GHRH

Growth hormone-releasing hormone attenuates amyloid deposition and neuroinflammation in Alzheimer's disease models.

Francesca Pedrolli, Giulia Morello, Iacopo Gesmundo +8 more

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau hyperphosphorylation, neuroinflammation, and synaptic loss. Existing therapies provide only modest symptomatic relief and fail to slow disease progression. Beyond its role in promoting pituitary growth hormone (GH) secretion, growth hormone-releasing hormone (GHRH) has shown neuroprotective effects in experimental ischemic stroke and spinal muscular atrophy. Here, we explored the therapeutic potential of GHRH and its agonist MR-409 in AD models. In vitro, GHRH(1-44)NH₂ promoted survival, proliferation, and neuronal differentiation of rat hippocampal neural stem cells (NSCs) and human SH-SY5Y neuroblastoma cells under growth factor deprivation and amyloid beta (Aβ)1-42 exposure. These effects involved the cAMP/PKA/CREB, ERK1/2, and PI3K/Akt signaling pathways. GHRH also attenuated Aβ-induced neurotoxicity by reducing apoptosis, suppressing GSK-3β activity and tau phosphorylation, restoring nuclear β-catenin, and inhibiting NF-κB-mediated inflammation. In vivo, subcutaneous administration of MR-409 in 5xFAD mice reduced Aβ deposition, tau phosphorylation, gliosis, and proinflammatory cytokine expression. In addition, MR-409 mitigated neuronal and synaptic loss, activated survival and neurogenic pathways, and improved cognitive performance, without altering systemic GH and IGF1 levels. MR-409 also elevated NRF2 mRNA expression while reducing its negative regulator KEAP1. Overall, these findings indicate that GHRH and its analog MR-409 exert neuroprotective effects by modulating key pathological features of AD, including neurodegeneration, impaired neurogenesis, neuroinflammation, and oxidative stress. Given their ability to modulate multiple pathological pathways, GHRH agonists may represent promising therapeutic candidates for AD and other neurodegenerative disorders.

Acromegaly and histopathology.

Gabriela A Caballero, Teresa Ribalta, Iban Aldecoa

Acromegaly is a chronic disorder caused by sustained excess of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), most commonly due to GH-secreting pituitary neuroendocrine tumors (PitNETs), mainly limited to Pit-1 expressing lineages. Histopathology remains central to diagnosis, prognosis, and treatment planning. Among GH-secreting or somatotroph neoplasms, densely and sparsely granulated are the most relevant clinicopathological subgroups, as they show distinct morphological, radiological, and clinical profiles. Risk assessment is refined by combining routine histology with immunohistochemistry (IHC), including lineage factors, proliferative markers, and somatostatin receptor (SSTR) subtypes, as well as selected molecular tests. Some assays, such as standardized evaluation of SSTR expression, still require further validation. Radiological signs of invasion complement tissue findings and contribute to practical grading systems. Optimal care requires a multidisciplinary approach that integrates endocrine evaluation, high-quality MRI, and expert neuropathology, essential not only for routine care but also for recognizing atypical presentations of acromegaly, such as pituitary hyperplasia, or ectopic growth hormone-releasing hormone (GHRH) or GH secretion. The integration of clinical, pathological, and molecular information provides the foundation for accurate diagnosis and personalized therapy in acromegaly.

GH and GnRH-gonadotropin secretion.

Adriana De Sousa Lages, Valentim Lopes, Richard Anderson

The hypothalamic pituitary gonadal (HPG) and hypothalamic pituitary somatotropic (HPS) axes are interconnected, orchestrating growth, metabolism, and reproduction through reciprocal feedback. Growth hormone (GH) and insulin like growth factor 1 (IGF-1) stimulate gonadotropin releasing hormone (GnRH) and kisspeptin neurons, support luteinizing hormone release, and regulate gonadal steroidogenesis and gametogenesis. Conversely, sex steroids, particularly estradiol, potentiate GH secretion by sensitizing somatotrophs to growth hormone releasing hormone and enhancing ghrelin driven pathways. This crosstalk evolves across developmental stages, most prominently during puberty, when the synergistic rise of sex steroids, GH, and IGF-1 creates an anabolic environment driving linear growth, skeletal maturation, and reproductive competence. From a translational perspective, this interplay has important diagnostic and therapeutic implications. In short stature with delayed diagnosis, combined GH and GnRH analogue therapy may extend growth potential and improve adult height. In central or peripheral precocious puberty, particularly when growth velocity declines during GnRH analogue treatment, co-treatment can prevent growth deceleration and optimize stature. In reproductive medicine, GH has been explored as an adjuvant in assisted reproductive technologies, with evidence suggesting benefits in follicular recruitment, oocyte quality, embryo development, and endometrial receptivity, although consistent effects on live birth rates remain uncertain. Emerging strategies, including kisspeptin analogues, highlight opportunities to modulate reproductive and somatotropic axes simultaneously, offering potential interventions in hypogonadism and functional hypothalamic disorders. By integrating mechanistic insights with clinical application, the coordinated regulation of GnRH and GH illustrates how translational neuroendocrinology can bridge molecular discovery with diagnostic innovation and therapeutic progress in growth and reproductive health.

Growth hormone: Synthesis and regulation.

