Health ConditionsGrowth Hormone (GH) is a master regulator hormone produced in somatotroph cells and plays a major role in somatic development. Human growth hormone (hGH) is composed of 191 amino acids. The observed effects of GH are mediated in part via a growth factor initially labelled "somatomedin" and subsequently identified as insulin-like growth factor (IGF-1). However, recent evidence suggests that not all actions of GH are mediated by IGF-1, and many factors other than GH contribute to the expression of serum IGF-1, including nutritional state, liver function, serum protease activity, IGF-1 binding proteins, and sex hormones.
Human growth hormone is synthesized and secreted in a pulsatile manner by somatotrophs located in the anterior pituitary. Following the successful isolation and purification of hGH in 1944, GH secretion in humans has been heavily studied. Serum levels of hGH vary considerably over the course of the day and during the night as it is dependent on a variety of factors including the circadian rhythm, sleep–wake cycle, diet, metabolism, age, and sex.
In mammals, the neuroendocrine system, which includes the communication between the hypothalamus and the pituitary, plays a major role in controlling body growth and cellular metabolism. GH produced from the pituitary somatotroph is considered the master regulator of somatic development and is involved, directly and indirectly, in carbohydrate and lipid metabolism via complex, yet well-defined, signaling pathways. GH production from the pituitary gland is primarily regulated by the counter-regulatory effects of the hypothalamic GHRH and somatostatin (SST) hormones.
Regulatory factors include GH releasing hormone (GHRH), somatostatin, GH releasing peptide (ghrelin), and IGF-1. GH secretion is controlled by short and long negative feedback loops. Both GH (short-loop feedback) and insulin-like growth factor 1 (IGF-1; long-loop feedback) can target somatotropic cells of the pituitary gland and neuroendocrine hypothalamic neurons to regulate the GH/IGF-1 axis.
At the cellular level, human GH binds to GH receptor (GHR) molecules and induces signal transduction through receptor dimerization. When GHRH interacts with its corresponding transmembrane domains on somatotropic (GH-producing) cells, a G protein-mediated interaction with ion channels causes an increase in intracellular cAMP accumulation, which ultimately promotes GH release from secretory granules.
Ghrelin, a 28 amino acid acylated peptide predominantly produced by the stomach, displays strong growth hormone-releasing activity mediated by the hypothalamus-pituitary GH secretagogue receptors. It also acts on other central and peripheral receptors and exhibits other actions, including stimulation of lactotroph and corticotroph secretion, orexigenic effects, influences on gastroenteropancreatic functions, and has metabolic, cardiovascular and antiproliferative effects.
GH and IGF-1 play an important role in the maintenance of normal body composition, by exerting both anabolic and catabolic actions on different tissues in the human body, with overall stimulatory effects on protein synthesis in muscle and lipolysis in adipose tissue.
Disorders of the GH/IGF-1 system result either from GH hypersecretion (gigantism, acromegaly) or GH deficiency.
The deficiency of growth hormone is an endocrine disorder that may be isolated or associated with other pituitary hormone deficiencies. Growth hormone deficiency occurs in both children and adults. As the Endocrine Society indicates, childhood-onset GHD may be triggered by organic causes, or it can be idiopathic, with an unknown cause.
GHD has been associated with neuropsychiatric-cognitive, cardiovascular, neuromuscular, metabolic, and skeletal abnormalities. Patients with GHD frequently complain of low energy levels, emotional lability, and mental fatigue, resulting in a low perceived quality of life.
IGF-1 deficiency throughout childhood causes dwarfism (final height if untreated, 100–135 cm in female and 110–142 cm in male patients), with an abnormally high upper to lower body ratio.
In acromegaly, GH hypersecretion occurs despite elevated insulin-like growth factor-I (IGF-I) levels, implying defective IGF-I feedback. This interaction has clinically significant implications as it may at least partly explain the phenotypes of acromegaly and adult GH deficiency and the effects that treatment of these conditions has on body composition.
