Pituitary Growth Hormone Research Articles

Pathogenic variants in RNPC3 are associated with hypopituitarism and primary ovarian insufficiency

PurposeWe aimed to investigate the molecular basis underlying a novel phenotype including hypopituitarism associated with primary ovarian insufficiency. MethodsWe used next-generation sequencing to identify variants in all pedigrees. Expression of Rnpc3/RNPC3 was analyzed by in situ hybridization on murine/human embryonic sections. CRISPR/Cas9 was used to generate mice carrying the p.Leu483Phe pathogenic variant in the conserved murine Rnpc3 RRM2 domain. ResultsWe described 15 patients from 9 pedigrees with biallelic pathogenic variants in RNPC3, encoding a specific protein component of the minor spliceosome, which is associated with a hypopituitary phenotype, including severe growth hormone (GH) deficiency, hypoprolactinemia, variable thyrotropin (also known as thyroid-stimulating hormone) deficiency, and anterior pituitary hypoplasia. Primary ovarian insufficiency was diagnosed in 8 of 9 affected females, whereas males had normal gonadal function. In addition, 2 affected males displayed normal growth when off GH treatment despite severe biochemical GH deficiency. In both mouse and human embryos, Rnpc3/RNPC3 was expressed in the developing forebrain, including the hypothalamus and Rathke’s pouch. Female Rnpc3 mutant mice displayed a reduction in pituitary GH content but with no reproductive impairment in young mice. Male mice exhibited no obvious phenotype. ConclusionOur findings suggest novel insights into the role of RNPC3 in female-specific gonadal function and emphasize a critical role for the minor spliceosome in pituitary and ovarian development and function.

Effects of Ghrelin on intestinal cell proliferation, the expression of protein absorption and metabolism factors in juvenile grass carp (Ctenopharyngodon idella)

Ghrelin can stimulate pituitary growth hormone (GH) release, and has a key role in the regulation of food intake and adiposity in vertebrates. At present, no relevant studies have reported the effects of Ghrelin on intestinal cell proliferation, protein absorption and metabolism. In this paper, firstly we established the intestinal epithelial cell lines of juvenile grass carp (Ctenopharyngodon idella) that can be passed stably and identified by the intestinal specific expression proteins E-cadherin and ZO-1. And we used this cell line as a model to investigate the effects of Ghrelin, Ala-Gln, Ala-Gln+Ghrelin on the proliferation of juvenile grass carp intestinal cells. We found that the use of Ghrelin, Ala-Gln and Ala-Gln+Ghrelin could promote the proliferation of intestinal cells of juvenile grass carp, but Ala-Gln+Ghrelin had the strongest promoting effect. Further, we investigated the effects of Ghrelin on the expression of cdx2, PepT1 and mTOR which are related to intestinal cell proliferation, protein absorption and metabolism of grass carp in vitro and in vivo experiments. And we studied the effects of different protein sources on the expression of Ghrelin, PepT1 and mTOR in grass carp at individual level. The results suggested that Ghrelin can promote grass carp intestinal cell proliferation, and affect the expression of genes which are related to intestinal peptide absorption and metabolism in juvenile grass carp.

Ghrelin Gene Deletion Alters Pulsatile Growth Hormone Secretion in Adult Female Mice.

Using preproghrelin-deficient mice (Ghrl-/-), we previously observed that preproghrelin modulates pulsatile growth hormone (GH) secretion in post-pubertal male mice. However, the role of ghrelin and its derived peptides in the regulation of growth parameters or feeding in females is unknown. We measured pulsatile GH secretion, growth, metabolic parameters and feeding behavior in adult Ghrl-/- and Ghrl+/+ male and female mice. We also assessed GH release from pituitary explants and hypothalamic growth hormone-releasing hormone (GHRH) expression and immunoreactivity. Body weight and body fat mass, linear growth, spontaneous food intake and food intake following a 48-h fast, GH pituitary contents and GH release from pituitary explants ex vivo, fasting glucose and glucose tolerance were not different among adult Ghrl-/- and Ghrl+/+ male or female mice. In vivo, pulsatile GH secretion was decreased, while approximate entropy, that quantified orderliness of secretion, was increased in adult Ghrl-/- females only, defining more irregular GH pattern. The number of neurons immunoreactive for GHRH visualized in the hypothalamic arcuate nucleus was increased in adult Ghrl-/- females, as compared to Ghrl+/+ females, whereas the expression of GHRH was not different amongst groups. Thus, these results point to sex-specific effects of preproghrelin gene deletion on pulsatile GH secretion, but not feeding, growth or metabolic parameters, in adult mice.