Pedro Iglesias, Fernando Guerrero-Pérez

Growth hormone (GH) plays an essential role in the regulation of postnatal growth and metabolism through both direct and GH-IGF-1 axis-mediated mechanisms. GH action involves a complex interplay of endocrine, paracrine and autocrine signals that affect multiple tissues and organs. This review addresses the molecular and physiological fundamentals of GH secretion and action, as well as the multiple factors that modulate it, including central and peripheral signals, metabolic variables, physiological and pharmacological states. The relevance of GH receptor signaling and intracellular pathways involved in tissue response is discussed, as well as the mechanisms of hormone resistance that may arise in different clinical contexts. GH secretion, which is pulsatile, is subject to strict regulation by the hypothalamic-pituitary system, involving GHRH, somatostatin and ghrelin, together with negative feedback from GH and IGF-1. In addition, factors such as sleep, nutrition, stress, age or sex contribute significantly to its physiological variability. The implications of the somatotropic axis in pathological conditions such as GH deficiency, acromegaly or GH insensitivity syndromes are also explored.

Pathogenesis of Non-Familial Somatotroph Adenomas.

Anat Ben-Shlomo, Shlomo Melmed

Excess growth hormone (GH) production leading to acromegaly most commonly emanates from an adenomatous pituitary somatotroph. Understanding the pathogenesis of these adenomas will elucidate how biologic behavior affects acromegaly treatment outcomes.

Effects of commercial genetic selection on gene expression in the developing neuroendocrine system of broilers.

Panpradub Sinpru, Kristen Diehl, Laura E Ellestad +1 more

Selective breeding of broilers has significantly improved growth rates, muscle mass, and feed efficiency and may have influenced the neuroendocrine systems that regulate growth and metabolism. Embryonic development represents one-third of the life of a modern broiler. To assess the impact of genetic selection on the neuroendocrine regulation of growth and metabolism during embryonic development, we examined mRNA expression of growth-related genes in the hypothalamus and anterior pituitary of two chicken breeds: the modern Ross 708 broiler and the Athens Canadian Random Bred (ACRB) line, the oldest established strain for meat-type chickens. Hypothalami and pituitary glands were dissected from embryos at days 10, 12, 14, 16, and 18 of incubation (n = 4 for each combination of breed, age, and gender). Levels of mRNA for each target gene were quantified using reverse transcription-quantitative PCR. In the adrenocorticotropic axis, pituitary corticotropin-releasing hormone receptor 1 mRNA levels were influenced by the interaction of breed, age, and gender (P < 0.05). In the thyrotropic axis, pituitary thyroid-stimulating hormone β-subunit mRNA levels were affected by the interaction of breed, age, and gender (P < 0.05). In the somatotropic axis, mRNA levels of hypothalamic somatostatin were higher in ACRB than Ross, whereas overall pituitary growth hormone mRNA levels were greater in Ross than ACRB (P < 0.05). Pituitary growth hormone-releasing hormone receptor 2 and pituitary adenylate cyclase-activating polypeptide receptor 1 were influenced by the interaction between breed and age (P < 0.05). In the gonadotropic axis, hypothalamic gonadotropin-releasing hormone 1 and gonadotropin-inhibiting hormone were influenced by breed, age, and gender, while mRNA levels of pituitary follicle-stimulating hormone β-subunit were affected by the interaction between breed and age (P < 0.05). Hypothalamic agouti-related peptide, neuropeptide Y, and proopiomelanocortin mRNA levels were higher in ACRB than Ross in females (P < 0.05). These findings indicate that genetic selection of broilers has altered the adrenocorticotropic, somatotropic, thyrotropic, and gonadotropic axes, as well as hypothalamic control of appetite and metabolism during embryonic development.

Evaluation of the Therapeutic Potential of Synthetic Growth Hormone-Releasing Hormone Antagonist MIA-690 as a Cognitive Modulator in a Mouse Model of Gulf War Illness.

Luis Manuel Salgueiro-Tosta, Arumugam Radhakrishnan Jayakumar, William Kochen +7 more

Gulf War illness (GWI) is a multi-symptom disorder affecting veterans of the Persian Gulf operations. Persistent neuroendocrine dysregulation contributes to impairing cognitive capacity and generates anxiety-like behavior. Effective treatments for this illness are challenging due to compromised metabolism, increased oxidative stress and neuroinflammation, perpetuated by chronic stress and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. This neuroinflammation can be alleviated with synthetic antagonistic analogs of the growth hormone-releasing hormone (GHRH) through modulation of the HPA axis. We evaluated the efficacy of the GHRH antagonist analog, MIA-690, against cognitive impairment and anxiety-like behavior in GWI. Mice exposed to an experimental GWI model involving corticosterone (CORT) and diisopropylfluorophosphate (DFP), followed by CORT and lipopolysaccharide (LPS), received a daily subcutaneous dose of 10 μg of MIA-690 for 10 days. Assessments of spatial memory, recognition capacity, somatic health, anxiety and innate survival were carried out, combining the Morris water maze (MWM), novel object recognition (NORT), grip strength (GST), and open field (OFT) tests. Learning efficiency was selectively enhanced in females using the MWM. There were no significant differences in the recall capacity and performance on the OFT, NOR, and GST tasks. Our findings suggest that the MIA-690 dosage is sufficient to improve learning deficits in experimental GWI exposures.

