Anterior Pituitary Hormone Secretion Research Articles

THU069 Growth Hormone Secretion And Serum High-sensitivity C-reactive Protein Levels In Adult Patients With Non-functioning Pituitary Tumors

Abstract Disclosure: Y. Seki: None. S. Morimoto: None. K. Bokuda: None. D. Watanabe: None. S. Watanabe: None. K. Yamashita: None. N. Takano: None. A. Ichihara: None. Background: Growth hormone (GH) deficiency, which causes visceral obesity and non-alcohol fatty liver disease, increases cardiovascular event risks. Serum high-sensitivity C-reactive protein (hs-CRP) levels has been reported to estimate those risks. GH supplementation therapy was reported to decrease the serum hs-CRP levels in GH deficient patients, however, the association between GH secretion and serum hs-CRP levels have been unclear. Patients and Methods: We retrospectively reviewed charts of the patients with non-functioning pituitary adenoma and Rathke’s cysts who underwent preoperative GH-releasing peptide-2 (GHRP-2) tests to assess GH secretion, and investigated the association between GH secretion and background characteristics. Patients who had a history of pituitary surgery, severe renal insufficiency or active inflammatory diseases, or received GH supplementation therapy were excluded. Results: Among 171 patients (100 NFPA and 71 Rathke’s cysts), 55 (32%) presented severe GH deficiency, as diagnosed using GHRP-2 tests. Serum hs-CRP levels were significantly higher in the patients with severe GH deficiency than in those without severe GH deficiency (754 [393—1330] vs 249 [113—537] ng/mL, P < 0.001). Serum hs-CRP levels were significantly correlated with logarithm of peak GH response to GHRP-2 (r = -0.50, P < 0.001), but not with IGF-1 SD score (r = -0.10, P = 0.21). In the multiple regression analysis, peak GH response to GHRP-2 was a significant variable for determining serum hs-CRP levels (β = -0.340, P = 0.001) after adjustment with age, sex, BMI, smoking habit, alcohol consumption, hypertension, diabetes mellitus, dyslipidemia, abnormal liver function, and other pituitary hormone deficiencies. Severe GH deficiency were significantly associated with for serum hs-CRP levels higher than 1000 ng/mL (Odds ratio, 2.58 ;95% Confidence interval 1.15-5.78) when adjusted for obesity and abnormal liver function. Conclusion: GH secretion was significantly and negatively associated with serum hs-CRP levels independent of atherosclerotic risk factors, metabolic complications of GH deficiency, and other anterior pituitary hormone secretions. Presentation: Thursday, June 15, 2023

Hypopituitarism in Adults: Rational Approaches to Diagnosis and Treatment

AbstractPituitary hormones are responsible for the regulation of growth, development, metabolism, reproduction, and homeostasis. Hypopituitarism is a condition that is defined as partial or complete insufficiency of anterior pituitary hormone secretion, and rarely, posterior pituitary hormone secretion. This condition can result from diseases of the pituitary gland or the hypothalamus. The annual incidence of hypopituitarism has been estimated to be 4.2 per 100,000 yearly, and the prevalence has been estimated at 45.5 per 100,000. The symptoms of hypopituitarism vary. The onset is insidious and depends on the number of hormone deficiencies and their degree of severity. Pituitary hormone deficiency can result in substantial clinical changes that increase the risk of morbidity and mortality. People commonly report persistent symptoms and a decline in their quality of life, both of which can be explained, at least in part, by the inherent shortcomings of hormone replacement strategies in their ability to imitate the normal hormone secretion processes. The diagnosis of hypopituitarism can be straightforward by measuring the lowered basal hormone levels. In cases where the basal hormone levels are uncertain or partial hormone deficiencies have been identified, it may be necessary to perform provocative testing of the hypothalamic–pituitary axis. The hypothalamus and pituitary region can be imaged using magnetic resonance imaging, which provides useful anatomical information. When necessary, genetic studies may be added to the diagnostic approach. The treatment consists of physiological replacement of the individual end-organ hormone deficiencies, and careful monitoring is required throughout the patient's entire life. Individualized hormone replacement therapy that considers potential interactions is recommended. This article provides an overview of the pathophysiology, clinical presentation, general diagnostic guidelines, and treatment options of hypopituitarism.