Improvement of goose embryonic and muscular developments by wider angle egg turning during incubation and the regulatory mechanisms

Egg turning during incubation plays important roles in achieving high hatching performance and gosling quality. The objective of this study was to improve embryonic and muscular developments so to achieve better gosling quality by wider egg turning angles during incubation, and to unravel the associated regulatory molecular mechanisms. In each of three consecutive incubations, 1,728 goose eggs were divided into 3 groups that were set in the same type of commercial incubators with turning angles adjusted differently to 50°, 60°, and 70°, respectively. On average of the 3 tests, incubation with wider 70° turning angle reduced the post-18-day embryo mortality, promoted embryonic growth and development, improved the hatchability and gosling quality. On embryonic day of 29, gene mRNA expression levels of the hypothalamic growth hormone-releasing hormone (GHRH), pituitary growth hormone (GH), and liver insulin-like growth factor 1 (IGF-1) were higher in the 70° turning group than in the 50° or 60° groups. Wider angle turning also increased mRNA expression levels of the muscle development regulatory genes such as MYF5, MyoD, Myogenin (MyoG), and MRF4. Changes in expression of the above genes, together with the upregulation of the Pax3 and Pax7 genes in leg muscles, well explained the enhancement of the muscular growth and development when eggs were incubated by wider turning angles. These results also extended our understanding of the impacts and mechanisms of egg turning during incubation on hatching performance and gosling quality.

Pituitary hormones are specifically expressed in trigeminal sensory neurons and contribute to pain responses in the trigeminal system

Trigeminal (TG), dorsal root (DRG), and nodose/jugular (NG/JG) ganglia each possess specialized and distinct functions. We used RNA sequencing of two-cycle sorted Pirt-positive neurons to identify genes exclusively expressing in L3–L5 DRG, T10-L1 DRG, NG/JG, and TG mouse ganglion neurons. Transcription factor Phox2b and Efcab6 are specifically expressed in NG/JG while Hoxa7 is exclusively present in both T10-L1 and L3–L5 DRG neurons. Cyp2f2, Krt18, and Ptgds, along with pituitary hormone prolactin (Prl), growth hormone (Gh), and proopiomelanocortin (Pomc) encoding genes are almost exclusively in TG neurons. Immunohistochemistry confirmed selective expression of these hormones in TG neurons and dural nerves; and showed GH expression in subsets of TRPV1+ and CGRP+ TG neurons. We next examined GH roles in hypersensitivity in the spinal versus trigeminal systems. Exogenous GH produced mechanical hypersensitivity when injected intrathecally, but not intraplantarly. GH-induced thermal hypersensitivity was not detected in the spinal system. GH dose-dependently generated orofacial and headache-like periorbital mechanical hypersensitivity after administration into masseter muscle and dura, respectively. Periorbital mechanical hypersensitivity was reversed by a GH receptor antagonist, pegvisomant. Overall, pituitary hormone genes are selective for TG versus other ganglia somatotypes; and GH has distinctive functional significance in the trigeminal versus spinal systems.

Фактори ризику рецидиву неактивних аденом гіпофіза у хворих із дефіцитом гормона росту

Актуальність. На даний час залишається актуальним пошук діагностично значущих маркерів агресивності неактивних аденом гіпофіза (НАГ) для визначення подальшого прогнозу в постопераційному періоді. Аденоми гіпофіза, що не мають клінічних проявів гіперсекреції гіпофізарних гормонів, є формами доброякісних пухлин аденогіпофіза. У загальній популяції частота НАГ становить 50 випадків на 1 млн населення. Мета дослідження: визначити клініко­діагностичні маркери агресивності пухлини у хворих із НАГ і дефіцитом гормона росту і їх роль у формуванні тяжкості нейроендокринної симптоматики захворювання. Матеріали та методи. Під наглядом перебувало 87 хворих (із них чоловіків — 44, жінок — 43) із верифікованим діагнозом НАГ після трансназальної гіпофізектомії; період спостереження — від одного до трьох років. Результати. При розподілі хворих на групи залежно від гістологічної характеристики НАГ переважали пацієнти з крупноклітинною хромофобною аденомою гіпофіза (77,5 %). НАГ у жінок супроводжувалася ожирінням, первинним і вторинним гіпотиреозом, вторинним гіпогонадизмом, синдромом персистуючої галактореї — аменореї (симптоматична й ідіопатична форми), нецукровим діабетом, синдромом порожнього турецького сідла та ін. У чоловіків НАГ супроводжувалася ожирінням, первинним і вторинним гіпотиреозом, вторинним гіпогонадизмом, нецукровим діабетом, гінекомастією. Розроблена шкала маркерів агресивності НАГ дозволила ідентифікувати фактори за трьома ступенями і розробити комплекс профілактичних заходів, покликаних унеможливлювати рецидив зростання пухлини. Висновки. Маркерами агресивності перебігу НАГ є: молодий вік пацієнта, перші симптоми маніфестації хвороби, великі розміри пухлини, асиметричність і деформація гіпофіза, ознаки інвазії пухлини в сусідні тканини/артерії/кавернозний синус, наявність дрібноклітинних і/або темноклітинних хромофобних аденом, пангіпопітуїтаризм.