Growth hormone-releasing hormone in retinal disorders and uveitis: an updated review.

Sha-Lin Yi, Yu-Qiang Huang

Growth hormone-releasing hormone (GHRH) is a hypothalamic releasing hormone that plays a crucial physiological role in regulating the synthesis and release of anterior pituitary hormones. In recent years, studies have found that GHRH possesses functions like anti-inflammation, promoting cell proliferation, and facilitating cell migration. It participates in regulating the development of uveitis and diabetic retinopathy. Additionally, it also has an impact on the development of retinal ganglion cells by modulating the inflammatory response and mediating the immune response. Given the important roles of GHRH in ophthalmic diseases, elucidating the molecular regulation of the GHRH-GHRH receptor (GHRHR) signal and the innovative development of intervention pathways that directly or indirectly target GHRH serve as strong evidence of how basic research guides innovation and translation. In this review, research reports on GHRH in ophthalmic diseases including retinal diseases and uveitis were summarized and analyzed.

Putative genes coding for pituitary adenylate cyclase-activating polypeptide and immunohistochemical localization of their mature peptides in the brain-pituitary axis of the inshore hagfish Eptatretus burgeri.

Masafumi Amano, Shima Furuya, Naoyuki Yamamoto +3 more

Hagfish and lampreys, which are both members of the class Agnatha, are widely considered to represent one of the most basal evolutionary lineages of vertebrates. Pituitary adenylate cyclase-activating polypeptide (PACAP) and growth hormone-releasing hormone (GHRH) are both members of the secretin/PACAP family. We searched the Ensembl database for putative PACAP and GHRH sequences in the inshore hagfish, Eptatretus burgeri. We identified three putative GHRH/PACAP precursors (hagfish-1/2/3) whose expression in various tissues, including the brain, was confirmed using RNA sequencing. The hagfish-1 precursor encodes both GHRH/PRP (PACAP-related peptide) and PACAP, whereas the hagfish-2 and -3 precursors encod only PACAP. Of the three putative hagfish PACAPs, PACAP-2, encoded by hagfish-2, showed relatively high identity (77.8%) and similarity (85.2%) with PACAP from other species. In contrast, hagfish GHRH/PRP encoded by hagfish-1 showed low identity (27.3%) and similarity (50.3%) with other GHRHs, and low identity (26.7%) and similarity (46.7%) with other PRPs. Phylogenetic analysis confirmed that the hagfish-2 sequence clustered within the same clade as lamprey PACAP. PACAP-like-immunoreactive (ir) cell bodies and dense punctate fibers have been detected in several brain regions, including the preoptic area, infundibular nucleus of the hypothalamus, midbrain tegmentum, and medulla oblongata. In the pituitary gland, PACAP-like-ir fibers were observed in the dorsal wall of the neurohypophysis. GHRH/PRP immunoreactivity was also observed in the medulla oblongata. The present study demonstrated that PACAP-like- and GHRH/PRP-like peptides are expressed in the brain of the inshore hagfish E. burgeri.

Neuroendocrine plasticity and crosstalk in pubertal development.

Carol Fuzeti Elias, Xingfa Han, David Garcia-Galiano +1 more

Puberty is a critical developmental stage during which individuals acquire the capacity for sexual reproduction. This transition involves a series of complex biological events primarily orchestrated by the activation of the hypothalamo-pituitary-gonadal (HPG) axis. Central to this process are gonadotropin-releasing hormone (GnRH) neurons, which play a key role in regulating reproductive maturation and function throughout life. However, the precise mechanisms that trigger the pubertal increase in GnRH activity remain incompletely understood. Evidence from our laboratory indicates that a profound remodeling of the hypothalamus is crucial for sexual maturation. In this review, we discuss findings from our research utilizing a combination of RNA sequencing, conditional genetic manipulation with mouse models and viral vectors, and systems neuroscience approaches. Our results reveal that the pubertal transition involves changes in the chemical phenotype and site-specific innervation of key hypothalamic neurons. Among these neuronal populations, those expressing growth hormone-releasing hormone (GHRH), kisspeptin, or dopamine transporter (DAT) are the focus of this review. Building upon data from other laboratories, our findings offer new insights into the neural and molecular mechanisms by which the hypothalamus orchestrates sexual maturation.

Functional Divergence of adcyap1b Splice Variants in Regulating Pituitary Hormone Expression in the Chinese Tongue Sole (Cynoglossus semilaevis).