There are four isolated GHD (IGHD) types, differentiated by their clinical spectrum, inheritance pattern, and associated genetic factors. Two IGHD subtypes are caused by GH1 and GHRHR gene defects. A wide variety of mutations in genes encoding transcription factors involved in pituitary development have been reported, such as HESX1, OTX2, SOX2, SOX3, LHX3, PITX2, PROP1, POU1F1 and TCF7L1.
Pituitary tumors are the commonest cause for adult GHD (AGHD). Traumatic brain injury (6–20%) and subarachnoid hemorrhage (12–37%) may result in GHD more frequently than previously suspected.
Growth hormone secretion—either spontaneous or evoked by provocative stimuli—is markedly disrupted in obesity. The alterations of the GH/IGF-1 axis in obesity are characterized by the decrease in the half-life of GH along with a reduction in both frequency and amplitude of GH secretory bursts. These phenomena are associated with an increased GH metabolic clearance rate, which at the end results in low plasma GH levels.
Furthermore, dysregulation of GHRH, somatostatin, ghrelin pathways, and hyperinsulinemia contribute to blunting GH secretion in obesity.
Circulating IGF-1 values were lower in obese patients than in controls, while circulating GH and IGF-1 values increased significantly over time after bariatric surgery.
During the process of aging there is a gradual decrement and alteration in the pattern and production of GH secretion and IGF-1, respectively. Age, nutrition, and body composition are also related to the amount and pattern of GH secretion in humans.
The regulation of growth hormone secretion in humans is a complex process. Although GHRH and somatostatin are the primary regulators of GH secretion, they most likely function as the final pathway through which numerous factors influence GH synthesis and secretion. Some of the modulators of GH secretion include neurotransmitters, circulating glucose, insulin-like growth factor I, and gonadal steroid concentrations.
After 24-hour fasting, plasma GH on average increased by 5-fold, confirming previous studies showing equivalent increases in GH. The increased GH concentration during prolonged fasting is likely caused by higher frequency and amplitude of GH secretion, which may play a role in the prevention of protein breakdown and loss of lean mass during famine.
Typically, hGH secretion peaks shortly after sleep onset during the slow-wave sleep stage of non-rapid eye movement sleep. Sleep deprivation can result in the suppression of hGH nocturnal peaks, where increases in GH secretion can occur during the day as a way to compensate.
Several in vivo and ex vivo studies have shown that the GH-IGF-I system inhibits the expression and activity of 11β-HSD1 in adipose tissues and the liver, resulting in reduced local regeneration of cortisol.
Scientific Evidence: A systematic review and meta-analysis aimed to review the effects of L-arginine supplementation alone and combined with GHRH in different doses on GH secretion. The electronic literature search was conducted on Medline/PubMed, Scopus, and Web of Science. All eligible studies were randomized clinical trials. Meta-analyses showed significant effects of arginine alone on GH release (MD = 10.07, 95% CI: 7.87, 12.28). Moreover, the response of GH was greater with arginine in combination with GHRH (MD = 24.96, 95% CI: 17.51, 32.42). There was no significant difference between patients and healthy individuals and between oral and injection use of arginine.
In GH-deficient individuals, high doses of arginine supplementation in combination with GHRH and/or other amino acids might have potential therapeutic effects on increasing GH concentrations. These findings propose that arginine supplementation can be considered as a potential stimulator in management of GH deficiency.
Importantly, oral arginine shows more modest effects than intravenous administration. One study reported that subjects supplemented with 7 g of L-arginine orally for 7 days showed no significant alteration in the levels of GH and IGF-1 at the end of the supplementation period in adults, illustrating that the evidence is mixed and context-dependent.