Anterior pituitary hormones in first-episode psychosis: a systematic review and meta-analysis

IntroductionAlthough the role of pituitary gland in schizophrenia and psychotic disorders has been studied for decades, evidence on anterior pituitary hormones in the early phases of psychoses – without the influence of chronicity, comorbidities, and pharmacological treatment – is mostly unclear and inconsistent.ObjectivesOur systematic review and meta-analysis was aimed at comparing the blood concentrations of adrenocorticotropic hormone (ACTH), follicle stimulating and luteinizing hormones (FSH and LH), growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) between people with drug-naïve first-episode psychosis (FEP) and healthy controls.MethodsWe searched main electronic databases for articles indexed up to September 2022. We appraised the quality of data. We carried out random-effects meta-analyses, generating pooled standardized mean differences (SMDs) and estimating between-study heterogeneity. Moreover, we performed sensitivity and meta-regression analyses.ResultsTwenty-six studies were included. People with drug-naïve FEP had higher ACTH (p<0.001; moderate-to-high heterogeneity) and PRL (p<0.001; high heterogeneity) concentrations, as well as lower TSH concentrations (p=0.001; low heterogeneity), than healthy subjects. Sensitivity analyses confirmed these findings. Data were not sufficient to perform meta-analyses on other hormones (FSH, LH, and GH).ConclusionsPeople with drug-naïve FEP have abnormal ACTH, PRL, and TSH blood concentrations, supporting the hypothesis that anterior pituitary hormone secretion is altered in the first stages of schizophrenia and psychoses. Additional research is needed to clarify the complex interconnections between vulnerability, environmental factors, and pituitary hormones in FEP.Disclosure of InterestNone Declared

A Boy with Reset Osmostat Who Developed Chronic Hyponatremia due to Hypothalamic Injury Caused by a Giant Arachnoid Cyst.

Reset osmostat (RO) is classified as type C among the four subtypes of the syndrome of inappropriate secretion of antidiuretic hormone based on antidiuretic hormone (ADH) secretion. It is characterized by a lower plasma osmolality threshold for ADH excretion when plasma sodium concentration is reduced. We report the case of a boy with RO and a giant arachnoid cyst (AC). The patient had been suspected of having AC since the fetal period, and a giant AC in the prepontine cistern was confirmed by brain magnetic resonance imaging 7 days after birth. During the neonatal period, there were no abnormalities in the general condition or blood tests, and he was discharged from the NICU at the 27 after birth. He was born with a -2 standard deviation short stature and mild mental retardation. When he was 6 years old, he was diagnosed with infectious impetigo and had hyponatremia of 121 mmol/L. Investigations revealed normal adrenal and thyroid functions, plasma hyposmolality, high urinary sodium, and high urinary osmolality. The 5% hypertonic saline and water load tests confirmed that ADH was secreted under low sodium and osmolality conditions, and the ability to concentrate urine and excrete a standard water load; therefore, RO was diagnosed. In addition, an anterior pituitary hormone secretion stimulation test was performed, which confirmed growth hormone secretion deficiency and gonadotropin hyperreactivity. Hyponatremia was untreated, but fluid restriction and salt loading were started at age 12 because of the risk of growth obstacles. The diagnosis of RO is important from the viewpoint of clinical hyponatremia treatment options.

Perioperative fluctuation and overall evaluation of adenohypophyseal hormone secretion in patients with nonfunctioning pituitary adenoma.