Qian Zhang, Xihong Li, Yue Zhang +5 more

Sexual size dimorphism (SSD) refers to the phenomenon where males and females of the same species exhibit differences in overall or partial body size, and it is widespread among mammals, birds, reptiles, and fish. Notably, this dimorphism is significantly influenced by the sexually dimorphic secretion of growth hormone (gh), a key pituitary-derived growth regulator. Commonly, the secretion of gh is positively regulated by glucagon family members such as growth hormone-releasing hormone (ghrh) and adenylate cyclase-activating polypeptide 1 (adcyap1). To explore the stimulators for pituitary hormones (especially gh) in the teleost, we performed genome-wide identification and functional characterization of the glucagon family on Chinese tongue sole (Cynoglossus semilaevis) that exhibits typical female-biased sexual size dimorphism. Four members of adcyap1/vasoactive intestinal polypeptide(vip)/ghrh family and ten members of their receptor family were identified. Expression pattern analysis revealed high expression of adenylate cyclase-activating polypeptide 1b (adcyap1b) and its receptors in the brain. Moreover, two alternative splice variants for the adcyap1b gene were discovered, resulting from the skipping of exon 4. Following the acquisition of the two eukaryotic recombinant protein splice variants (ADCYAP1b_tv1 and ADCYAP_tv2) from HEK 293T cells, incubation experiments were conducted using C. semilaevis pituitary cell line. The results demonstrated that both variants promoted the expression of gh, pro-opiomelanocortin (pomc), and corticoliberin (crh), but ADCYAP1b_tv1 had a significantly stronger effect and uniquely stimulated prolactin (prl) and somatolactin (sl). This study demonstrates a functional divergence between the two ADCYAP1b splice variants in teleosts, with ADCYAP1b_tv1 acting as a more potent and versatile pituitary hormone stimulator. Further research on their receptor-binding affinity and downstream signaling pathways would be valuable for exploring the mechanism underlying sexual size dimorphism.

IGF-I bioavailability in congenital isolated growth hormone deficiency.

Viviane C Campos, Manuel H Aguiar Oliveira, Martin Bidlingmaier +8 more

The Itabaianinha cohort in Brazil carries a homozygous growth hormone-releasing hormone (GHRH) receptor (GHRH-R) gene mutation, causing congenital isolated GH deficiency (GHD). Affected individuals present with severe short stature, central obesity, hypercholesterolemia, and marked reductions in serum GH, IGF-I, and IGFBP 3 concentrations yet show no premature atherosclerosis and maintain a normal lifespan. IGF-I mostly circulates bound to IGFBPs and requires proteolytic cleavage for IGF-I receptor activation. Pregnancy-associated plasma protein A (PAPP-A) is an important IGF-dependent cleavage enzyme, binding to IGFBP 4 and releasing IGF-I. PAPP-A activity is inhibited by stanniocalcin-2 (STC2). The IGFBP 4-STC2-PAPP-A axis (ISPa) has emerged as a key regulator of IGF-I bioactivity.

The role of dopamine release and D2 dopamine receptor in GHRH and somatostatin cells in controlling growth hormone secretion.

Gabriel O de Souza, Daniela O Gusmao, Maria E de Sousa +3 more

Pituitary growth hormone (GH) secretion is primarily controlled by GH-releasing hormone (GHRH) and somatostatin (SST), peptides produced by hypothalamic neurons. Evidence indicates that dopamine also modulates GH secretion, potentially via D2 dopamine receptor (D2R). Additionally, a subset of GHRH neurons in the arcuate nucleus of the hypothalamus expresses tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine biosynthesis. However, the role of dopamine release from GHRH neurons and the neuronal population that expresses D2R to regulate GH secretion remain currently unknown.

Possible Involvement of Hypothalamic Dysfunction in Long COVID Patients Characterized by Delayed Response to Gonadotropin-Releasing Hormone.

Yuki Otsuka, Yoshiaki Soejima, Yasuhiro Nakano +12 more

Long COVID (LC) may involve endocrine dysfunction; however, the underlying mechanism remains unclear. To examine hypothalamic-pituitary responses in patients with LC, we conducted a single-center retrospective study of patients with refractory LC referred to our University Hospital who underwent anterior pituitary stimulation tests. Between February 2021 and November 2025, 1251 patients with long COVID were evaluated, of whom 207 (19%) had relatively low random ACTH or cortisol levels. Ultimately, 16 underwent anterior pituitary stimulation tests and were included. All tests were performed in an inpatient setting without exogenous steroids. Fifteen patients (six women, mean age 35.6 years) underwent corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone (GnRH) tests. All patients had mild acute COVID-19, eight had ≥2 vaccinations, and the mean interval from infection was 343 days. Frequent symptoms included fatigue (100%), insomnia (66.7%), headache (60.0%), anorexia/nausea (40.0%), and brain fog (40.0%). Mean early-morning cortisol and 24 h urinary free cortisol were 7.5 μg/dL and 41.0 μg/day, respectively. MRI showed an empty sella in one case. Peak hormonal responses were preserved (ΔACTH 247%, ΔTSH 918%, ΔPRL 820%, ΔFSH 187%, ΔLH 1150%); however, peaks were delayed beyond 60 min in ACTH (13%), LH (33%), and FSH (87%). Notably, significantly delayed elevations remained at 120 min in the responses of TSH (4.1-fold), PRL (1.8-fold), LH (9.3-fold), and FSH (2.8-fold), suggesting possible hypothalamic involvement, particularly in the gonadotropin responses. Additionally, serum IGF-I was lowered (-0.70 SD), while GH response (mean peak 35.5 ng/mL) was preserved by growth hormone-releasing peptide (GHRP)-2 stimulation. Low-dose hydrocortisone and testosterone were initiated for three patients. Although direct viral effects and secondary suppression have been proposed, our findings may suggest that, at least in part, the observed response characteristics are consistent with functional secondary hypothalamic dysfunction rather than irreversible primary injury. These findings highlight the need for objective endocrine evaluation before initiating hormone replacements.