Scientific Evidence: A study was carried out in 15 male volunteers to evaluate qualitatively the secretion of growth factors following stimulation by oral amino acids. The results showed that oral administration of a combination of two amino acids (1200 mg L-lysine plus 1200 mg L-arginine) provoked a release of pituitary somatotropin and insulin. This phenomenon was reproducible and the growth hormone secreted in response had biological activity. The effect appeared to be specific to the combination of the two amino acids; neither of the amino acids demonstrated appreciable stimulating activity when administered alone at the same doses. This is an older small study; evidence remains preliminary.
Scientific Evidence: Plasma concentrations of GH increase 2 to 4.5-fold higher in comparison with controls following oral ingestion of glutamine or arginine, or a combination. The mechanistic literature notes that glutamine may contribute indirectly: in the small intestine, glutamine is converted into citrulline, which in turn triggers the synthesis of arginine, an amino acid shown to release growth hormone in some studies. Moreover, glutamine is converted into glutamate, which can directly enhance growth hormone secretion. Evidence is largely from small acute studies and mechanistic proposals; long-term clinical evidence is limited.
Scientific Evidence: Preclinical studies have found L-ornithine to act as an indirect growth hormone secretagogue and enhance the activity of its main effector molecule, IGF-1. In clinical trials, course treatment with L-ornithine L-aspartate as an add-on to standard therapy increased the levels of circulating growth hormone, promoted arm muscle growth, improved handgrip strength and standing balance. L-ornithine alpha-ketoglutarate increased appetite and skeletal muscle gain in malnourished older adults, mitigated glutamine loss by skeletal muscle following major surgery, and improved quality of life in elderly convalescent subjects. Evidence is primarily from specific clinical populations (surgical, malnourished) and should be interpreted cautiously for healthy adults.
Scientific Evidence: Oral administration of the amino acid and inhibitory neurotransmitter gamma aminobutyric acid (GABA) reportedly elevates resting serum growth hormone concentrations. A randomized, double-blind, placebo-controlled crossover study enrolled 11 resistance-trained men (aged 18–30 years). During each experimental bout, participants ingested either 3 g of GABA or a sucrose placebo, followed either by resting or resistance exercise sessions. Fasting venous blood samples were acquired at multiple time points. At rest, GABA ingestion elevated both immunoreactive GH and immunofunctional GH compared with placebo. The data indicate that ingested GABA elevates resting and post-exercise immunoreactive GH and immunofunctional GH concentrations. The physiological significance and long-term implications remain unclear.
Scientific Evidence: Melatonin, a signaling molecule secreted by the pineal gland, is closely associated with physiological activities such as animal growth, development, and reproduction. Multiple studies have indicated that melatonin acts on the adenohypophysis to promote the synthesis and secretion of growth hormone (GH).
There is evidence that melatonin plays a role in the regulation of GH secretion. One human study investigated the neuroendocrine mechanisms by which melatonin modulates GH secretion, assessing the effect of oral melatonin on the GH responses to GHRH administration and comparing the effects of melatonin with those of pyridostigmine, a cholinergic agonist drug which likely suppresses hypothalamic somatostatin release. Prior melatonin administration approximately doubled the GH release induced by supramaximal or submaximal doses of GHRH. This was a small, controlled mechanistic study in normal adult males; findings are considered preliminary and most evidence remains at the in vitro or animal level for the specific mechanism.
Scientific Evidence: Controversy exists about the effect of zinc on growth and the GH-IGF system. Zinc supplementation has been shown to stimulate linear growth in zinc-deficient children. However, the mechanism of this effect has not been well characterized. The relationship between zinc and GH is best established in the context of frank deficiency, not supplementation beyond adequacy. Evidence quality is moderate for deficiency states and weak for healthy, replete individuals.
Traditional Use: Deer antler velvet (DAV), obtained from the male deer, is commonly used in traditional Asian medicine and has been valued for centuries for its various health benefits. Hailing from Traditional Chinese Medicine, velvet antler has been used for preventative health purposes.