IGF-1 and IGFBP-3 in Inflammatory Cachexia.

Inflammation induces a wide response of the neuroendocrine system, which leads to modifications in all the endocrine axes. The hypothalamic–growth hormone (GH)–insulin-like growth factor-1 (IGF-1) axis is deeply affected by inflammation, its response being characterized by GH resistance and a decrease in circulating levels of IGF-1. The endocrine and metabolic responses to inflammation allow the organism to survive. However, in chronic inflammatory conditions, the inhibition of the hypothalamic–GH–IGF-1 axis contributes to the catabolic process, with skeletal muscle atrophy and cachexia. Here, we review the changes in pituitary GH secretion, IGF-1, and IGF-1 binding protein-3 (IGFBP-3), as well as the mechanism that mediated those responses. The contribution of GH and IGF-1 to muscle wasting during inflammation has also been analyzed.

Updated key points of Chinese Consensus for the Diagnosis and Treatment of Acromegaly (2021 edition)

Led by the China Pituitary Adenoma Specialist Council, the Chinese Consensus for the Diagnosis and Treatment of Acromegaly (2021 Edition) is developed combined with the research progress of pituitary growth hormone (GH)-secreting adenoma both at home and abroad, evidence-based evidence of the diagnosis and treatment of acromegaly, and China's national conditions. Based on the guideline for acromegaly (2013 Edition), the new version of consensus emphasizes the importance of multidisciplinary team (MDT) and individual therapy. The criteria for control of acromegaly is discussed. Pathological criteria for the diagnosis of pituitary GH-secreting adenoma is updated. New developments in surgery, drug and radiotherapy are introduced. Meanwhile, the diagnosis and treatment of acromegaly patients concurrent with other particular scenarios, including pregnancy and refractory pituitary GH-secreting adenoma is suggested. This article aims to describe the updated key points of the new version of the consensus, and thus facilitate the clinical implementation of standardized diagnosis and treatment for acromegaly patients.

Pituitary Iron: Effect on Pituitary Volume and Function in Transfusion Dependent Thalassemia