Perioperative adenohypophyseal hormone assessment can improve therapeutic strategies and be used to evaluate the prognosis of pituitary adenomas. An individual hormone level does not entirely reflect the pituitary gland. Thus, this study aimed to analyze perioperative hormonal changes and propose a normalized method to facilitate overall assessment of the adenohypophysis. The authors retrospectively analyzed 89 male patients with nonfunctioning pituitary adenoma (NFPA) who underwent transsphenoidal surgery. Preoperative clinical data, imaging data, and perioperative hormone levels of the anterior pituitary gland were evaluated. Hormone values were rescaled using minimum-maximum normalization. The sum of the normalized hormone levels was defined as the total hormonal rate (THR). Preoperative findings indicated correlations among different adenohypophyseal hormones. Luteinizing hormone (p = 0.62) and adrenocorticotropic hormone (p = 0.89) showed no significant changes after surgery, but growth hormone levels increased (p < 0.001). On the contrary, the levels of thyroid-stimulating hormone (p < 0.001), follicle-stimulating hormone (p = 0.02), and prolactin (p < 0.001) decreased. THR indicated a significant postoperative reduction in adenohypophyseal function (p = 0.04). Patients with postoperative hypopituitarism had significantly lower THR than those without (p = 0.003), with an area under the curve of 0.66. For NFPAs that presented with normal preoperative hormone levels, THR was a good clinical predictor of immediate postoperative hypopituitarism, with an area under the curve of 0.74. The normalized synthesis index of hormones is a novel and clinically valuable method used to reflect adenohypophyseal secretion. Compared with individual hormones, these results indicated that THR can facilitate the analysis of general hormone levels despite various fluctuations in adenohypophyseal hormones. THR may also contribute to the effective prediction of short-term surgery-induced hypopituitarism.

Hormone supply to the pituitary gland: A comprehensive investigation of female‑related tumors (Review).

The hypothalamus acts on the pituitary gland after signal integration, thus regulating various physiological functions of the body. The pituitary gland includes the adenohypophysis and neurohypophysis, which differ in structure and function. The hypothalamus-hypophysis axis controls the secretion of adenohypophyseal hormones through the pituitary portal vein system. Thyroid-stimulating hormone, adrenocorticotropic hormone, gonadotropin, growth hormone (GH), and prolactin (PRL) are secreted by the adenohypophysis and regulate the functions of the body in physiological and pathological conditions. The aim of this review was to summarize the functions of female-associated hormones (GH, PRL, luteinizing hormone, and follicle-stimulating hormone) in tumors. Their pathophysiology was described and the mechanisms underlying female hormone-related diseases were investigated.

Substance P-Immunoreactive Fiber Varicosities Appear to Innervate Galaninergic Perikarya in the Human Hypothalamus.

Introduction: Substance P (SP) is a member of the tachykinin family. In the central nervous system, SP participates among others, in the regulation of pain, learning, memory, emotion, and sexual functions. In the periphery, SP affects the gastrointestinal, cardiovascular, and urinary systems. Galanin, similarly to SP, appears to be involved in wide range of physiologic functions, including cognition, waking and sleep, feeding, mood, blood pressure, reproduction, and development, where acts as a trophic factor. The similar distribution of SP-immunoreactive (SP-IR) fibers and galanin-IR perikarya in the human hypothalamus suggests functional interaction between these neuropeptides. Methods: We have utilized double-label immunohistochemistry to reveal these putative juxtapositions. Results: The majority of galanin-IR neurons receive contacting SP-IR fibers that often cover a significant area of the galaninergic perikarya forming multiple en passant type contacts. These SP-galanin juxtapositions are located mainly in the basal part of the infundibulum/median eminence, populating the basal periventricular region as well as the basal perifornical area. Discussion: The density and the morphology of these associations suggest that these contacts are functional synapses and therefore may represent the morphological substrate of the control of SP on multiple functions regulated/modulated by galanin. SP via galanin may modulate anterior pituitary hormone secretion, as contrary to SP, high density of galanin immunoreactivity is present in the median eminence, and by innervating galanin-IR neurons projecting to other parts of the brain, SP can modulate indirectly their activities. Impact statement The present study is the first describing juxtapositions between the substance P (SP)-immunoreactive (IR) and galanin-IR neurons in the human hypothalamus. These juxtapositions may be functional synapses and they may represent the morphological substrate of the control of SP on the galaninergic system. SP via galanin may modulate anterior pituitary hormone secretion, as contrary to SP, high density of galanin immunoreactivity is present in the median eminence. Galanin, released into the hypothalamo-hypophyseal circulation, can reach the anterior pituitary and function as a hypophysiotropic substance and regulates anterior pituitary hormone secretion. SP by innervating galanin-IR neurons, which project to other parts of the brain, can modulate indirectly their activities.

