Growth Hormone (GH) is an important peptide hormone secreted by the anterior pituitary. Through GHR–JAK2–STAT5 signaling and the GH–IGF-1 axis, it regulates linear growth, skeletal and muscle development, lipid mobilization, and glucose metabolism. GH research requires simultaneous consideration of pulsatile secretion, receptor function, secondary IGF-1 effects, and tissue-specific responses.

Keywords: Growth Hormone; GH; GHR; JAK2–STAT5; IGF-1; growth plate; metabolic regulation

1 GH Secretion and Physiological Regulation

1.1 Source and Molecular Characteristics of GH

GH is mainly synthesized and secreted by Somatotrophs in the anterior pituitary, and approximately 22 kDa GH is the major circulating form in humans. GH is a protein hormone that initiates intracellular signaling through the cell-surface Growth Hormone Receptor (GHR). Its physiological functions include linear growth during childhood and adolescence as well as regulation of body composition, protein metabolism, lipid metabolism, and glucose homeostasis in adulthood.

1.2 Hypothalamic–Pituitary Regulation of GH

(1) GHRH-Mediated Secretory Signaling

Growth Hormone-Releasing Hormone (GHRH) is produced by the hypothalamus and activates Gs–Adenylyl Cyclase–cAMP–PKA signaling through the GHRH receptor on pituitary Somatotrophs, thereby promoting GH synthesis and release. GHRH is an important secretagogue controlling GH pulse amplitude and pituitary secretory reserve.

(2) Somatostatin-Mediated Inhibitory Signaling

Somatostatin inhibits Somatotroph secretory activity through Somatostatin receptors and, together with GHRH, forms an excitatory–inhibitory regulatory system for GH secretion. Periodic changes in the strength of Somatostatin inhibition participate in the generation of GH pulses and restrict excessive GH release.

(3) Ghrelin/GHSR Signaling

Ghrelin promotes GH release through the Growth Hormone Secretagogue Receptor (GHSR) and links energy status and gastrointestinal signals with the GH axis. Ghrelin and GHRH act through different receptors and proximal signaling mechanisms, and the two can jointly enhance the GH secretory response of Somatotrophs.

1.3 Pulsatile Secretion and Feedback Regulation

GH shows pronounced pulsatile secretion, and its circulating levels are influenced by sleep, age, sex, nutritional status, exercise, stress, and other factors. GH promotes IGF-1 production in the liver and peripheral tissues, and IGF-1 further participates in hypothalamic–pituitary negative feedback. Therefore, random-time-point GH concentration, GH secretion rhythm, and relatively stable IGF-1 levels represent information from different levels of the GH axis.

2 GHR and Its Signal Transduction Mechanisms

2.1 Receptor Characteristics of GHR

Growth Hormone Receptor belongs to the class I cytokine receptor family and is expressed in multiple tissues including the liver, bone, cartilage, skeletal muscle, and adipose tissue. GHR does not possess intrinsic tyrosine kinase activity. GH binding induces receptor conformational changes, activates receptor-associated JAK2, and initiates downstream signal transduction.

2.2 Classical JAK2–STAT5 Signaling

(1) JAK2 Activation

The intracellular region of GHR forms a signaling complex with JAK2. After GH stimulation, JAK2 is activated and promotes tyrosine phosphorylation of GHR and related signaling proteins, providing the basis for STAT recruitment and activation. Therefore, p-JAK2 is an important indicator for evaluating proximal GHR function.

(2) STAT5-Mediated Transcriptional Regulation

Both STAT5A and STAT5B can participate in GH signaling, with STAT5B being particularly important for GH-mediated growth and metabolic transcriptional regulation. After phosphorylation, STAT5 enters the nucleus and regulates expression of IGF1, SOCS2, and other GH-responsive genes.

(3) Signaling Negative Feedback

GH stimulation can induce expression of Suppressor of Cytokine Signaling proteins such as SOCS2, which subsequently restrict the duration of JAK2–STAT5 signaling. SOCS-mediated feedback allows short pulsatile stimulation and sustained GH exposure to generate different intracellular signaling states.

2.3 PI3K–AKT and MAPK Signaling

GH can also affect signaling networks such as PI3K–AKT and RAS–RAF–MEK–ERK and participate in regulation of cell survival, proliferation, and metabolism. Because IGF-1 and Insulin can also markedly affect AKT and ERK, detection of p-AKT or p-ERK alone is insufficient to determine the source of an effect. Analysis should be combined with p-STAT5, GHR/JAK2 blockade, and stimulation time windows.