The association of iron toxicity with vital organ dysfunction has been extensively investigated in transfusion-dependent-thalassemia (TDT). However, pituitary iron load and its effect on function have been infrequently addressed. Growth delay, hypogonadism and infertility resulting from iron-induced pituitary toxicity are still prevalent, impacting clinical care and patients' quality of life. Early recognition and timely intervention can potentially prevent irreversible damage and restore partial function.AimsWe aimed to determine pituitary iron load and anterior pituitary volume by MRI in various age groups of TDT and examine their association with systemic and organ-specific iron measures. Additionally, we attempted to stratify the occurrence of abnormal anterior pituitary function by these MRI findings. Identifying such risk thresholds could assist in establishing timing and effectiveness of treatment intervention.MRI (1.5T) measurements of anterior pituitary iron (R2) and volume (Vol) were compared to normal controls (Noetzli 2011) with resultant Z-scores. Mean annual ferritin was calculated and cardiac and liver iron concentration (LIC) were determined by MRI-T2* and superconducting quantum interference device (SQUID) biosusceptometry, respectively. Pituitary hormones (LH and FSH) and growth hormone (Z scores for IGF-1 and IGF-BP3) were determined.ResultsFifty-three TDT patients (51% females) age 25±8 years, (range 10-45 years) were enrolled. Thirty-three (62%) had a ZR2 value >2 (mean 5.4) indicating iron accumulation above 97.5th percentile. Thirty-two patients (60%) had a Z-score for anterior-volume (ZVOL) of less than -2 (mean -2.8) indicating gland shrinkage below the 2.5th percent. In 23 patients (43%) both ZR2 and ZVOL exceeded these thresholds. ZR2 inversely correlated with ZVOL; r =-0.32, p<0.02. Pituitary iron increased with age and differed between patients <18 yr (n=14) and those 18-45 yr (n=39) with a mean ZR2 at 0.9±0.6 and 4.3±0.5, respectively (p<0.001). Anterior pituitary volume declined in older patients, lagging after the iron accumulation (Figure).LH/FSH values and ZR2 showed inverse correlation: r = -0.27 (p<0.03) and -0.3 (p< 0.006) respectively. ZVOL and LH/FSH demonstrated a positive correlation: r = 0.40, p<0.05 and 0.37, p<0.003, respectively. Z(IGF-BP3) but not Z(IGF-1) had an inverse correlation with ZR2: r = -0.5 (p<0.001).ZR2 > 4 was found to be a significant predictor for gland shrinkage; Zvol < -2 was present in 17/33 patients with a ZR2>4 compared to 3/20 with a ZR2<4 (p<0.009). Receiver operator (ROC) analysis confirmed it with an AUC of 0.68. ZR2 >4 was also predictive of presence of clinically important cardiac (T2* <20ms, AUC=0.92, p<0.001) and hepatic iron (LIC >10mg/gd.w., AUC= 0.74, p<0.005). Mean ferritin significantly correlated with ZR2 (p<0.001) but not with the gland's volume.ConclusionsAnterior pituitary iron assessed by MRI, increases with age and correlates with total body iron burden in TDT, suggesting cumulative iron toxicity. It results in a decrease in gland size and impaired gonadotropin and growth hormone secretion. Pituitary iron exceeding ZR2 >4, appears to be a significant predictor for change in gland size, that also is associated with cardiac and liver iron-overload. Pituitary MRI and the concomitant liver and cardiac iron quantification can identify patients at high-risk for further pituitary damage, suggesting that early intervention can potentially prevent additional decline in hormonal secretion. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Growth, Nutrition and Economy

Twenty-three scientists met at Krobielowice, Poland to discuss the role of growth, nutrition and economy on body size. Contrasting prevailing concepts, re-analyses of studies in Indonesian and Guatemalan school children with high prevalence of stunting failed to provide evidence for an association between nutritional status and body height. Direct effects of parental education on growth that were not transmitted via nutrition were shown in Indian datasets using network analysis and novel statistical methods (St. Nicolas House Analysis) that translate correlation matrices into network graphs. Data on Polish children suggest significant impact of socioeconomic sensitivity on child growth, with no effect of maternal money satisfaction. Height and maturation tempo affect the position of a child among its peers. Correlations also exist between mood disorders and height. Secular changes in height and weight varied across decades independent of population size. Historic and recent Russian data showed that height of persons whose fathers performed manual work were on average four cm shorter than persons whose fathers were high-degree specialists. Body height, menarcheal age, and body proportions are sensitive to socioeconomic variables. Additional topics included delayed motherhood and its associations with newborn size; geographic and socioeconomic indicators related to low birth weight, prematurity and stillbirth rate; data on anthropometric history of Brazil, 1850-1950; the impact of central nervous system stimulants on the growth of children with attention-deficit/hyperactivity disorder; and pituitary development and growth hormone secretion. Final discussions debated on reverse causality interfering between social position, and adolescent growth and developmental tempo.

Domino effect of pituitary growth hormone tumor complicated by diabetic ketoacidosis and pituitary apoplexy: a case report

BackgroundPatients with growth hormone (GH)-secreting adenoma usually develop glucose intolerance. GH increases metabolic rate and, when secreted aberrantly, may result in metabolic syndrome. Herein, we examine the associations of pituitary tumor-induced secretion of hormone with insulin resistance and metabolic syndrome, and determine the relation of pituitary tumor apoplexy-induced diabetic ketoacidosis (DKA) and acute pancreatitis.Case presentationA 44-year-old male with a history of hypertension presented to the emergency department of our hospital on February 14, 2019 with symptoms of headache, dizziness, and vomiting. Computed tomography of the head revealed pituitary tumor with bleeding. An ultrasound scan of the abdomen revealed fatty liver and acute pancreatitis. Further examination revealed the presence of DKA, hypertriglyceridemia, cortical hypofunction crisis and acute kidney injury. Surgical endoscopic resection of the pituitary tumor resection via the transsphenoidal approach was performed. The patient’s postoperative recovery was remarkable.ConclusionsLong-term growth hormone abnormality may trigger insulin resistance, leading to metabolic syndrome and impaired glucose and lipid metabolism. The pituitary adenoma apoplexy may also directly induce DKA, creating a domino effect, which further deteriorate the aberrant metabolism of glucose and lipids.