The Influence of Anandamide on the Anterior Pituitary Hormone Secretion in Ewes—Ex Vivo Study

Simple SummaryMankind has been using Cannabis sativa (marijuana) for a century, but the system of endogenous cannabinoids has only been recently described. This system modulates an array of physiological and psychological functions, including reproduction. Interaction between gonadotropin-releasing hormone (GnRH) neurons and the endogenous cannabinoid system plays an important role in this process. The presence of cannabinoid receptors in the pituitary raises a presumption that anandamide, the endogenous cannabinoid, may influence reproduction process directly in the anterior pituitary. The aim of the undertaken studies was to investigate the effect of anandamide on gonadotropins secretions from anterior pituitary explants downloaded from ewes. It was demonstrated that anandamide inhibited gonadotrophic hormones secretion from the anterior pituitary explants. This could suggest that negative effects of cannabinoids on reproductive processes could be caused by the direct action of these compounds at the pituitary level.Cannabinoids (CBs) are involved in the neuroendocrine control of reproductive processes by affecting GnRH and gonadotropins secretion. The presence of cannabinoid receptors (CBR) in the pituitary raises a presumption that anandamide (AEA), the endogenous cannabinoid, may act on gonadotrophic hormones secretion directly at the level of the anterior pituitary (AP). Thus, the aim of the study was to investigate the influence of AEA on gonadotropins secretions from AP explants taken from anestrous ewes. It was demonstrated that AEA inhibited GnRH stimulated luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion from the AP explants. Anandamide influences both LH and FSH gene expressions as well as their release. AEA also affected gonadoliberin receptor (GnRHR) synthesis and expression. The presence of CB1R transcript in AP explants were also demonstrated. It could be suggested that some known negative effects of cannabinoids on the hypothalamic-pituitary-gonadal axis activity may be caused by the direct action of these compounds at the pituitary level.

Nicotine inhibits expression of Prrx1 in pituitary stem/progenitor cells through epigenetic regulation, leading to a delayed supply of growth-hormone-producing cells

ObjectiveNicotine, a toxic component of smoking, adversely affects animal growth and reproduction by decreasing secretion of anterior pituitary hormones. However, it has not been clarified whether nicotine inhibits the supply of endocrine cells in the pituitary gland. The present study investigated short- and long-term effects of persistent nicotine exposure on the pituitary glands of young animals. DesignThree-week-old male Wistar rats were exposed to nicotine (1 mg/kg body weight/day) for 7 days, and gene expression, cell numbers, and DNA methylation status were analyzed on the following day and 4 weeks after final treatments. ResultsThe expression level of the stem cell marker Sox2 was not changed by nicotine exposure throughout the experiment. On the other hand, nicotine inhibited expression of a progenitor cell marker, Prrx1, and growth hormone (Gh). Immunohistochemical analysis showed that the SOX2-positive cells positive for PRRX1 in nicotine-treated groups decreased to 61% (4-week-old) and 70% (8-week-old) of the saline-treated controls. In addition, the proportion of GH-positive cells in nicotine-treated group was 14% lower than that of saline-treated controls. Furthermore, first intron hypermethylation of Prrx1 was detected by a bisulfite sequence of genomic DNA from the anterior lobe of the rat pituitary gland. ConclusionsWe show that persistent nicotine exposure in young animals inhibits expression of Prrx1 in pituitary stem/progenitor cells through epigenetic regulation, leading to a delayed supply of GH-producing cells.