Table 1 Major Signaling Nodes of the GH–GHR Pathway

3 GH–IGF-1 Axis

3.1 Liver-Derived IGF-1

After GH activates GHR–JAK2–STAT5 signaling in hepatocytes, IGF1 expression is promoted, and liver-derived IGF-1 enters the circulation and participates in systemic growth regulation. Circulating IGF-1 is more stable than instantaneous GH concentrations, although its level is also influenced by age, nutritional status, and other endocrine factors.

3.2 Local IGF-1

Tissues such as bone, cartilage, and skeletal muscle can produce local IGF-1. Therefore, GH-mediated growth effects include both direct GHR actions and effects mediated by local tissue IGF-1. Tissue growth does not depend entirely on liver-derived circulating IGF-1, and local GH–IGF-1 regulation is important for the growth plate, muscle, and bone tissues.

3.3 IGF1R Signaling

IGF-1 mainly acts through IGF1R. IGF1R is a receptor tyrosine kinase that can promote cell growth, survival, and protein synthesis through IRS–PI3K–AKT and RAS–MAPK signaling. Therefore, secondary IGF-1 signaling induced by GH can intersect with AKT/MAPK effects directly activated by GHR.

3.4 IGFBP Regulation

Circulating IGF-1 forms a regulatory system with IGF-binding proteins (IGFBPs) and Acid-Labile Subunit (ALS), influencing IGF-1 stability, half-life, and tissue availability. Therefore, total IGF-1 concentration can reflect GH-axis output but cannot fully represent the actual intensity of local IGF1R signaling.

4 Regulation of Growth and Development by GH

4.1 Growth Plate Cartilage

(1) Chondrocyte Proliferation and Differentiation

GH affects cell proliferation, maturation, and matrix formation through GHR on growth-plate chondrocytes and local IGF-1. Chondrocytes in the resting, proliferative, and hypertrophic zones are at different developmental stages, and the GH–IGF-1 axis promotes endochondral ossification by coordinating these cell populations.

(2) Linear Growth

Longitudinal growth of long bones depends on continuous production and maturation of chondrocytes by the growth plate. GH deficiency during childhood and adolescence can reduce growth velocity, whereas sustained GH excess before epiphyseal closure can cause abnormal linear growth. Therefore, bone length and growth-plate structure are important in vivo indicators for evaluating GH-mediated growth effects.

4.2 Bone Remodeling

GH and IGF-1 can influence osteoblast function, bone matrix formation, and bone turnover and act together with sex hormones, PTH, vitamin D, and mechanical loading to maintain bone homeostasis. After epiphyseal closure, GH no longer drives normal linear growth but can continue to influence bone mass and bone remodeling.

4.3 Skeletal Muscle

GH participates in nitrogen retention, protein metabolism, and maintenance of muscle tissue, with its effects involving both direct GH signaling and IGF-1-mediated pathways. Skeletal muscle protein synthesis is also regulated by Insulin, amino acid supply, and mechanical loading. Therefore, changes in muscle mass need to be interpreted using multiple levels of indicators.

5 Metabolic Effects of GH

5.1 Lipid Mobilization

GH can promote lipid mobilization in adipose tissue and increase the release of free fatty acids and Glycerol. Lipolysis is an important component of GH metabolic effects in adults. Experimental evaluation can combine FFA, Glycerol, adipose tissue mass, and lipid-droplet morphology to distinguish lipid mobilization from overall body-weight changes.

5.2 Glucose Homeostasis

Sustained or relatively high GH levels can reduce Insulin sensitivity in some tissues and affect glucose homeostasis through fatty acid supply, hepatic glucose metabolism, and peripheral substrate utilization. Although GH and Insulin intersect at signaling nodes such as AKT, their overall metabolic effects are not equivalent.

5.3 Protein Metabolism

GH promotes amino acid utilization, nitrogen retention, and protein metabolism and participates together with IGF-1 in tissue growth. These effects are influenced by Insulin, energy status, and amino acid availability. Therefore, in vitro GH studies need to control the background of culture medium, serum, and nutritional components.

6 GH Axis Dysfunction

6.1 GH Deficiency

GH deficiency can result from abnormalities of the hypothalamus, pituitary, or GH synthesis and secretion. During childhood, it mainly manifests as reduced growth velocity and restricted linear growth, whereas in adulthood it more commonly involves changes in body composition, bone metabolism, and lipid metabolism. Evaluation of the GH axis should combine IGF-1 and dynamic secretion information rather than relying solely on random GH concentrations.