Lack of Brain Insulin Receptor Substrate-1 Causes Growth Retardation, With Decreased Expression of Growth Hormone-Releasing Hormone in the Hypothalamus.

Insulin receptor substrate-1 (Irs1) is one of the major substrates for insulin receptor and insulin-like growth factor-1 (IGF-1) receptor tyrosine kinases. Systemic Irs1-deficient mice show growth retardation, with resistance to insulin and IGF-1, although the underlying mechanisms remain poorly understood. For this study, we generated mice with brain-specific deletion of Irs1 (NIrs1KO mice). The NIrs1KO mice exhibited lower body weights, shorter bodies and bone lengths, and decreased bone density. Moreover, the NIrs1KO mice exhibited increased insulin sensitivity and glucose utilization in the skeletal muscle. Although the ability of the pituitary to secrete growth hormone (GH) remained intact, the amount of hypothalamic growth hormone-releasing hormone (GHRH) was significantly decreased and, accordingly, the pituitary GH mRNA expression levels were impaired in these mice. Plasma GH and IGF-1 levels were also lower in the NIrs1KO mice. The expression levels of GHRH protein in the median eminence, where Irs1 antibody staining is observed, were markedly decreased in the NIrs1KO mice. In vitro, neurite elongation after IGF-1 stimulation was significantly impaired by Irs1 downregulation in the cultured N-38 hypothalamic neurons. In conclusion, brain Irs1 plays important roles in the regulation of neurite outgrowth of GHRH neurons, somatic growth, and glucose homeostasis.

Primary Amenorrhea and Hyperandrogenism: Presenting Features of a Growth Hormone Producing Pituitary Adenoma in a Female Adolescent

Background: The combination of obesity, metabolic syndrome, hyperandrogenism and amenorrhea can be a common presentation of conditions such as polycystic ovarian syndrome. Growth hormone (GH) secreting pituitary adenomas are rare in children, but can present with a similar picture. Clinical Case: A 15-year 4-month old female was evaluated for primary amenorrhea and metabolic syndrome. Her weight was +2.96 SD, height +3.0 SD (mid-parental height 44th percentile, -0.1 SD) and BMI +2.53 SD, all >99th percentile. Weight and BMI were >99th percentile (weight +3.0 SD, BMI +2.4 SD) since 11 years of age and height was >99th percentile (+ 2.7 SD) since 8 years of age. Physical exam was remarkable for acanthosis, deepened voice, no hirsutism, Tanner III breasts and Tanner IV pubic hair. Laboratory evaluation was notable for prolactin (PRL) 147.8 ng/dL (2.6-18.0), LH <0.02 mIU/mL, FSH <0.09 mIU/mL, estradiol 23 pg/mL, total testosterone 81 ng/dL (<41), androstenedione 673 ng/mL (43-180), DHEA-S 627 mcg/dL (42-162), dyslipidemia and normal 17 hydroxy-progesterone and thyroid function tests. Bone age was 16 years. Brain MRI showed a 15x7mm pituitary macroadenoma without suprasellar invasion. Pituitary evaluation revealed IGF-1 619 ng/mL (192-568), IGF-BP3 5.15 mg/L (2.64-6.43) and adrenal insufficiency. Treatment with cabergoline 0.5 mg/week and maintenance hydrocortisone were initiated. An OGTT demonstrated baseline GH 4.9 ng/mL (0-6) and nadir 3.62 ng/mL (normal <1) consistent with GH excess. Surgery for the pituitary adenoma was recommended but unfortunately postponed. Four months later, her BP was elevated, she had clinical signs of diabetes insipidus (DI), PRL was 43.2 ng/dL and she failed a repeat GH suppression test. Follow-up MRI showed pituitary mass enlargement (17x9mm). Patient underwent total trans-sphenoidal tumor resection. Pathology confirmed a sparsely granulated (SG) GH adenoma immunoreactive for GH, PRL and estrogen receptor. Post-operative OGTT showed adequate GH suppression, normal prolactin levels, persistent testosterone elevation and DI. Conclusions: Hyperprolactinemia, hyperandrogenism and metabolic syndrome could be the presenting features of pituitary GH adenomas even in the absence of acromegalic features. Specifically, SG pituitary adenomas are frequently seen in young adults, are larger, more invasive and less likely to respond to medical treatment. Timely diagnosis and surgical treatment of GH adenomas is essential to prevent the high morbidity and mortality.