The gatekeepers of growth: The neural roles and regulation of growth hormone-releasing hormone neurons.

Bradley B Jamieson

The neuroendocrine control of growth is mediated by the hypothalamic-pituitary-somatic (HPS) axis. This involves the hypothalamic release of growth hormone-releasing hormone (GHRH), which stimulates the pituitary secretion of growth hormone (GH). GH subsequently promotes growth both directly and indirectly by stimulating insulin-like growth factor 1 (IGF1) release from the liver. While extensive research has focused on the actions and mechanisms of GH and IGF1, comparatively little attention has been given to how GHRH neurons themselves are regulated. This review aims to provide insight into how GHRH neurons are controlled, emphasizing their intrinsic electrophysiological properties and the broader brain circuitry involved in detecting physiological signals such as hormonal and metabolic status. Central to this regulation is the balance of excitatory and inhibitory inputs that generate the pulsatile secretion pattern essential for growth regulation. Somatostatin (SST) provides critical inhibitory control over both GH secretion and GHRH neuronal activity. Feedback from peripheral hormones and integration of environmental and metabolic cues can further shape GHRH neuron function. Developmental, sex-dependent, and species-specific variations in GHRH neuron regulation are also discussed, highlighting important avenues for future research. This review offers a neuroendocrine perspective on growth regulation, with important implications for understanding the brain's role in regulating growth and development.

Diurnal and Daily Variations in Growth Hormone and Growth Hormone Stimulation Test in Male Cynomolgus Monkeys.

Yasunori Taniguchi, Tetsuya Yoshikawa, Tomonobu Yamada +1 more

Growth hormone (GH) secretion patterns differ across species. Humans exhibit a nocturnal surge, while rodents exhibit ultradian pulses. In cynomolgus monkeys, diurnal and daily variations and responsiveness to exogenous GH-releasing hormone (GHRH) remain insufficiently defined in non-clinical studies. This study aimed to characterize GH secretion patterns and evaluate responsiveness to exogenous GHRH in adult male cynomolgus monkeys for pituitary toxicity studies.

The Role of Growth Hormone-Releasing Hormone and the Hypothalamic-Pituitary-Somatotropic Axis in Aging: Potential Therapeutic Applications and Risks.

Ioannis Oikonomakos, Richard Siow, Stefan R Bornstein +1 more

Aging is marked by a gradual decline in multiple physiological functions, increasing the risk of age-related disorders. Multiple factors have been identified as contributors to aging, many of which are regulated by the hypothalamus. Growth hormone-releasing hormone (GHRH) produced in the hypothalamus is a key regulator of growth hormone (GH) secretion. With aging, both GHRH and GH levels decline, leading to muscle loss, increased fat accumulation, metabolic dysregulation, and cognitive impairments. GH replacement therapy has been explored as a potential intervention to counteract these effects; however, its long-term use is associated with significant risks, including metabolic disturbances, cardiovascular complications, and potential cancer promotion. In contrast, studies suggest that GHRH-based therapies can improve body composition, muscle strength, cognitive function, and cardiovascular health while avoiding the risks linked to direct GH administration. Additionally, preclinical findings indicate that GHRH agonists may offer cardioprotective and immunomodulatory benefits. In this review, we summarize current knowledge on the roles of GHRH and GH in aging, highlight the limitations of GH-based therapies, and discuss the potential of GHRH-based approaches in mitigating age-related decline and improving health span.

The Influence of Different Light Spectra on Broiler Chicken Endocrine Systems and Productivity.

Lenuța Galan, Gheorghe Solcan, Carmen Solcan

In birds, light can penetrate the cranial bones and reach deep brain regions, where non-visual photoreceptors, especially in the hypothalamus, detect spectral and photoperiodic cues. Alongside retinal photoreception, deep-brain light sensing contributes to circadian entrainment and regulates melatonin secretion by the pineal gland. These light-driven pathways modulate endocrine activity, playing a key role in muscle development. This review explores how monochromatic light-emitting diode (LED) illumination, particularly green and blue wavelengths, affects the somatotropic axis (growth hormone-releasing hormone [GHRH]-growth hormone [GH]-insulin-like growth factor 1 [IGF-1]), the gonadal axis (gonadotropin-releasing hormone [GnRH]-luteinizing hormone [LH]/follicle-stimulating hormone [FSH]-sex steroids [testosterone, estrogen, progesterone]), the thyroid axis (thyrotropin-releasing hormone [TRH]-thyroid-stimulating hormone [TSH]-thyroxine [T4]/triiodothyronine [T3]), and the hypothalamic-pituitary-adrenal (HPA) axis (corticotropin-releasing hormone [CRH]-adrenocorticotropic hormone [ACTH]-corticosterone). Green light enhances early-stage muscle growth via GHRH and IGF-1 upregulation, while blue light supports later myogenic activity and oxidative balance. Light schedules also influence melatonin dynamics, which in turn modulate endocrine axis responsiveness to photic cues. Furthermore, variations in photoperiod and exposure to artificial lights at night (ALAN) affect thyroid activity and HPA axis reactivity, influencing metabolism, thermoregulation, and stress resilience. Together, ocular and intracranial photoreception form a complex network that links environmental light to hormonal regulation and muscle growth. These insights support the strategic use of LED lighting to optimize broiler performance and welfare.

