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International Journal of Molecular... Aug 2023Gonadotropin-releasing hormone (GnRH) neurons are key neuroendocrine cells in the brain as they control reproduction by regulating hypothalamic-pituitary-gonadal axis...
Gonadotropin-releasing hormone (GnRH) neurons are key neuroendocrine cells in the brain as they control reproduction by regulating hypothalamic-pituitary-gonadal axis function. In this context, anti-Müllerian hormone (AMH), growth hormone (GH), and insulin-like growth factor 1 (IGF1) were shown to improve GnRH neuron migration and function in vitro. Whether AMH, GH, and IGF1 signaling pathways participate in the development and function of GnRH neurons in vivo is, however, currently still unknown. To assess the role of AMH, GH, and IGF1 systems in the development of GnRH neuron, we evaluated the expression of AMH receptors (AMHR2), GH (GHR), and IGF1 (IGF1R) on sections of ex vivo mice at different development stages. The expression of AMHR2, GHR, and IGF1R was assessed by immunofluorescence using established protocols and commercial antibodies. The head sections of mice were analyzed at E12.5, E14.5, and E18.5. In particular, at E12.5, we focused on the neurogenic epithelium of the vomeronasal organ (VNO), where GnRH neurons, migratory mass cells, and the pioneering vomeronasal axon give rise. At E14.5, we focused on the VNO and nasal forebrain junction (NFJ), the two regions where GnRH neurons originate and migrate to the hypothalamus, respectively. At E18.5, the median eminence, which is the hypothalamic area where GnRH is released, was analyzed. At E12.5, double staining for the neuronal marker ß-tubulin III and AMHR2, GHR, or IGF1R revealed a signal in the neurogenic niches of the olfactory and VNO during early embryo development. Furthermore, IGF1R and GHR were expressed by VNO-emerging GnRH neurons. At E14.5, a similar expression pattern was found for the neuronal marker ß-tubulin III, while the expression of IGF1R and GHR began to decline, as also observed at E18.5. Of note, hypothalamic GnRH neurons labeled for PLXND1 tested positive for AMHR2 expression. Ex vivo experiments on mouse sections revealed differential protein expression patterns for AMHR2, GHR, and IGF1R at any time point in development between neurogenic areas and hypothalamic compartments. These findings suggest a differential functional role of related systems in the development of GnRH neurons.
Topics: Animals; Mice; Anti-Mullerian Hormone; Gonadotropin-Releasing Hormone; Growth Hormone; Insulin-Like Growth Factor I; Neurons; Peptide Hormones; Pituitary Hormone-Releasing Hormones; Tubulin; Neuroendocrine Cells
PubMed: 37685880
DOI: 10.3390/ijms241713073 -
Pituitary Oct 2023Giant prolactinomas are a rare entity, representing approximately 5% of all prolactinomas. A systematic review of 196 adult cases was performed. A comparison of the... (Review)
Review
PURPOSE
Giant prolactinomas are a rare entity, representing approximately 5% of all prolactinomas. A systematic review of 196 adult cases was performed. A comparison of the clinical, biochemical and radiological characteristics, management and therapeutic outcomes in men versus women is made.
METHODS
A structured search was conducted using the term 'giant prolactinoma'. Following inclusion criteria were used: diameter ≥ 40 mm, prolactin levels > 1000 ng/ml and no concomitant GH/ ACTH secretion.
RESULTS
196 cases were included [age: 38 (28-50) years, F/M ratio: 1/3.6]. Median tumor diameter was 53 (43-69) mm. Pituitary deficiency was present in 91% of cases, with hypogonadotropic hypogonadism being the most frequent. Most common presenting symptoms were visual impairment (73%) and headache (50%) in men and amenorrhea (58%) in women. 82% of cases were treated with a dopamine agonist (DA) as first-line treatment which led to normoprolactinemia, tumor shrinkage and visual improvement in 51%, 88% and 85% of cases, respectively. Surgery was performed in 29% of cases and all showed tumor remnant and persistent hyperprolactinemia. Women had a lower prolactin level and a smaller tumor diameter at diagnosis but pituitary deficiencies were more frequent and outcome was worse.