Scientific Evidence: IGF-1 is one of several growth factors present in deer antler velvet. As a dietary supplement, deer antler velvet is often marketed as a "natural" source of various growth factors, including IGF-1, with claims that it can enhance athletic performance, strength, and endurance. However, it is unclear what substances are retained once the velvet is removed from the antler, dried, and formulated as a supplement. Although deer antler velvet is marketed for a variety of health benefits, there is no scientific evidence to support any of these claims.
IGF-1 is an anabolic molecule that appears to induce growth of the antlers themselves, although testosterone may be the primary growth factor. Currently there is no evidence that serum IGF-1 is increased following velvet antler ingestion; one study using 1.5 g of velvet antler for 11 weeks failed to increase serum IGF-1. Additionally, 1 g of velvet antler taken daily for 12 weeks in otherwise healthy adult men failed to significantly alter serum LH more than placebo. The overall evidence for velvet antler's effect on human GH or IGF-1 is currently negative or absent.
Traditional Use: Mucuna pruriens has a long history of use in Ayurvedic medicine, where the seeds (known as Kapikacchu) were traditionally prepared as a powder or decoction for conditions including nervous system support and vitality. Its seeds contain naturally occurring L-DOPA (levodopa), the precursor to dopamine.
Scientific Evidence: HP-200, a formulation made from the seed powder of Mucuna pruriens, contains among other constituents about 4% L-DOPA, and its potential connection to GH involves dopaminergic stimulation of GHRH release. However, direct human clinical evidence specifically demonstrating significant, sustained GH elevation from Mucuna pruriens supplementation in healthy adults has not been established in high-quality peer-reviewed studies and should be considered preliminary or theoretical at this time.
Derangements of the somatotropic axis are associated with a worse cardiometabolic profile in people with obesity. A high adherence to the Mediterranean diet—and in particular protein intake—was associated with a better GH status. This cross-sectional study in 200 women with severe obesity found that dietary pattern, not just calorie intake, predicted GH axis function.
GH is a metabolic hormone which stimulates lipolysis and influences catecholamine and insulin functions. It maintains blood glucose levels by reducing carbohydrate metabolism. GH also plays a role in protein synthesis through the release of IGF-1.
Because GH secretion is suppressed by elevated insulin, dietary patterns that produce sustained hyperinsulinemia — particularly those high in refined carbohydrates — may blunt GH pulsatility. Dysregulation of GHRH, somatostatin, ghrelin pathways, and hyperinsulinemia contribute to blunting GH secretion in obesity. The evidence supports that glycemic control is relevant to somatotropic axis health, although direct intervention trials reducing refined sugar and measuring GH outcomes are limited.
The increase in growth hormone secretion during a prolonged fast stimulates lipolytic rate, thereby augmenting the mobilization of endogenous energy at a time when fuel availability is very low.
After 24-hour fasting, plasma GH on average increased by 5-fold. The increased GH concentration during prolonged fasting is likely caused by higher frequency and amplitude of GH secretion, which may play a role in the prevention of protein breakdown and loss of lean mass during famine.
Regarding IGF-1, the picture is more nuanced. Total pooling of fasting and energy restriction randomized controlled trials in weighted mean difference analysis revealed no significant effect on circulating IGF-1 levels (WMD: −16.41 ng/ml, 95% CI: −35.88, 3.07). This suggests that acute fasting raises GH acutely, but sustained caloric restriction does not reliably elevate IGF-1, and may even reduce it.
GH is secreted in a pulsatile fashion, with the strongest physiologic stimuli being sleep and exercise. Research examined the combined effect of arginine (7 g) and resistance exercise on the GH response in healthy young males. Arginine alone resulted in a significant GH response (2-fold increase) over the placebo day, while exercise alone stimulated a 5-fold increase, highlighting that exercise is a dominant physiological stimulus for GH secretion.