Growth hormone in disease and treatment (Review).

Saikat Fakir, Md Matiur Rahman Sarker, Madan Sigdel +1 more

Growth hormone (GH) is a peptide hormone produced by the anterior pituitary gland, which regulates growth and development. Abnormal levels of GH have been associated with a diverse variety of disorders affecting life quality and longevity; including dwarfism, acromegaly, gigantism and cancer. Based on the fact that growth hormone-releasing hormone (GHRH) and somatostatin exert opposing effects on the regulation of GH, GHRH antagonists (GHRHAnts) and synthetic somatostatin analogs (SSAs) have been developed to alleviate GH-related illness. The present study provides information on the multifaceted role of GH in human health and disease. Furthermore, it summarizes recent findings on the protective effects of GHRHAnts and FDA-approved SSAs, such as octreotide, lanreotide and pasireotide, in GH-related and endothelium-dependent dysfunctions. Based on the provided bibliography, an emerging body of evidence suggests that GH modulators may represent a promising therapeutic possibility towards blood brain barrier dysregulation, keratitis, direct and indirect lung injury, sepsis, and acute respiratory distress syndrome.

Growth Hormone and IGF-1 Actions in the Brain and Neuropsychiatric Diseases.

Manuel H Aguiar-Oliveira, Margaret C S Boguszewski, Diego L Rovaris +1 more

Growth hormone (GH) is secreted by the anterior pituitary gland under the control of hypothalamic neuroendocrine neurons that express somatostatin or growth hormone-releasing hormone (GHRH). Ghrelin, originating primarily in the stomach, is also an important GH secretagogue. GH stimulates the hepatic secretion of insulin-like growth factor-1 (IGF-1) and the expression of IGF-1 in extrahepatic tissues, including the brain. Many regions of the brain express receptors for GH, IGF-1, and ghrelin. In recent decades, evidence from both human and animal studies has indicated that GH, IGF-1, and ghrelin regulate numerous brain functions. Alterations in the secretion or sensitivity to these hormones may represent risk factors for developing neurodegenerative diseases (e.g., Alzheimer's and Parkinson's) and neuropsychiatric conditions (such as depression, anxiety, posttraumatic stress disorder, schizophrenia, and bipolar disorder). Additionally, classical neurodevelopmental disorders such as autism spectrum and attention-deficit hyperactivity disorders may also be influenced by somatotropic hormones. This review aims to summarize and discuss the emerging role of GH and IGF-1 in influencing brain function and the predisposition to brain diseases and neuropsychiatric disorders.

The Mystery Actor in the Neuroendocrine Theater: Who Really Knows Obestatin? Central Focus on Hypothalamic-Pituitary Axes.

Michał Szlis, Anna Wójcik-Gładysz, Alina Gajewska +1 more

The available literature data indicate that obestatin, a peptide derived from the preproghrelin precursor, may modulate neuroendocrine function, particularly in appetite regulation and somatotrophic/gonadotrophic pathways. This review synthesizes animal studies assessing the influence of obestatin on central neuroendocrine systems. Obestatin has been shown to affect the hypothalamic appetite-regulating center through neuropeptides such as neuropeptide Y and agouti-related peptide, yet findings remain inconsistent between species. In rodents, its effects on food intake and energy balance are inconclusive, whereas sheep models demonstrate significant alterations in orexigenic gene expression and peptide immunoreactivity. Regarding the somatotrophic axis, obestatin showed no significant effect on growth hormone (GH) secretion in rodents; however, in sheep, it modulated growth hormone-releasing hormone and somatostatin mRNA expression, elevated pituitary GH synthesis, and increased circulating GH levels. Studies involving the gonadotrophic axis demonstrated the presence of obestatin in Leydig and pituitary cells, with in vitro evidence suggesting its ability to modulate intracellular pathways implicated in gonadoliberin, luteinizing hormone, and follicle-stimulating hormone release. The collective findings discussed in this article indicate that obestatin interacts with multiple hypothalamic-pituitary axes, though its effects vary depending on species and experimental conditions. This review highlights the complexity of obestatin's central actions and the need for further research to elucidate its functional relevance in neuroendocrine regulation.

Ectopic GHRH production: revisiting a rare cause of acromegaly.

Matheo A M Stumpf, Nathalie Oliveira Santana, Marcio Carlos Machado +5 more

Growth Hormone-Releasing Hormone (GHRH) is a hypothalamic hormone that stimulates GH secretion by the anterior pituitary gland. Ectopic production of GHRH by neuroendocrine tumors (NETs) is a rare cause of acromegaly, with some clinical and biochemical features indistinguishable from pituitary adenoma origin. Some clues for this diagnosis include pituitary MRI harboring hyperplasia, increased serum GHRH and extra-pituitary tumor detected in whole body scans. The preferable treatment, when possible, should be surgical resection of the NET. In cases with residual tumor, somatostatin analogs could be used as an alternative for adjuvant therapy for both tumoral and biochemical control of IGF-1. Life-long follow-up is needed as some patients may develop persistent pituitary hyperplasia or GH-adenomas due to prolonged GHRH exposure, with elevated IGF-1 levels even without NET recurrence. In such scenarios, medical therapy should be provided for hyperplasia cases and transsphenoidal surgery to patients with pituitary adenoma. If available, genetic test for MEN1 mutations should always be performed.