CONCLUSION
Giant prolactinomas are rare and have a male predominance. Visual impairment is the most frequent presenting symptom in men and amenorrhea in women. The gender-related difference in tumor size and level of prolactin was confirmed in this analysis where men had a larger diameter and a higher baseline prolactin level. DAs are the treatment of choice, irrespective of tumor size and presence of visual impairment. As only half of the cases achieved normoprolactinemia we do not, in contrast to previous literature, state giant prolactinomas to be exquisitely sensitive to DAs. Patient characteristics associated with persistent hyperprolactinemia after treatment with a DA were female gender, higher baseline prolactin and larger tumor size . This analysis did show TSH- and ACTH-deficiency to be more frequent after surgery which was not seen for LH/FSH deficiency.
Topics: Female; Adult; Male; Humans; Prolactinoma; Pituitary Neoplasms; Hyperprolactinemia; Prolactin; Amenorrhea; Dopamine Agonists; Hypopituitarism; Vision Disorders; Adrenocorticotropic Hormone
PubMed: 37544978
DOI: 10.1007/s11102-023-01337-0 -
Cells Dec 2023Corticotropin-releasing hormone (CRH) is known for its crucial role in the stress response system, which could induce pituitary adrenocorticotropic hormone (ACTH)...
Corticotropin-releasing hormone (CRH) is known for its crucial role in the stress response system, which could induce pituitary adrenocorticotropic hormone (ACTH) secretion to promote glucocorticoid release in the adrenal gland. However, little is known about other pituitary actions of CRH in teleosts. Somatolactin is a fish-specific hormone released from the neurointermediate lobe (NIL) of the posterior pituitary. A previous study has reported that ACTH was also located in the pituitary NIL region. Interestingly, our present study found that CRH could significantly induce two somatolactin isoforms' (SLα and SLβ) secretion and synthesis in primary cultured grass carp pituitary cells. Pharmacological analysis further demonstrated that CRH-induced pituitary somatolactin expression was mediated by the AC/cAMP/PKA, PLC/IP3/PKC, and Ca/CaM/CaMK-II pathways. Finally, transcriptomic analysis showed that both SLα and SLβ should play an important role in the regulation of lipid metabolism in primary cultured hepatocytes. These results indicate that CRH is a novel stimulator of somatolactins in teleost pituitary cells, and somatolactins may participate in the stress response by regulating energy metabolism.
Topics: Animals; Corticotropin-Releasing Hormone; Pituitary Hormones; Signal Transduction; Fish Proteins; Glycoproteins; Adrenocorticotropic Hormone
PubMed: 38132090
DOI: 10.3390/cells12242770 -
Spine Feb 2024Cross-sectional and retrospective cohort study.
STUDY DESIGN
Cross-sectional and retrospective cohort study.
OBJECTIVE
We investigated the effect of 3 types of short stature [partial growth hormone deficiency (GHD), GHD, and idiopathic short stature (ISS)] and recombinant human growth hormone (rhGH) therapy on scoliosis.
SUMMARY OF BACKGROUND DATA
In short stature, rhGH is widely used and the concentration of growth hormone varies among types. The epidemiologic characteristics of scoliosis and the role of rhGH in scoliosis remain unclear.
PATIENTS AND METHODS
A cross-sectional study was conducted among 3896 patients with short stature (partial GHD, GHD, and ISS), and a 1:1 age and sex-matched control group with preexisting whole-spine radiographs. The cohort study included 2605 subjects who underwent radiography more than twice to assess scoliosis development, progression, and the need for bracing and surgery. Adjusted logistic regression was used to assess differences in the prevalence of scoliosis among patients with partial GHD, GHD, ISS, and controls. The Kaplan-Meier method was used to analyze the time course of scoliosis development and progression. Cox regression was applied to assess the independent factors related to scoliosis development and progression. Mendelian randomization analyses were also performed.