Evaluation of thyroid disease and thyroid malignancy in acromegalic patients.

Differences in epidemiological data from different geographical regions have made the prevalence of thyroid disease and thyroid cancer controversial. No previous study has investigated whether thyroid disease and thyroid cancer prevalence are higher in acromegalic patients than in the general population in Türkiye. The aim of this study is to determine the prevalence of thyroid disease and thyroid cancer in acromegaly and to compare it with the control group. A total of 129 acromegalic patients (78 female, 51 male) and 247 control group patients (151 female, 96 male) were included in the study. Pituitary size, growth hormone (GH) and insulin-like growth factor (IGF)-1 levels in all patients with acromegaly and thyroid function tests, thyroid receptor autoantibody (TRAb), thyroid scintigraphy, thyroid ultrasonography (US), fine-needle aspiration cytology (FNAC) and histopathology findings after thyroidectomy were recorded. Thyroid lesions were present in 93 patients (72.1%) with acromegaly. While diffuse goiter (14.7%) and multinodular goiter (MNG) (47.3%) were significantly higher, Graves' disease (4.5%) was significantly lower in the acromegaly group compared to control group. The presence of thyroid lesions and thyroid nodules was significantly higher in patients with acromegaly (odds ratio 2.766; 95% CI 2.112-4.469, P<0.001 and OR 1.955; 95% CI 1.206-3.170, P=0.007). According to gender, the prevalence of thyroid lesions, MNG and thyroid cancer was significantly higher in female patients than in the control group. Thyroid cancer prevalence was found in 7% of acromegalic patients and the prevalence of thyroid cancer in the control group was 4.5%. It remains controversial whether the risk of thyroid cancer is increased or not in patients with acromegaly. In this study, there is no significant difference in thyroid cancer between acromegaly and control group, but thyroid lesions are significantly more common in acromegaly. Also, more research is required to determine if thyroid lesions are more prevalent in females with acromegaly.

Сучасні погляди на генетичну детермінованість СТГ-секретуючих аденом гіпофіза (огляд літератури та власні дослідження)

Актуальність. В роботі наведений огляд сучасних даних літератури щодо генетичної складової в етіології та патогенезі гормонально активної аденоми гіпофіза, що секретує соматотропний гормон (СТГ) і клінічними проявами якої є синдром акромегалії та/або гігантизму— синдром множинної ендокринної неоплазії 1, синдром Мак-К’юна— Олбрайта, комплекс Карні, акрогігантизм (Х-зчеплений), сімейні ізольовані аденоми гіпофіза (FIPA). Матеріали та методи. Для виявлення мутацій в гені AIP та з метою верифікації FIPA були обстежені 26 хворих української популяції (19 жінок та 7 чоловіків), в яких акромегалія була діагностована в підлітковому або молодому віці, і проведений генетичний аналіз. Для визначення генетичної детермінованості щодо розвитку СТГ-секретуючої аденоми гіпофіза та диференціальної діагностики синдромів FIPA та MEN1 методом секвенування (MLPA— Ligation-dependent Probe Amplification) було проведене дослідження генів (MLPA, P244-C1) за участю екзонів 1–6 MEN1, (MLPA, P017-D1) AIP. Результати. Серед обстежених тільки у двох осіб були визначені мутації гена AIP. В одного хворого генетичний скринінг на мутацію гена MEN1 був негативним, і жодних клінічних симптомів, що свідчать про синдром Мак-К’юна— Олбрайта, не було виявлено. Варіант гетерозиготного місенсу c.714C&gt;G (p.Cys238Trp) виявлений у гені AIP. Цей аналіз гена AIP сумісний з генетичною схильністю до аденом гіпофіза. У нащадків даного пацієнта 50% шансів успадкувати цей варіант. У іншої хворої з діагнозом «синдром множинної ендокринної неоплазії типу1 (синдром Вермера): інсулінома, аденоми прищитоподібних залоз (2), первинний гіперпаратиреоз» встановлений варіант гетерозиготного місенсу c.134A&gt;G (p.Glu45Gly), що був виявлений у гені MEN1. Варіант c.l34A&gt;G (p.Glu45Gly), клас 4, ймовірно, є патогенним. Поширеність цього варіанта в загальній популяції невідома, тому він є дуже рідкісним. Висновки. Проведення генетичного аналізу є доцільним у хворих дитячого та молодого віку або в осіб, у яких СТГ-секретуюча макро-/гігантська аденома гіпофіза була діагностована в молодому віці (до 35 років), незалежно від сімейної обтяженості щодо аденом гіпофіза. У хворих з обтяженою спадковістю генетичний аналіз доцільно проводити у будь-якому разі для виявлення FIPA та прогнозування подальшого перебігу захворювання та ефективності лікування аналогами соматостатину.