Typically, hGH secretion peaks shortly after sleep onset during the slow-wave sleep stage of non-rapid eye movement sleep. The major secretory GH pulse occurs just after sleep onset and continues to rise during the first 4 hours.
Sleep deprivation can alter hypothalamus and pituitary function, which de-synchronizes GH release timing. During complete sleep deprivation of 24–36 hours, GH release is attenuated and in some cases absent.
The alterations of the GH/IGF-1 axis in obesity are characterized by a decrease in the half-life of GH along with a reduction in both frequency and amplitude of GH secretory bursts. These phenomena are associated with an increased GH metabolic clearance rate, resulting in low plasma GH levels. A worse cardiovascular risk profile and body composition with increased cardiometabolic consequences has been detected in obese individuals with low GH status compared to obese individuals without impairments in the somatotropic axis.
5-HTP (a serotonin precursor) has been shown in clinical studies to significantly increase GH release via serotoninergic pathways. A 1977 JCEM study (Lancranjan et al.) found a significant GH increase (p < 0.01) 30–120 minutes after IV 5-HTP infusion in both men and women, with a mean peak of 32.0 ± 8.8 ng/mL. Oral 5-HTP (200 mg) also demonstrated significant GH elevation in a clinical study in healthy adults.
Alpha-ketoglutarate (AKG), a key Krebs cycle intermediate, is a component of OKG and has been studied for its role in amino acid metabolism and anabolic hormone (including GH) secretion. As part of OKG, AKG contributes to the compound's established GH-stimulating properties. AKG's independent role in GH secretion is based partly on its metabolic precursor relationship to arginine and glutamine, which are documented GH secretagogues.
L-arginine is a well-established stimulant of pituitary growth hormone secretion, acting by suppressing endogenous somatostatin. AAKG's arginine moiety shares this property; acute arginine supplementation has been shown in RCTs to modestly increase GH levels. A 2022 systematic review and meta-analysis confirmed significant GH release with arginine supplementation alone.
D-aspartic acid accumulation in the anterior pituitary (adenohypophysis) has been shown in animal studies to stimulate secretion of growth-hormone releasing hormone (GHRH) and consequently growth hormone (GH). In vivo animal injection studies confirm D-Asp induces GH release. This mechanistic link is documented but direct human clinical trials specifically measuring GH endpoints after DAA supplementation are absent.
A clinical study in sprinters and long-distance runners demonstrated that creatine supplementation significantly increased GH levels after 6 weeks. Creatine is proposed to support GH indirectly through enhanced exercise performance and acute metabolic effects that stimulate pituitary GH release. This study and supporting references are cited in authoritative nutrition sources including Healthline and Examine.com.
D-Asp has been observed in animal and in vitro studies to stimulate growth hormone (GH) release from the pituitary gland. This is part of its broader neuroendocrine signaling role, acting upstream via hypothalamic GnRH stimulation and directly at the pituitary. Human clinical data specifically measuring GH responses to DAA supplementation are limited.
Multiple clinical trials have demonstrated that oral GABA supplementation (3 g) significantly elevates resting and post-exercise GH concentrations. A randomized double-blind crossover study (Powers et al., 2008, PMID 18091016) in 11 resistance-trained men found significant increases in immunoreactive and immunofunctional GH at rest and augmented exercise-induced GH. A 12-week RCT (Sakashita et al., JOCMR, 2019) showed elevated resting plasma GH at 4 and 8 weeks and greater fat-free mass gains with GABA plus whey vs. whey alone.
Multiple human clinical studies confirm that glycine infusion (4–12 g IV) produces dose-dependent increases in serum GH in normal subjects. Oral administration also demonstrated stimulatory effects. A 1978 study (Kasai et al., Metabolism) and a 1981 study (Baudry et al.) both showed significant GH elevation, with glycine described as 'one of the stimulatory agents inducing the pituitary gland to secrete hGH.'