RESULTS
Compared with controls, patients with short stature had a higher incidence of scoliosis (34.47% in partial GHD, 31.85% in GHD, 32.94% in ISS vs . 8.83% in control, P < 0.001), a higher risk of scoliosis development [hazard ratio (HR) = 1.964 in partial GHD, P < 0.001; HR = 1.881 in GHD, P = 0.001; HR = 1.706 in ISS, P = 0.001), but not a higher risk of progression, brace, or surgery. Among the 3 types of short stature, there were no differences in the incidence, development, and progression of scoliosis or the need for bracing or surgery. RhGH treatment increased the risk of scoliosis development in each short-stature group (HR = 2.673 in partial GHD, P < 0.001; HR = 1.924 in GHD, P = 0.049; HR = 1.564 in ISS, P = 0.004). Vitamin D supplementation was protective against scoliosis development (HR = 0.456 in partial GHD, P = 0.003; HR = 0.42 in GHD, P = 0.013; HR = 0.838 in ISS, P = 0.257).
CONCLUSIONS
More attention should be paid to the spinal curve in patients with partial GHD, GHD, or ISS. For short stature treated with rhGH, the risk of scoliosis development was increased. Vitamin D supplementation may be beneficial for prevention.
LEVEL OF EVIDENCE
Level III.
Topics: Humans; Human Growth Hormone; Growth Hormone; Cross-Sectional Studies; Cohort Studies; Retrospective Studies; Scoliosis; Dwarfism, Pituitary; Vitamin D; Body Height
PubMed: 37871182
DOI: 10.1097/BRS.0000000000004853 -
Equine Veterinary Journal Mar 2024Equine thyroid disorders pose a diagnostic challenge in clinical practice because of the effects of nonthyroidal factors on the hypothalamic-pituitary-thyroid axis, and... (Review)
Review
Equine thyroid disorders pose a diagnostic challenge in clinical practice because of the effects of nonthyroidal factors on the hypothalamic-pituitary-thyroid axis, and the horse's ability to tolerate wide fluctuations in thyroid hormone concentrations and survive without a thyroid gland. While benign thyroid tumours are common in older horses, other disorders like primary hypothyroidism or hyperthyroidism in adult horses and congenital hypothyroidism in foals are rare. There is a common misunderstanding regarding hypothyroidism in adult horses, especially when associated with the clinical profile of obesity, lethargy, and poor performance observed in dogs and humans. Low blood thyroid hormone concentrations are often detected in horses as a secondary response to metabolic and disease states, including with the nonthyroidal illness syndrome; however, it is important to note that low thyroid hormone concentrations in these cases do not necessarily indicate hypothyroidism. Assessing equine thyroid function involves measuring thyroid hormone concentrations, including total and free fractions of thyroxine (T4) and triiodothyronine (T3); however, interpreting these results can be challenging due to the pulsatile secretion of thyroid hormones and the many factors that can affect their concentrations. Dynamic testing, such as the thyrotropin-releasing hormone stimulation test, can help assess the thyroid gland response to stimulation. Although true hypothyroidism is extremely rare, thyroid hormone supplementation is commonly used in equine practice to help manage obesity and poor performance. This review focuses on thyroid gland pathophysiology in adult horses and foals, interpretation of blood thyroid hormone concentrations, and evaluation of horses with thyroid disorders. It also discusses the use of T4 supplementation in equine practice.