Fertility and Pregnancy in Women With Hypopituitarism: A Systematic Literature Review

Human reproduction is mainly governed from the hypothalamic-adrenal-gonadal (HPG) axis, which controls both ovarian morphology and function. Disturbances in the secretion of other anterior pituitary hormones (and their respective endocrine axes) interfere with HPG activity and have been linked to fertility problems. In normal pregnancy, maintenance of homeostasis is associated with continuous changes in pituitary morphology and function, which need to be considered during hormone replacement in patients with hypopituitarism. We conducted a systematic PubMed literature review from 1969 to 2019, with the following keywords: fertility and hypopituitarism, pregnancy and hypopituitarism, and ovulation induction and hypopituitarism. Case reports or single-case series of up to 2 patients/4 pregnancies were excluded. Eleven publications described data on fertility (n = 6) and/or pregnancy (n = 7) in women with hypopituitarism. Women with hypopituitarism often need assisted reproductive treatment, with pregnancy rates ranging from 47% to 100%. In patients achieving pregnancy, live birth rate ranged from 61% to 100%. While glucocorticoids, levothyroxine, and desmopressin are safely prescribed during pregnancy, growth hormone treatment regimens vary significantly between countries, and several publications support a positive effect in women seeking fertility. In this first systematic review on fertility, ovulation induction, and pregnancy in patients with hypopituitarism, we show that while literature is scarce, birth rates are high in patients achieving pregnancy. However, prospective studies are needed for evaluating outcomes in relationship to treatment patterns. Replacement therapy in hypopituitarism should always mimic normal physiology, and this becomes challenging with changing demands during pregnancy evolution.

Effect of oestrogen-dependent vasopressin on HPA axis in the median eminence of female rats

The median eminence (ME) anatomically consists of external (eME) and internal (iME) layers. The hypothalamic neurosecretory cells terminate their axons in the eME and secrete their neurohormones regulating anterior pituitary hormone secretion involved in stress responses into the portal vein located in the eME. Magnocellular neurosecretory cells (MNCs) which produce arginine vasopressin (AVP) and oxytocin in the paraventricular (PVN) and supraoptic nuclei (SON) terminate their axons in the posterior pituitary gland (PP) through the iME. Here, we provide the first evidence that oestrogen modulates the dynamic changes in AVP levels in the eME axon terminals in female rats, using AVP-eGFP and AVP-DREADDs transgenic rats. Strong AVP-eGFP fluorescence in the eME was observed at all oestrus cycle stages in adult female rats but not in male transgenic rats. AVP-eGFP fluorescence in the eME was depleted after bilateral ovariectomy but re-appeared with high-dose 17β-oestradiol. AVP-eGFP fluorescence in the MNCs and PP did not change significantly in most treatments. Peripheral clozapine-N-oxide administration induced AVP-DREADDs neurone activation, causing a significant increase in plasma corticosterone levels in the transgenic rats. These results suggest that stress-induced activation of the hypothalamic-pituitary-adrenal axis may be caused by oestrogen-dependent upregulation of AVP in the eME of female rats.

A Case of Evolutionary Hypopituitarism Following Traumatic Brain Injury in Infancy

The long-term clinical course of hypopituitarism resulting from traumatic brain injury in children is unclear. We here present a case involving a 31-year-old Japanese male with hypopituitarism caused by traumatic brain injury at the age of 5 months. His height velocity began to decrease around 3 years of age. At age 7, growth hormone and thyroid-stimulating hormone deficiencies were diagnosed. At age 10, hydrocortisone therapy was started, and testosterone enanthate therapy was needed at age 14. The secretion of anterior pituitary hormones gradually decreased. We should check endocrinological tests in patients with traumatic brain injury who have retarded growth.