GPC reliably stimulates growth hormone (GH) secretion in human studies. The mechanism involves ACh-mediated catecholamine release that amplifies pituitary GH response, particularly to exercise and GHRH. Effects have been demonstrated in both young and older adults.
L-arginine is the most extensively studied nutritional GH secretagogue. It suppresses endogenous somatostatin release from the hypothalamus, disinhibiting pituitary GH output. A 2022 systematic review and meta-analysis (PMC9712012) of randomized clinical trials found a significant mean GH increase (MD = 10.07 µg/L, 95% CI: 7.87–12.28) with arginine alone, with even greater responses when combined with GHRH. Oral doses of ~10 g have produced modest but statistically significant GH elevations in resting adults.
An early clinical study found that a 2 g oral dose of L-glutamine transiently elevated GH levels by up to 78% in healthy subjects. A randomized double-blind trial using a mixture of glycine, glutamine, and niacin increased serum GH by ~70% vs. placebo over 3 weeks in middle-aged adults. L-glutamine is thought to act via hypothalamic and pituitary pathways to stimulate GH secretion.
Oral glycine administration acutely stimulates pituitary growth hormone (GH) secretion in a dose-dependent manner. A bolus of 22.5 g has been reported to cause a ~60% surge in GH levels within minutes. Smaller doses of 4–12 g also raise serum GH in a dose-dependent fashion, per early pharmacological studies.
L-lysine, especially when combined with L-arginine, has been shown in clinical studies to significantly increase GH secretion in resting subjects. One study of 15 healthy males found that the combination of arginine pyroglutamate and L-lysine significantly elevated GH compared to either amino acid alone. Lysine alone at lower doses (1,200 mg) did not reliably raise GH, but synergistic effects with arginine are documented.
L-ornithine is an amino acid that has been shown to augment post-exercise GH levels. A 2010 clinical study found that L-ornithine (100 mg/kg) administered 30 minutes after exercise produced a significantly greater GH peak compared to controls. L-ornithine is also a component of OKG, which has documented GH-stimulating activity in clinical nutritional studies.
Melatonin, the pineal gland hormone, is documented in multiple clinical studies to stimulate GH secretion in humans. A 1993 Clinical Endocrinology RCT (Valcavi et al.) showed oral melatonin (10 mg) approximately doubled GHRH-stimulated GH release and increased basal GH through pathways involving somatostatin suppression. Exogenous oral melatonin at both 0.5 mg and 5.0 mg has been shown to produce significant increases in plasma GH concentrations.
Ornithine alpha-ketoglutarate (OKG), a salt of two ornithine molecules and one alpha-ketoglutarate molecule, has been associated with GH and insulin secretion in enteral and parenteral nutrition studies. When fed enterally to trauma and burn patients, OKG significantly increased both IGF-1 and GH levels. Its anabolic mechanism involves generating glutamine and arginine, both of which are independent GH secretagogues.
Dopamine stimulates growth hormone (GH) secretion from the anterior pituitary via hypothalamic GHRH and dopamine receptors. L-DOPA (the active principle in MP) has been documented in clinical pharmacology studies to stimulate GH secretion in humans, a mechanism used in GH stimulation testing. A blend of MP and Chlorophytum borivilianum in exercise-trained men raised serum GH. However, direct RCTs using MP alone for GH augmentation are limited.
Zinc has documented effects on the GH–IGF-1 axis. Clinical trials in prepubertal children show that zinc supplementation raises serum IGF-1 and IGFBP-3 levels. The effect is most pronounced in zinc-deficient populations and with doses ≤10 mg/day over more than 8 weeks. Zinc appears to act downstream of GH secretion, directly stimulating IGF-1 production rather than altering pituitary GH output.
Anterior pituitary glandular supplements have been traditionally theorized to support growth hormone output, based on the gland's role as the exclusive source of endogenous GH. Early glandular therapy texts and contemporary naturopathic sources cite this application. Human clinical data for the oral supplement form are absent.
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