Topics: Humans; Horses; Animals; Dogs; Thyrotropin; Thyroid Hormones; Thyroid Diseases; Thyroxine; Triiodothyronine; Hypothyroidism; Obesity; Horse Diseases; Dietary Supplements; Dog Diseases
PubMed: 37533378
DOI: 10.1111/evj.13981 -
Endocrine Practice : Official Journal... Nov 2023Bioinactive growth hormone (BGH) is a structurally abnormal, biologically inactive, but immunoreactive form of growth hormone encoded by pathogenic growth hormone 1 gene... (Review)
Review
OBJECTIVE
Bioinactive growth hormone (BGH) is a structurally abnormal, biologically inactive, but immunoreactive form of growth hormone encoded by pathogenic growth hormone 1 gene variants. The underlying cause of the defective physiology is decreased BGH binding affinity to both growth hormone binding proteins and growth hormone receptors (GHRs). GHR cannot dimerize when it is in a quiescent state because BGH cannot activate it. Nondimerized GHR is unable to activate intracytoplasmic signaling pathway molecules such as Janus kinase 2 and signal transducer and activator of transcription, which initiate insulin-like growth factor-1 (IGF-1) transcription. IGF-1 cannot therefore be synthesized and IGF-1 levels in the circulation decrease. In contrast to children with growth hormone insensitivity, children with short stature due to BGH, known as Kowarski syndrome, exhibit an outstanding linear growth response to recombinant growth hormone therapy. For a number of reasons, differential diagnosis presents some difficulties. Similar diseases caused by genetic abnormalities that cause short stature range in severity from minor to severe clinical spectrum. Furthermore, some patients with Kowarski syndrome have previously been diagnosed with familial short stature, constitutional delayed puberty, and idiopathic short stature. This paper aims to review the particular clinical and laboratory findings of BGH.
METHODS
This study collected clinical and laboratory data from KS cases reported in the literature.
RESULTS
This review reports that KS cases have lower SDSs for height and IGF-1 compared to growth hormone deficiency.
CONCLUSION
The diversity of genetic defects underlying Kowarski syndrome (KS) will provide new insights into growth hormone insensitivity. As the availability of genetic analysis, including functional investigations expands, researchers will identify new underlying genetic pathways.
Topics: Child; Humans; Growth Hormone; Insulin-Like Growth Factor I; Dwarfism, Pituitary; Human Growth Hormone
PubMed: 37657628
DOI: 10.1016/j.eprac.2023.08.013 -
Archives of Medical Research Sep 2023Despite the inherent heterogeneity of the information derived from national registries, they are a useful tool to investigate the epidemiological, clinical, biochemical... (Review)
Review
INTRODUCTION
Despite the inherent heterogeneity of the information derived from national registries, they are a useful tool to investigate the epidemiological, clinical, biochemical and treatment outcome characteristics of low prevalence conditions such as acromegaly. Although the information provided by single-center experiences is more homogeneous, these studies usually comprise a limited number of patients and thus, frequently lack statistical power.
AREAS COVERED
Registry-based Information regarding the epidemiology, clinical presentation, biochemical and imaging diagnosis, as well as therapeutic outcome and mortality in acromegaly is critically analyzed.
EXPERT OPINION
By gathering data from multiple centers in a specific Country, these registries generate important insights into the real-life behavior of this condition, that should be considered, both, in international consensus meetings and in the design of local, Country-specific diagnostic and therapeutic strategies.
Topics: Humans; Acromegaly; Human Growth Hormone; Adenoma; Somatostatin; Treatment Outcome; Registries; Insulin-Like Growth Factor I; Pituitary Neoplasms
PubMed: 37481822
DOI: 10.1016/j.arcmed.2023.102856 -
Best Practice & Research. Clinical... Dec 2023The predominant features of the adult growth hormone deficiency (GHD) syndrome may vary between patients of different age and age of onset of GHD. Evidence from clinical... (Review)
Review
The predominant features of the adult growth hormone deficiency (GHD) syndrome may vary between patients of different age and age of onset of GHD. Evidence from clinical trials and long-term observational studies has informed our ability to understand the unique considerations regarding risks and benefits of daily growth hormone replacement therapy (GHRT) and specific dosing and monitoring strategies for these patient subgroups. High rates of nonadherence with daily GHRT presents a challenge to achieving optimal treatment outcomes and long-acting growth hormone (LAGH) formulations have been developed with the promise of improving treatment adherence resulting in improved therapeutic outcomes. While existing data from short-term studies have demonstrated noninferiority of efficacy and safety of LAGH compared to daily GHRT, long-term studies are needed to assess the full spectrum of outcomes of interest and long-term safety considerations specific to patients in adolescence, adulthood and the elderly GHD population. Since each LAGH formulation has a unique pharmacodynamic and pharmacokinetic profile optimal dosing and monitoring strategies will need to be developed to allow for the provision of individualized patient treatment.