Pituitary adenylate cyclase-activating polypeptide: Postnatal development in multiple brain stem respiratory-related nuclei in the rat

The pituitary adenylate cyclase-activating polypeptide (PACAP) plays an important role in anterior pituitary hormone secretion, neurotransmission, and the control of breathing. Mice lacking PACAP die suddenly mainly in the 2nd postnatal week, coinciding temporally with a critical period of respiratory development uncovered by our laboratory in the rat. The goal of the current study was to test our hypothesis that PACAP expression is reduced during the critical period in normal rats. We undertook immunohistochemistry and optical densitometry of PACAP (specifically PACAP38) in several brain stem respiratory-related nuclei of postnatal days P2-21 rats, and found that PACAP immunoreactivity was significantly reduced at P12 in the pre-Bötzinger complex, nucleus ambiguus, hypoglossal nucleus, and the ventrolateral subnucleus of the nucleus tractus solitarius. No changes were observed in the control, non-respiratory cuneate nucleus at P12. Results imply that the down-regulation of PACAP during normal postnatal development may contribute to the critical period of vulnerability, when the animals’ response to hypoxia is at its weakest.

Resistin regulates reproductive hormone secretion from the ovine adenohypophysis depending on season

Work in cattle and rodents has shown that resistin, in addition to its roles in insulin resistance and inflammation, is involved in the regulation of gonadal steroidogenesis. However, the role of resistin in the regulation of reproductive processes in other species, such as seasonally breeding sheep, is completely unknown. Herein, we tested the hypothesis that resistin can influence the secretion of anterior pituitary hormones and that its effect in ewes is dependent on the day length. Thirty Polish Longwool ewes, a breed that exhibits a strong seasonal reproductive pattern, were ovariectomized with estrogen replacement using subcutaneously inserted estradiol implants. Ewes were fed ad libitum and housed under a natural photoperiod (longitude: 19°57′ E, latitude: 50° 04′ N). Intravenous treatments consisted of control or recombinant bovine resistin (rbresistin) in saline: (1) control (saline; n = 10), (2) low resistin dose (1.0 μg/kg BW; n = 10), and (3) high resistin dose (10.0 μg/kg BW; n = 10). Experiments were conducted during both short-day (SD) and long-day (LD) seasons using 5 sheep per group within each season. Blood samples were collected every 10 min over 4 h. Blood plasma concentrations of FSH, LH, and prolactin (PRL) were assayed using RIA. A season × dose interaction was observed for all hormonal variables measured. Greater concentrations (P < 0.001) of LH and FSH were observed during SDs than during LDs in all groups. During SDs, the high dose (10 μg/kg BW) decreased (P < 0.001) basal LH levels and amplitude (P < 0.05) of LH pulses and increased (P < 0.001) circulating concentrations of FSH. However, the low dose of resistin decreased (P < 0.001) FSH concentrations compared to those of controls. During LDs, both the low and high resistin doses increased mean concentrations of LH (P < 0.001 and P < 0.05, respectively) and FSH (P < 0.001). A high dose of rbresistin increased (P < 0.001) the mean circulating concentrations of PRL during both seasons. However, in all groups, concentrations of PRL were greater during LDs than SDs. These results demonstrate for the first time that resistin is involved in the regulation of pituitary hormone secretion and that this effect is differentially mediated during LDs and SDs.

Fifty Years of Advances in Neuroendocrinology.