Markers of Genetic Variation in Blue Gourami (Trichogaster trichopterus) as a Model for Labyrinth Fish.

Simple SummaryThis review is a summary of recent studies of genes, many of them involved in growth and reproduction, which can be used for distinguishing between species of the Anabantoidei suborder of fish, focusing on the Blue Gourami as a model species. This is important in both basic science and aquaculture applications. Markers of genetic variation between species are important for both applied and basic research. Here, various genes of the blue gourami (Trichogaster trichopterus, suborder Anabantoidei, a model labyrinth fish), many of them involved in growth and reproduction, are reviewed as markers of genetic variation. The genes encoding the following hormones are described: kisspeptins 1 and 2, gonadotropin-releasing hormones 1, 2, and 3, growth hormone, somatolactin, prolactin, follicle- stimulating hormone and luteinizing hormone, as well as mitochondrial genes encoding cytochrome b and 12S rRNA. Genetic markers in blue gourami, representing the suborder Anabantoidei, differ from those in other bony fishes. The sequence of the mitochondrial cytochrome c oxidase subunit 1 (COI) gene of blue gourami is often used to study the Anabantoidei suborder. Among the genes involved in controlling growth and reproduction, the most suitable genetic markers for distinguishing between species of the Anabantoidei have functions in the hypothalamic–pituitary–somatotropic axis: pituitary adenylate cyclase-activating polypeptide and growth hormone, and the 12S rRNA gene.

The Complex World of Regulation of Pituitary Growth Hormone Secretion: The Role of Ghrelin, Klotho, and Nesfatins in It.

The classic concept of how pituitary GH is regulated by somatostatin and GHRH has changed in recent years, following the discovery of peripheral hormones involved in the regulation of energy homeostasis and mineral homeostasis. These hormones are ghrelin, nesfatins, and klotho. Ghrelin is an orexigenic hormone, released primarily by the gastric mucosa, although it is widely expressed in many different tissues, including the central nervous system and the pituitary. To be active, ghrelin must bind to an n-octanoyl group (n = 8, generally) on serine 3, forming acyl ghrelin which can then bind and activate a G-protein-coupled receptor leading to phospholipase C activation that induces the formation of inositol 1,4,5-triphosphate and diacylglycerol that produce an increase in cytosolic calcium that allows the release of GH. In addition to its direct action on somatotrophs, ghrelin co-localizes with GHRH in several neurons, facilitating its release by inhibiting somatostatin, and acts synergistically with GHRH stimulating the synthesis and secretion of pituitary GH. Gastric ghrelin production declines with age, as does GH. Klotho is an anti-aging agent, produced mainly in the kidneys, whose soluble circulating form directly induces GH secretion through the activation of ERK1/2 and inhibits the inhibitory effect that IGF-I exerts on GH. Children and adults with untreated GH-deficiency show reduced plasma levels of klotho, but treatment with GH restores them to normal values. Deletions or mutations of the Klotho gene affect GH production. Nesfatins 1 and 2 are satiety hormones, they inhibit food intake. They have been found in GH3 cell cultures where they significantly reduce the expression of gh mRNA and that of pituitary-specific positive transcription factor 1, consequently acting as inhibitors of GH production. This is a consequence of the down-regulation of the cAMP/PKA/CREB signaling pathway. Interestingly, nesfatins eliminate the strong positive effect that ghrelin has on GH synthesis and secretion. Throughout this review, we will attempt to broadly analyze the role of these hormones in the complex world of GH regulation, a world in which these hormones already play a very important role.