High fat diet-induced loss of pituitary plasticity in aging female mice with ablated leptin signaling in somatotropes.

Tiffany K Miles, Angela K Odle, Stephanie D Byrum +7 more

Somatotropes lacking leptin receptors (LEPR) produce less growth hormone and are poorly responsive to growth hormone releasing hormone (GHRH). Transcriptomic analysis reveals that the mutant somatotropes contain progenitor cell markers (Sox9+) and multiple pituitary hormone transcripts-(Pomc, Prl, Lhb, Tshb and Cga), suggesting that the cells are progenitor cells. The resulting GH deficiency contributes to adult-onset obesity in the mutant, due to an increase in abdominal fat.

One Case of Sudden Isolated Adrenocorticotropic Hormone (ACTH) Deficiency Diagnosed Based on Repeated Hypoglycemic Attacks.

Tomohide Sato

Our patient is a 28-year-old male who was being treated by a local doctor for Hashimoto's thyroiditis. Four days prior to admission, nausea and diarrhea appeared, and it gradually became difficult for him to eat. The night before admission, his level of consciousness decreased (Japan Coma Scale (JCS) II-20), and he was rushed to the hospital. His other vital signs were stable. After completing a detailed examination, the cause was diagnosed as hypoglycemia with a blood glucose level of 21 mg/dl. After the administration of glucose, he regained consciousness and became alert, allowing him to return home, with the expectation that he would return to the hospital for a follow-up visit at a later date. However, an altered consciousness (JCS I-3) appeared again the next morning. Similar to the previous day, the cause of the altered consciousness was determined to be hypoglycemia. After making a detailed inpatient examination, his early morning fasting serum cortisol level was found to be less than 0.1 μg/dL, and his blood adrenocorticotropic hormone (ACTH) was 3.1 pg/mL, thus indicating decreases in both. After performing rapid ACTH testing, almost no increase in the serum cortisol levels was observed after 30 minutes and 60 minutes following ACTH administration, thus suggesting the presence of adrenal insufficiency. According to a contrast-enhanced CT of the abdomen, atrophy of both adrenal glands was observed; however, there was no macroadenoma or the like according to the contrast-enhanced MRI of the brain. Based on the results of the ACTH continuous load test, triple anterior pituitary stimulation test with corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone (GnRH), growth hormone-releasing peptide-2 (GHRP-2) load test, and insulin hypoglycemic load test, no abnormalities were found in his pituitary functions other than ACTH-cortisol, and no history of trauma or adenoma lesions, leading to a diagnosis of a sudden isolated ACTH deficiency. The patient has remained stable with no hypoglycemic episodes since treatment with hydrocortisone was initiated. Based on the fact that isolated ACTH deficiency is often associated with a complication of autoimmune endocrine disease, an autoimmune mechanism has been speculated. Although the disease is rare, it is an important disease that affects the quality of life (QOL) of patients, and it should therefore be considered when making a differential diagnosis.

Growth hormone-releasing hormone receptor (GHRH-R) and its signaling.

Gabor Halmos, Zsuzsanna Szabo, Nikoletta Dobos +2 more

The hypothalamic polypeptide growth hormone-releasing hormone (GHRH) stimulates the secretion of growth hormone (GH) from the pituitary through binding and activation of the pituitary type of GHRH receptor (GHRH-R), which belongs to the family of G protein-coupled receptors with seven potential membrane-spanning domains. Various splice variants of GHRH-R (SV) in human neoplasms and other extrapituitary tissues were demonstrated and their cDNA was sequenced. Among the SVs, splice variant 1 (SV1) possesses the greatest similarity to the full-length GHRH-R and remains functional by eliciting cAMP signaling and mitogenic activity upon stimulation by GHRH. In this review, we briefly discuss the activation, regulation, molecular mechanisms and signaling pathways of GHRH-Rs and their SVs in various tissues and also summarize the expression, biological activities and potential function of GHRH, its analogs and their receptors. A large body of work have extensively studied and evaluated potential clinical applications of agonists and antagonists of GHRH in diverse fields, including oncology, endocrinology, obesity, diabetes, other metabolic dysfunctions, cardiology, immune functions, mood disorders, Alzheimer's and lung disease, ophthalmology, inflammation, wound healing and other applications. These results strongly support the potential therapeutic use of GHRH analogs in human medicine in the near future.

The diagnosis of GH deficiency in adult β-thalassemic patients: are two different stimulation tests necessary to improve specificity?

Daniele Sola, Mirna Solange Barrio Lower Daniele, Leila Danesi +6 more

β-thalassemia major (βTM) frequently leads to endocrinological complications of chronic transfusion-induced iron overload, including growth hormone deficiency (GHD). With contrasting data on GHD in adult βTM populations, our study aimed to reevaluate the diagnosis of GHD using multiple tests and its progression over time.

A 50-year journey in the development of treatment for benign prostatic hyperplasia.

