, liver and testis. Finally, enhanced levels of ␣and ␤-globin mRNAs at the pituitary were also demonstrated after neonatal administration of the anti-androgen flutamide. In summary, ␣and ␤-globin genes may prove as sensitive, pituitary-specific biomarkers of exposure to estrogenic (and/or anti-androgenic) compounds at critical periods of sex development, whose potential in the assessment of endocrine disrupting events at the HP unit merits further investigation.

In previous studies, we assessed the effects of intrapituitary injection of a recombinant adenoviral vector (RAd) harboring the cDNA for rat insulin-like growth factor type I (RAd-IGF-I) on the lactotrope and somatotrope populations in estrogen-induced prolactinomas. In the present study, we aimed to confirm these findings and further analyze the effect of transgenic RAd-IGF-I on the other pituitary cell populations in female rats. All animals except the intact group (no estrogen and no stereotaxic injection) received subcutaneous estrogen for 30 days, and the groups which received RAd-IGF-I or RAd expressing green fluorescent protein (control) were additionally treated with the appropriate vectors on experimental day 0. The RAd-IGF-I group showed a significant decrease in serum growth hormone and prolactin levels and lactotrope and somatotrope cell size induced by estrogen treatment. Cell density was not affected by 7 days of IGF-I gene therapy. Estrogen had an inhibitory effect on...

Department of Experimental Endocrinology, Institute of Endocrinology, Medical Academy of Łódź, Dr Sterling sir. 3, 91–425 Łódź, Poland (Received 22 May 1978) Lloyd, Meares & Jacobi (1975) observed inhibition of mitotic activity in the anterior pituitary gland by the dopamine receptor agonist, bromocriptine, in oestrogen-treated male rats. This observation has been confirmed in our laboratory (Stępień, Wolaniuk & Pawlikowski, 1978). Suppression of mitotic activity in the pars intermedia of the rat pituitary gland by bromocriptine has also been observed (Rychter & Stępień, 1977). Furthermore, it has been found that the dopamine receptor blocker, pimozide, enhances mitotic activity in the rat anterior pituitary gland (Stępień et al. 1978). By the use of various ergot alkaloids, MacLeod & Lehmeyer (1973) succeeded in inhibiting the growth of transplantable rat pituitary tumours. There have also been observations suggesting an antiproliferative effect of bromocriptine on human ...

The case report is presented of a 47-year-old white woman with Cushing&#39;s disease treated by bilateral adrenalectomy in June 1981. A first computed tomography (CT) scan in September 1984 showed a voluminous pituitary adenoma with invasion of the sphenoid sinus and left parasellar extension. The tumour increased progressively in size, a suprasellar extension developed and the optic chiasm was eventually affected. In March 1988 and June 1989 the patient underwent two surgeries for the pituitary tumour, the second followed by radiotherapy. During this period, the ACTH values varied between 100 pmol/l and 403 pmol/l (normal: &lt; 13 pmol/l). After radiotherapy, a progressive shrinking of the tumour was observed and the ACTH concentrations decreased to a lowest value of 27.5 pmol/l. The patient was clinically well until September 1993 when, suddenly, the plasma ACTH concentration increased to very high levels (greater than 965 pmol/l). There was no evidence of tumour growth on the sel...

A 39-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) presented with acromegaly and a pituitary macroadenoma. There was a family history of this renal disorder. She had undergone surgery for pituitary adenoma 6 years prior. Physical examination disclosed bitemporal hemianopsia and elevation of both basal growth hormone (GH) 106 ng/mL (normal 0-5) and insulin-like growth factor (IGF-1) 811 ng/mL (normal 48-255) blood levels. A magnetic resonance imaging scan disclosed a 3.0 cm sellar and suprasellar mass with both optic chiasm compression and left cavernous sinus invasion. Histologic, immunohistochemical and ultrastructural studies of the lesion disclosed a sparsely granulated somatotroph adenoma. Standard chromosome analysis on the blood sample showed no abnormality. Sequence analysis of the coding regions of PKD1 and PKD2 employing DNA from both peripheral leukocytes and the tumor revealed the most common PKD1 mutation, 5014_5015delAG. Analysis of the entire SSTR5 gene disclosed the variant c.143C>A (p.L48M, rs4988483) change in the heterozygous state in both blood and tumor, while no pathogenic mutations were noted in the MEN1, AIP, p27Kip1 and SSTR2 genes. To our knowledge, this is the fourth reported case of a GH-producing pituitary adenoma associated with ADPKD, but the first subject to extensive morphological,