Topics: Adult; Humans; Adolescent; Aged; Dwarfism, Pituitary; Human Growth Hormone; Growth Hormone; Hormone Replacement Therapy; Treatment Outcome
PubMed: 37802712
DOI: 10.1016/j.beem.2023.101825 -
International Journal of Molecular... Nov 2023Pituitary neuroendocrine tumors (PitNETs) are divided into multiple histological subtypes, which determine their clinical and biological variable behavior. Despite their...
Pituitary neuroendocrine tumors (PitNETs) are divided into multiple histological subtypes, which determine their clinical and biological variable behavior. Despite their benign evolution, in some cases, prolactin (PRL) and growth hormone (GH)-secreting PitNETs may have aggressive behavior. In this study, we investigated the potential predictive role of ER∝, alongside the clinicopathological classification of PitNETs (tumor diameter, tumor type, and tumor grade). A retrospective study was conducted with 32 consecutive cases of PRL- and mixed GH- and PRL-secreting PitNETs (5 patients with prolactinomas and 27 with acromegaly, among them, 7 patients with GH- and PRL- co-secretion) who underwent transsphenoidal intervention. Tumor specimens were histologically and immunohistochemical examined: anterior pituitary hormones, ki-67 labeling index, CAM 5.2, and ER∝; ER∝ expression was correlated with basal PRL levels at diagnosis (rho = 0.60, < 0.01) and postoperative PRL levels (rho = 0.58, < 0.001). In our study, the ER∝ intensity score was lower in female patients. Postoperative maximal tumor diameter correlated with Knosp grade ( = 0.02); CAM 5.2 pattern (densely/sparsely granulated/mixed densely and sparsely granulated) was correlated with postoperative PRL level ( = 0.002), and with ki-67 ( < 0.001). The IGF1 level at diagnosis was correlated with the postoperative GH nadir value in the oral glucose tolerance test (OGTT) (rho = 0.52, < 0.05). Also, basal PRL level at diagnosis was correlated with postoperative tumor diameter ( = 0.63, < 0.001). At univariate logistic regression, GH nadir in OGTT test at diagnostic, IGF1, gender, and invasion were independent predictors of remission for mixed GH- and PRL-secreting Pit-NETs; ER∝ can be used as a prognostic marker and loss of ER∝ expression should be considered a sign of lower differentiation and a likely indicator of poor prognosis. A sex-related difference can be considered in the evolution and prognosis of these tumors, but further studies are needed to confirm this hypothesis.
Topics: Humans; Female; Adenoma; Retrospective Studies; Ki-67 Antigen; Pituitary Neoplasms; Prolactinoma; Prolactin; Neuroendocrine Tumors
PubMed: 38003353
DOI: 10.3390/ijms242216162 -
Best Practice & Research. Clinical... Dec 2023Daily administration of growth hormone (GH) treatment has been in clinical use for treatment for GH deficiency (GHD) in adults for more than 30 years. Numerous studies... (Review)
Review
Daily administration of growth hormone (GH) treatment has been in clinical use for treatment for GH deficiency (GHD) in adults for more than 30 years. Numerous studies have demonstrated evidence that GH treatment improves body composition, cardiovascular risk factors and quality of life with few side effects. Less frequent GH injections are hypothesized to improve adherence and several long-acting GH (LAGH) formulations have been developed and a few have been approved and marketed. Different pharmacological modifications have been applied and the pharmacokinetics and pharmacodynamics of LAGH are different to each other and to those of daily injections and require different dosing and monitoring specific for each LAGH. Studies have shown improved adherence with LAGH, and short-term efficacy and side effects are comparable between daily GH injections and LAGHs. Long-term treatment with daily GH injections is effective and safe, while long-term studies for LAGHs are awaited. In this review challenges, benefits, and risks of treatment with daily and long-acting GH preparations will be compared.
Topics: Adult; Humans; Growth Hormone; Quality of Life; Human Growth Hormone; Hypopituitarism; Dwarfism, Pituitary
PubMed: 37308376
DOI: 10.1016/j.beem.2023.101788