Importance of the neuroendocrine brain for health and happiness has become clear since the 1960s. Foundations laid 100 years ago culminated in Geoffrey W Harris’s model of control by the brain of secretion of anterior and posterior pituitary gland hormones through, respectively, releasing factors secreted into the hypothalamic-hypophysial portal system, and directly from axon terminals into the systemic circulation. Confirmation, expansion and deepening of knowledge and understanding have followed increasingly sophisticated technology. This allowed chemical characterisation of the posterior pituitary hormones, oxytocin and vasopressin, the releasing factors, their receptors and genes, location of the neurosecretory neurons in the hypothalamus, and how their activity is controlled, including by neural and hormonal feedback, and how hormone rhythms are generated. Wider roles of these neurons and their peptides in the brain are now recognised: in reproductive and social behaviours, emotions and appetite. Plasticity and epigenetic programming of neuroendocrine systems have emerged as important features.

Distinctive actions of connexin 46 and connexin 50 in anterior pituitary folliculostellate cells.

Folliculostellate cell gap junctions establish a network for the transmission of information within the anterior pituitary. Connexins make up gap junction channels. Changes in connexin (Cx) turnover modify gap junction-mediated intercellular communication. We have reported that cytokines and hormones influence Cx43 turnover and coupling in folliculostellate cells and in the folliculostellate cell line TtT/GF. In addition, the expression of different connexins alters intercellular communication and connexins may have functions besides cell coupling. Here we assessed the expression, turnover and subcellular localization of Cx46 and Cx50 in the anterior pituitary and TtT/GF cells. Then, we assessed the impact of various natural (lactation, annual reproductive cycle, bFGF) and pathological (autoimmune orchitis, diabetes/obesity) conditions associated with altered anterior pituitary hormone secretion on Cx46 and Cx50. Anterior pituitary Cx46 and Cx50 expression and subcellular distribution were cell-dependent. Cx46 was expressed by folliculostellate, TtT/GF and endocrine cells. In the cytoplasm, Cx46 was chiefly associated with lysosomes. Variously sized Cx46 molecules were recovered exclusively in the TtT/GF cell nuclear fraction. In the nucleus, Cx46 co-localized with Nopp-140, a nucleolar factor involved in rRNA processing. Neither cytoplasmic nor nuclear Cx46 and Cx43 co-localized. Cx50 localized to folliculostellate and TtT/GF cells, and to the walls of blood capillaries, not to endocrine cells. Cx50 was cytoplasmic and associated with the cell membrane, not nuclear. Cx50 did not co-localize with Cx46 but it co-localized in the cytoplasm and co-immunoprecipitated with Cx43. Cx46 and Cx50 responses to various physiological and pathological challenges were different, often opposite. Cx46 and Cx43 expression and phosphorylation profiles differed in the anterior pituitary, whereas Cx50 and Cx43 were similar. The data suggest that Cx46 participates to cellular growth and proliferation and that Cx50, together with Cx43, contributes to folliculostellate cell coupling.

Effect of Gonadotropin and Adrenocorticotropic Hormone Secretion on Invasiveness of Clinically Nonfunctioning Pituitary Adenomas: A Cell Culture Study

The aim of this study was to clarify the correlation between clinical features (especially cyst formation and cavernous sinus invasion) and minor secretion of anterior pituitary hormones, especially adrenocorticotropic hormone (ACTH) and gonadotropin, by clinically nonfunctioning pituitary adenomas (CNFPAs) in cell culture. We examined anterior pituitary hormones secreted by samples from 63 cases of CNFPAs grown in cell culture. Magnetic resonance imaging, including determination of the Knosp grade, cystic changes, and intraoperative cavernous sinus invasion, was performed. Detection of minor hormone secretion using cell culture showed that 61.9% (39/63) of CNFPAs secreted luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone, 44.4% (28/63) secreted ACTH, 57.1% (36/63) secreted prolactin, and 28.6% (18/63) secreted growth hormone; only 1 case of the null-cell adenoma was observed (1.6%). Cystic changes, Knosp grade 4 status, and cavernous sinus invasion were predominantly observed in cases of ACTH-secreting adenomas. Gonadotropin-secreting adenomas showed opposite characteristics to ACTH-secreting adenomas. Minor secretion of ACTH and gonadotropin may be related to clinical features, especially cystic changes and invasiveness of CNFPAs, suggesting that our cell culture method could be helpful for elucidating the mechanisms of pituitary cyst formation and the invasiveness of CNFPAs.