The monoclonal origin of gonadotropin-secreting pituitary adenomas has been well demonstrated but only few molecular abnormalities have so far been recognized in these tumors. For many years, several authors have suggested a role for GnRH and/or GnRH receptors (GnRH-R) in the development of these pituitary adenomas. To test the hypothesis that mutant genes encoding a constitutively activated GnRH-R might be involved in the pathogenesis of these tumors, the sequence of the GnRH-R gene was analyzed in tumoral pituitary tissue obtained from ten patients (six female, four male). The pituitary gonadotropin-secreting adenoma was associated with in vivo hypersecretion of FSH, LH and/or free a-subunit (n ¼ 7) or was clinically silent (normal plasma levels of gonadotropins or free a-subunit, n ¼ 3). In all cases, immunocytochemical studies of the removed adenoma confirmed their gonadotroph nature by revealing positivity for FSH, LH and/or a-subunit. Genomic DNA was extracted from the pathological tissue obtained at neurosurgery. Eight sequencing primers were used to amplify the three exons of the GnRH-R gene from tumoral DNA. The entire coding sequence of the GnRH-R gene was sequenced in the ten adenomas. No mutation was found in any of the tumor specimens examined. In conclusion, mutations in the GnRH receptor coding sequence occur infrequently if at all in gonadotropin-secreting pituitary adenomas.

The 6-h plasma profiles of adrenocorticotropic hormone (ACTH), cortisol, α-melanocyte-stimulating hormone (α-MSH), and GH were studied in 17 dogs with pituitary-dependent hyperadrenocorticism (PDH) before and after hypophysectomy. The aim of the study was to investigate the relation between the hormone profile characteristics and recurrence of PDH after surgery. The hormones were secreted in a pulsatile fashion. The basal plasma cortisol concentration and area under the curve (AUC) for cortisol were significantly higher in the PDH cases than in eight controls. The characteristics of the plasma profiles of ACTH and α-MSH were not significantly different between the PDH cases and the controls. In the PDH cases, less GH was secreted in pulses than in the controls, but the difference was not significant. The basal plasma cortisol concentration, the AUC for ACTH and cortisol, and the pulse frequency of ACTH and cortisol decreased significantly after hypophysectomy for the group of PDH ca...

Obtaining new insights by discovering novel neuropeptides and neurosteroids regulating pituitary and brain functions is essential for the progress of neuroendocrinology. At the beginning of 1970s, gonadotropin-releasing hormone (GnRH) was discovered in mammals. Since then, it was generally accepted that GnRH is the only hypothalamic neuropeptide regulating gonadotropin release in vertebrates. In 2000, however, gonadotropin-inhibitory hormone (GnIH), a novel hypothalamic neuropeptide that actively inhibits gonadotropin release, was discovered in quail. The follow-up studies demonstrated that GnIH acts as a new key player for regulation of reproduction across vertebrates. It now appears that GnIH acts on the pituitary and the brain to serve a number of behavioral and physiological functions. On the other hand, a new concept has been established that the brain synthesizes steroids, called neurosteroids. The formation of neurosteroids in the brain was originally demonstrated in mammals ...

We recently identified a novel hypothalamic dodecapeptide inhibiting gonadotropin release in the Japanese quail (Coturnix japonica). This novel peptide was therefore named gonadotropin-inhibitory hormone (GnIH). The GnIH precursor encoded one GnIH and two GnIH-related peptides (GnIH-RP-1 and GnIH-RP-2) that shared the same C-terminal motif, Leu-Pro-Xaa-Arg-Phe-NH2 (Xaa=Leu or Gln; LPXRF-amide peptides). Identification of the receptor for GnIH is crucial to elucidate the mode of action of GnIH. We therefore identified the receptor for GnIH in the quail diencephalon and characterized its expression and binding activity. We first cloned a cDNA encoding a putative GnIH receptor by a combination of 3′ and 5′ rapid amplification of cDNA ends (RACE) using PCR primers designed from the sequence for the receptor for rat RF-amide-related peptide (RFRP), an orthologous peptide of GnIH. Hydrophobic analysis revealed that the putative GnIH receptor possessed seven transmembrane domains, indicati...