Leptin Modulates the Response of Brown Adipose Tissue to Negative Energy Balance: Implication of the GH/IGF-I Axis.

The growth hormone (GH)/insulin-like growth factor I (IGF-I) axis is involved in metabolic control. Malnutrition reduces IGF-I and modifies the thermogenic capacity of brown adipose tissue (BAT). Leptin has effects on the GH/IGF-I axis and the function of BAT, but its interaction with IGF-I and the mechanisms involved in the regulation of thermogenesis remains unknown. We studied the GH/IGF-I axis and activation of IGF-I-related signaling and metabolism related to BAT thermogenesis in chronic central leptin infused (L), pair-fed (PF), and control rats. Hypothalamic somatostatin mRNA levels were increased in PF and decreased in L, while pituitary GH mRNA was reduced in PF. Serum GH and IGF-I concentrations were decreased only in PF. In BAT, the association between suppressor of cytokine signaling 3 and the IGF-I receptor was reduced, and phosphorylation of the IGF-I receptor increased in the L group. Phosphorylation of Akt and cyclic AMP response element binding protein and glucose transporter 4 mRNA levels were increased in L and mRNA levels of uncoupling protein-1 (UCP-1) and enzymes involved in lipid anabolism reduced in PF. These results suggest that modifications in UCP-1 in BAT and changes in the GH/IGF-I axis induced by negative energy balance are dependent upon leptin levels.

Attenuation of growth hormone production at the fetal stage is critical for dioxin-induced developmental disorder in rat offspring

Although dioxins and related chemicals have been suspected to disrupt child development, their toxic mechanism remains poorly understood. Our previous studies in rat fetuses revealed that maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly-toxic dioxin, suppresses fetal synthesis of pituitary growth hormone (GH) that is essential for development. This study examined the hypothesis that attenuating GH expression in fetuses triggers developmental disorders. Treating pregnant rats with 1 μg/kg TCDD reduced the circulating level of GH and its downstream factor, insulin-like growth factor-1 (IGF-1), in the offspring only during the fetal and early neonatal stages. Although maternal TCDD exposure resulted in low body weight and length at babyhood and defects in the learning and memory ability at adulthood, GH supplementation in TCDD-exposed fetuses restored or tended to restore the defects including IGF-1 downregulation. Moreover, maternal TCDD exposure decreased the number of GH-positive cells during the fetal/neonatal stage. A microarray analysis showed that TCDD reduced the expression of death-associated protein-like 1 (DAPL1), a cell cycle-dependent proliferation regulator, in the fetal pituitary gland. In addition, TCDD treatment attenuated proliferating cells and cyclin mRNA expression in the fetal pituitary gland. Aryl hydrocarbon receptor (AHR)-knockout fetuses were insensitive to TCDD treatment, indicating that the TCDD-induced reduction in DAPL1 and GH mRNAs expression was due to AHR activation. Finally, DAPL1 knockdown suppressed GH and cyclin D2 expression in fetal pituitary cells. These results provide a novel evidence that dioxin suppresses GH-producing cell proliferation and GH synthesis due to partly targeting DAPL1, thereby impairing offspring development.

Cerebral Insulin Bolus Revokes the Changes in Hepatic Lipid Metabolism Induced by Chronic Central Leptin Infusion.

Central actions of leptin and insulin on hepatic lipid metabolism can be opposing and the mechanism underlying this phenomenon remains unclear. Both hormones can modulate the central somatostatinergic system that has an inhibitory effect on growth hormone (GH) expression, which plays an important role in hepatic metabolism. Using a model of chronic central leptin infusion, we evaluated whether an increase in central leptin bioavailability modifies the serum lipid pattern through changes in hepatic lipid metabolism in male rats in response to an increase in central insulin and the possible involvement of the GH axis in these effects. We found a rise in serum GH in leptin plus insulin-treated rats, due to an increase in pituitary GH mRNA levels associated with lower hypothalamic somatostatin and pituitary somatostatin receptor-2 mRNA levels. An augment in hepatic lipolysis and a reduction in serum levels of non-esterified fatty acids (NEFA) and triglycerides were found in leptin-treated rats. These rats experienced a rise in lipogenic-related factors and normalization of serum levels of NEFA and triglycerides after insulin treatment. These results suggest that an increase in insulin in leptin-treated rats can act on the hepatic lipid metabolism through activation of the GH axis.