The Circadian Timing System and Environmental Circadian Disruption: From Follicles to Fertility.

The internal or circadian timing system is deeply integrated in female reproductive physiology. Considerable details of rheostatic timing function in the neuroendocrine control of pituitary hormone secretion, adenohypophyseal hormone gene expression and secretion, gonadal steroid hormone biosynthesis and secretion, ovulation, implantation, and parturition have been reported. The molecular clock, an autonomous feedback loop oscillator of interacting transcriptional regulators, dictates the timing and amplitude of gene expression in each tissue of the female hypothalamic-pituitary-gonadal (HPG) axis. Although multiple targets of the molecular clock have been identified, many associated with critical physiological functions in the HPG axis, the full extent of clock-driven gene expression and physiology in this critical system remains unknown. Environmental circadian disruption (ECD), the disturbance of temporal relationships within and between internal clocks (brain and periphery), and external timing cues (eg, light, nutrients, social cues) due to rotating/night shift work or transmeridian travel have been linked to reproductive dysfunction and subfertility. Moreover, ECD resulting from exposure to endocrine disrupting chemicals, environmental toxins, and/or irregular hormone levels during sexual development can also reduce fertility. Thus, perturbations that disturb clock function at the molecular, cellular or systemic level correlate with significant declines in female reproductive function. Here we briefly review the evidence for molecular clock function in each tissue of the female HPG axis (GnRH neuron, pituitary, uterus, oviduct, and ovary), describe the human epidemiological and animal data supporting the negative effects of ECD on fertility, and explore the potential for novel chronotherapeutics in women's health and fertility.

In vivo xenoestrogenic actions of cadmium and arsenic in anterior pituitary and uterus.

Cadmium (Cd) and arsenic (iAs) are toxic metals ubiquitously present in the environment. Both pollutants exert nonmonotonic dose responses, being mostly cytotoxic at high concentrations but mimicking estrogen (E2) effects at low doses. Xenoestrogenic activity of Cd and iAs has been demonstrated in different hormone-dependent tumor cell lines; however, their actions in vivo remain largely unknown. Here, we investigated whether in vivo administration of low doses of Cd and iAs through drinking water would display xenoestrogenic effects in the anterior pituitary gland and uterus of ovariectomized rats. Cd (1ppm) and iAs (0.1ppm) exposure increased the wet weight of anterior pituitary gland and uterus and induced proestrus- and estrus-like vaginal smears. Both metals stimulate cell proliferation of these tissues as they increased the expression of proliferation markers. More importantly, they augmented soluble guanylyl cyclase α1 subunit expression, which has been linked to hormone-dependent tumor progression. Also, Cd and iAs modified protein levels of full-length estrogen receptor α and its truncated variants in an E2-like manner. Anterior pituitary hormone secretion was differentially affected by both metals. Luteinizing hormone synthesis and release were strongly diminished after Cd exposure and only mildly reduced by iAs. Both metals were able to increase prolactin synthesis, although only iAs augmented serum prolactin levels. This study shows for the first time that Cd and iAs exert strong xenoestrogenic effects on anterior pituitary gland at low doses. The differences between Cd and iAs E2-like behavior indicate that other Cd- and iAs-specific mechanisms could be involved. Altogether, these results contribute to the knowledge of reproductive disorders associated with Cd and iAs environmental contamination.

Effects of Somatostatin Analogues on Glucose Metabolism in Acromegaly: Friend of Foe?

Effects of Somatostatin Analogues on Glucose Metabolism in Acromegaly: Friend of Foe?