The presence and localization of endogenous lipocortin-1 (LC-1, a protein which has been proposed to mediate the anti-inflammatoi'y actions of the giucocorticoids) was studied by immunohistochemical techniques in rat brain and pituitary. A polyclonai antiserum specific for a fragment of lipocortin-1 (aa1-188) was used to visualize immunoreactive LC-1 (iLC-1) in both neuronal and non-neuronal cell structures. Neuronal staining, which was independent of microtubuiar axonal transport mechanisms (in that it was not affected by blockade of axonal transport), was found in varicose nerve fibres in various regions of the brain. In addition, iLC-1 was found in the cytoplasm of neuronal cells throughout the brain. Of all brain regions which showed iLC-1, only the hippocampal neurons showed a reduced staining intensity after adrenalectomy. However, iLC-1 was not affected by dexamethasone treatment. Non-neuronal iLC-1 was found in ependymocytes lining the cerebral ventricles and aqueduct. In addition, iLC-1 was found in tanycytes in all circumventficuiar organs studied and in the ventral walls of the third ventricle, where some of the branching tail processes appeared to envelop local capillaries and neuronal cell bodies. A tancycyte-mediated release of LC-1 from varicose nerve fibres into the portal vasculature is proposed.

Pituitary abscess is extremely rare and often misdiagnosed as pituitary tumor pre-operatively. We document a case of a 64-year-old lady presented to the outpatient department with complaints of headache and blurring vision of right eye for one month. Based on preliminary investigations, a clinical diagnosis of pituitary adenoma was made and the pituitary gland was surgically excised. Histopathological examination showed Actinomyces infection. This case has been documented due to the extremely rare involvement of the pituitary gland by actinomyces infection. Pituitary abscess is a rare pathology, but it must be considered during evaluating sellar masses, since its prognosis depends on surgical drainage and on the use of specific antibiotics. We report, to our knowledge, the fourth case of Actinomyces israelii infection of the pituitary region.

The effects of PHI-27, a peptide of the glucagon-secretion family , on luteinizing hormone (LH) release and on LH-releasing hormone (LH-RH)-or estradiol-induced LH release were examined in a sequential double chamber perifusion system by perifusing the pituitary alone or in sequence with the mediobasal hypothalamus (MBH) from normal female rats in diestrus . PHI at 10-7M had no significant effect on LH release from the pituitary in series with the MBH. Moreover, on perifusion of the pituitary alone with medium containing 10-7M PHI, LH release induced by 20ng/ml LH-RH from the pituitary was not significantly different from that without PHI. Furthermore, PHI had no effect on estradiol-induced LH release from the pituitary in sequence with the MBH. These data indicate that PHI has no effect on LH release in vitro.

This new multi-compartment model for secretion, distri- bution, binding, and metabolism of cortisol is capable of simulating the rapid fluctuations in plasma cortisol concentration observed in normal people during the early morning hours. In addition to the well- established principles of cortisol secretion, binding to plasma proteins, distribution, and metabolic clearance, the proposed model defines the presence of different cortisol binding sites in cells, as well as the com- plex adrenal response to changing blood levels of the pituitary hormone, ACTH. By incorporating these physiological principles into the model, a more detailed and accurate simulation of cortisol dynamics has been achieved.

This new multi-compartment model for secretion, distri- bution, binding, and metabolism of cortisol is capable of simulating the rapid fluctuations in plasma cortisol concentration observed in normal people during the early morning hours. In addition to the well- established principles of cortisol secretion, binding to plasma proteins, distribution, and metabolic clearance, the proposed model defines the presence of different cortisol binding sites in cells, as well as the com- plex adrenal response to changing blood levels of the pituitary hormone, ACTH. By incorporating these physiological principles into the model, a more detailed and accurate simulation of cortisol dynamics has been achieved.