6.2 GH Excess

Sustained GH excess can chronically activate GHR and the GH–IGF-1 axis. Before epiphyseal closure, it mainly manifests as abnormal linear growth, whereas after epiphyseal closure it mainly produces Acromegaly-related skeletal, soft-tissue, and metabolic changes and may be accompanied by reduced Insulin sensitivity.

6.3 GH Insensitivity

Abnormalities in GH insensitivity mainly occur downstream of GH secretion and include defects in GHR expression, receptor function, or JAK2–STAT5 signaling. Such conditions can show normal or elevated GH with insufficient IGF-1 output. Therefore, GH, GHR, STAT5, and IGF-1 need to be evaluated together.

7 Differences Among GH, IGF-1, and Insulin Signaling

7.1 GH and IGF-1

GH first acts on GHR and uses JAK2–STAT5 as its typical proximal pathway, whereas IGF-1 mainly acts on IGF1R and produces effects through IRS–PI3K–AKT and MAPK. Although the two have a clear upstream–downstream relationship, GH still has direct actions independent of circulating IGF-1.

7.2 GH and Insulin

Insulin mainly promotes glucose uptake, glycogen synthesis, and lipid storage, whereas GH in the adult metabolic environment enhances lipid mobilization and reduces Insulin sensitivity in some tissues. Both can affect AKT-related signaling, so a single p-AKT readout is insufficient to determine the final metabolic effect.

7.3 Determination of Signal Origin

When GH stimulation induces changes in p-STAT5, p-AKT, and p-ERK, p-STAT5 more closely reflects classical proximal GHR function, whereas AKT and ERK may be influenced by both direct GH effects and secondary IGF-1 signaling. Combining GHR/JAK2 and IGF1R blockade conditions can improve the specificity of signal-source determination.

8 Key Experimental Designs for GH Research

8.1 Evaluation of GHR Function

GH receptor functional experiments can use recombinant GH or Somatropin for concentration-gradient stimulation and detect p-JAK2 and p-STAT5 to establish concentration–response relationships. When GHR expression or functional abnormalities are involved, total GHR, membrane GHR, and downstream STAT5 responses should be analyzed simultaneously to distinguish insufficient receptor expression from signal-transduction defects.

8.2 Signaling Time Windows

(1) Proximal Phosphorylation

JAK2 and STAT5 phosphorylation are rapid signaling events and should be evaluated using short stimulation times to establish dynamic curves. Excessively late detection may underestimate actual GHR activity because of signal attenuation and SOCS-mediated feedback.

(2) Transcriptional Responses

Target genes such as IGF1 and SOCS2 require longer periods to develop clear expression changes and should be evaluated separately from early p-JAK2/p-STAT5 experiments. Using different time windows for proximal phosphorylation and subsequent transcriptional output helps resolve the sequence of GH signaling.

8.3 Deconvolution of GH and IGF-1 Effects

(1) Parallel Stimulation

GH, IGF-1, and Vehicle conditions can be established to separately observe STAT5, AKT, and ERK responses and define the basic signaling characteristics of GHR and IGF1R. GH stimulation is generally more appropriately evaluated together with p-STAT5, whereas IGF-1 stimulation focuses on IGF1R–AKT/MAPK output.

(2) Blockade Validation

JAK2- or GHR-related blockade can be used to validate direct GH signaling, whereas IGF1R inhibition can determine the contribution of secondary IGF-1. If AKT responses after prolonged GH stimulation are affected by IGF1R blockade, this can further support the presence of an IGF-1-mediated component.

8.4 In Vivo Phenotype Evaluation

Depending on the experimental objective, GH animal studies can simultaneously record body length, bone length, Lean Mass, Fat Mass, serum IGF-1, Glucose, Insulin, and related indicators. Because GH shows pronounced temporal rhythms and sex differences, sampling time, age, sex, and nutritional status should be kept consistent.

9 GH-Related Research Products

9.1 GH, GHR, and Upstream Secretory Regulation Products

9.2 Somatostatin and GH–IGF-1 Axis-Related Products

9.3 JAK2–STAT5 Signaling and Quantitative Detection Products for the GH Axis

The core of GH research is to distinguish hormone secretion, direct GHR signaling, and secondary IGF-1 effects. Combining proximal GHR–JAK2–STAT5 responses, the GH–IGF-1 axis, and tissue growth and metabolic phenotypes can establish a relatively complete system for evaluating GH function.

For more related articles, please see below:

[1] Biological functions of somatostatin and its receptors

[2] Applications of Endocrinology/Hormones in Metabolic Regulation, Reproductive Function, and Disease Research