Andrew V Schally, George Theodoropoulos, Wei Sha +2 more

Recent research underscores the crucial role of hormone regulation in benign prostatic hyperplasia (BPH) and the therapeutic promise of growth hormone-releasing hormone (GH-RH) antagonists. BPH incidence in aging men doubled over three decades, driven by prostatic enlargement and lower urinary tract symptoms (LUTS). Aging-related changes in GH-RH and luteinizing hormone-releasing hormone (LH-RH) biology promote BPH through hormonal and inflammatory processes. Traditional therapies provide symptomatic relief but often fail to prevent progression. This review explores the 50-year extensive development of LH-RH and GH-RH peptide analogs from discovery to delivery and their potential in BPH treatment. In preclinical studies, GH-RH antagonists reduced prostate volume, improved LUTS, and modulated inflammation mediated by NF-κB and IGF-I. Clinical trials are needed to validate antagonist efficacy and safety. Given BPH's public health impact among the aged, and especially among aging Veterans, integrating GH-RH antagonists into management strategies may offer precision-based therapeutic advancements.

Mice with Heterozygous Deletion of Exon 3 in the Gh Gene Demonstrate Growth Retardation Caused by Reduced Ghrhr mRNA.

Daisuke Ariyasu, Daisuke Higa, Ryo Tokudome +4 more

Isolated Growth Hormone Deficiency Type 2 (IGHD2) is caused by a heterozygous splice site variant in intron 3 of the GH1 gene. The resulting exon 3-skipped growth hormone (Δ3 GH), produced from the mutated allele, exerts a dominant-negative effect, leading to growth hormone (GH) deficiency. However, the precise molecular mechanisms underlying this effect remain poorly understood. While several model murine models expressing human Δ3 GH have been developed, no IGHD2 mouse models featuring variants in the endogenous Gh gene currently exist. We generated a mouse model (Gh+/Δ3) with a heterozygous deletion of exon 3 in the Gh gene using CRISPR/Cas9 system. The Gh+/Δ3 model exhibited GH deficiency caused by a dominant-negative effect at the mRNA level, characterized by reduced Gh mRNA expression. This mechanism parallels findings in our previous humanized IGHD2 mouse model, where the deficiency was driven by decreased Ghrhr mRNA expression. Transcriptome analysis of the pituitary revealed widespread downregulation of mRNAs encoding membrane and secretory proteins. The dominant-negative effect of Δ3 GH in IGHD2 is mediated by properties of Δ3 GH that are conserved across both humans and mice. This mechanism involves the downregulation of mRNAs, including those encoding membrane and secretory proteins, such as Ghrhr mRNA.

Benchmark for Setting ACTH Cell Dosage in Clinical Regenerative Medicine for Post-Operative Hypopituitarism.

Tatsuma Kondo, Hidetaka Suga, Kazuhito Takeuchi +6 more

Our objective is to develop hormone-producing pituitary cells that can function in the same manner as the human body and provide more effective treatments than current hormone replacement therapy. We have already established a technique for generating hypothalamic-pituitary organoids using feeder-free human pluripotent stem cells (hPSCs) and demonstrated their effectiveness in vivo through transplantation into hypopituitary mouse models. To prospectively determine the upper limit of transplanting adenohypophyseal cells into humans, we investigated the human maximum secretion capacity of adrenocorticotropic hormone (ACTH) and growth hormone (GH).

GH-Releasing Hormone Neurons Regulate the Hypothalamic-Pituitary-Somatotropic Axis via Short-Loop Negative Feedback.

Daniela O Gusmao, Maria E de Sousa, Ligia M M de Sousa +5 more

Growth hormone (GH)-releasing hormone (GHRH) neurons are master regulators of GH secretion. However, the role of these cells in controlling pituitary GH secretion through short-loop negative feedback has not yet been fully clarified. Thus, GHRH-specific GH receptor (GHR) knockout (GHRHΔGHR) mice were generated, and possible consequences on GH secretion and body growth were determined. Approximately 60% of arcuate nucleus GHRH neurons exhibited GH-induced STAT5 phosphorylation, a marker of GHR-expressing cells. This response was practically eliminated in GHRHΔGHR mice. GHR ablation in GHRH-expressing cells increased body weight, lean mass, and naso-anal length in male and female mice without affecting fat mass. The higher body growth of GHRHΔGHR mice was associated with increases in GH secretion, mainly via higher pulsatile GH secretion and GH pulse amplitude. GHRHΔGHR female mice also showed increased GH pulse frequency and basal (non-pulsatile) secretion compared to control females. Liver Igf1 expression was increased only in GHRHΔGHR male mice. Mice carrying ablation of the insulin-like growth factor-1 (IGF-1) receptor (IGF1R) or both GHR and IGF1R in GHRH-expressing cells were generated. The increases in body growth and serum IGF-1 levels were significantly higher in GHRHΔGHR/IGF1R mice compared to GHRHΔGHR mice but similar to levels observed in GHRHΔIGF1R mice. Electrophysiological experiments showed no acute changes in the activity of GHRH neurons after GH or IGF-1 exposure. In conclusion, GH feeds back on GHRH cells to control the hypothalamic-pituitary-somatotropic axis. However, IGF1R signaling prevails over GHR as the primary signal sensed by GHRH neurons to regulate GH secretion.