Background: The adequate replacement dose of estrogens during infancy and childhood is still not known in girls. Aromatase deficiency offers an excellent model to study how much estrogens are needed during infancy, childhood and adulthood. Objectives: We studied the impact of oral 17β-estradiol treatment, on longitudinal growth, bone age maturation, pituitary gonadotropin feedback, multicystic ovaries and bone mass in the long-term follow-up of a girl compound heterozygote for two point mutations of the CYP19A1 gene. Results: Low doses of 17β-estradiol were needed to achieve normal height velocity and adequate bone age maturation from early childhood on. Serum estradiol levels needed for breast development and for the appearance of an endometrial reflex were not sufficient to achieve physiological gonadotropin levels. Without 17β-estradiol treatment the ovaries of the patient showed a multicystic appearance, which reversed on 17β-estradiol replacement. Bone mass was within normal ra...

Vascular injury is an unusual and serious complication of transsphenoidal surgery. We aimed to define the role of angiography and endovascular treatment in patients with vascular injuries occurring during transsphenoidal surgery. During the last ten-year period, we retrospectively evaluated nine patients with vascular injury after transsphenoidal surgery. Eight patients were symptomatic due to vascular injury, while one had only suspicion of vascular injury during surgery. Four patients presented with epistaxis, two with subarachnoid hemorrhage, one with exophthalmos, and one with hemiparesia. Emergency angiography revealed a pseudoaneurysm in four patients, contrast extravasation in two, vessel dissection in one, vessel wall irregularity in one, and arteriovenous fistula in one. All patients but one were treated successfully with parent artery occlusion, with one covered stent implantation, one stent-assisted coiling method, while one patient was managed conservatively. One patient...

Metastatic tumors to the pituitary gland are an unusual complication typically seen in elderly patients with diffuse malignant disease. Breast and lung are the commonest sites of the primary tumor. Prognosis of patients with breast cancer metastasis is poor and depends on the primary neoplastic extension. We report a 54 year-old woman with breast cancer metastasis to the pituitary stalk first diagnosed because of visual disturbance with no other symptoms. Pituitary gland stalk metastasis is a very uncommon find and this case report includes a literature review.

Sheehan syndrome or postpartum hypopituitarism is a condition characterized by necrosis of the pituitary gland leading to hormones deficiency. Severe postpartum haemorrhage is the most common cause for the development of Sheehan syndrome. Pituitary gland enlargement, small sella turcica size, vasospasm, thrombosis, and coagulation abnormalities are among predisposing factors for restricted pituitary blood supply. The diagnosis of Sheehan syndrome is not always apparent in immediate postpartum.Symptoms may not present until months to years after delivery. The first and most common symptom of Sheehan syndrome is agalactorrhea with hyponatraemia being the most observedelectrolyte abnormality. Pituitary MRI is the imaging of choice for differential diagnosis. A partially or completely empty sella turcica point out the diagnosis of Sheehan syndrome. Management is based on lifelong hormone replacement therapy.

ituitary apoplexy is a complex clinical entity that is typically characterized by the acute onset of headache, visual disturbance, and subsequent hormonal dysfunction secondary to disruption of the hypothalamicpituitary axis. The diagnosis is primarily based on abnormal MR or CT imaging findings with clinical and laboratory evidence reflecting hormonal disturbance. Suprasellar extension of the enlarged gland can affect the optic chiasm, cavernous sinus, and cranial nerves. However, retroclival extension of the hemorrhage beyond the pituitary is unusual and is not typically considered in the imaging evaluation. To the best of our knowledge, spontaneous retroclival expansion of hemorrhage secondary to pituitary apoplexy has only been reported twice in the literature. This clinical report describes 18 patients with pituitary apoplexy, of whom 10 had retroclival hematoma. This is a single-institution review of over 10,000 brain imaging studies performed between 1999 and 2009 utilizing CT or MRI, which identified 2598 patients with sellar and parasellar masses. Eighteen patients (13 men and 5 women; mean age 54 years) were identified with the presenting symptoms of sudden onset of headache and ophthalmoplegia and laboratory findings consistent with pituitary apoplexy. Ten of these patients (8 men and 2 women; mean age 55 years) had imaging findings consistent with retroclival hematoma. Of these 10 patients, 6 patients underwent follow-up imaging after resolution of their acute symptoms. The primary clinical information was obtained via retrospective chart review, which revealed a wide range of