HGH Injections For Sale

Alzheimers revelation: How the brain disease was spread between humans via a growth hormone given to children in the UK up until 1985  The Olive Press

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Alzheimers revelation: How the brain disease was spread between humans via a growth hormone given to children in the UK up until 1985 - The Olive...

GH is a single chain protein with 191 amino-acids and two disulfide bonds. The human GH gene is located on chromosome 17q22 as part of a locus that comprises five genes. In addition to two GH related genes (GH1 that codes for the main adult growth hormone, produced in the somatotrophic cells found in the anterior pituitary gland and, to a minor extent, in lymphocytes, and GH2 that codes for placental GH), there are three genes coding for chorionic somatomammotropin (CSH1, CSH2 and CSHL) (also known as placental lactogen) genes (2,3). The GH1 gene encodes two distinct GH isoforms (22 kDa and 20 kDa). The principal and most abundant GH form in the pituitary and blood is the monomeric 22K-GH isoform, representing also the recombinant GH available for therapeutic use (and subsequently for doping purposes) (3). Administration of recombinant 22K-GH exogenously leads to a decrease in the 20K-GH isoform, and thus testing both isoforms is used to detect GH doping in sports (4).

As already mentioned, GH is secreted by the somatotroph cells located primarily in the lateral wings of the anterior pituitary. A recent single cell RNA sequencing study performed in mice showed that GH-expressing cells, representing the somatotrophs, are the most abundant cell population in the adult pituitary gland (5). The differentiation of somatotroph cell is governed by the pituitary transcription factor 1 (Pit-1). Data in mice suggest that the pituitary holds regenerative competence, the GH-producing cells being regenerated form the pituitarys stem cells in young animals after a period of 5 months (6).

The morphological characteristics and number of somatotrophs are remarkably constant throughout life, while their secretion pattern changes. GH secretion occurs in a pulsatile fashion, and in a circadian rhythm with a maximal release in the second half of the night. So, sleep is an important physiological factor that increases the GH release. Interestingly, the maximum GH levels occur within minutes of the onset of slow wave sleep and there is marked sexual dimorphism of the nocturnal GH increase in humans, constituting only a fraction of the total daily GH release in women, but the bulk of GH output in men (7).

GH secretion is also gender-, pubertal status- and age- dependent ( and ) (8). Integrated 24h GH concentration is significantly greater in women than in men and greater in the young than in older adults. The serum concentration of free estradiol, but not free testosterone, correlates with GH, and when correcting for the effects of estradiol, neither gender nor age influence GH concentration. This suggests that estrogens play a crucial role in modulating GH secretion (8). During puberty, a 3-fold increase in pulsatile GH secretion occurs that peaks around the age of 15 years in girls and 1 year later in boys (9).

The secretory pattern of GH in young and old female and male. In young individuals the GH pulses are larger and more frequent and that female secrete more GH than men (modified from (8)).

Pituitary synthesis and secretion of GH is stimulated by episodic hypothalamic hormones. Growth hormone releasing hormone (GHRH) stimulates while somatostatin (SST) inhibits GH production and release. GH stimulates IGF-I production which in turn inhibits GH secretion at both hypothalamic and pituitary levels. The gastric peptide ghrelin is also a potent GH secretagogue, which acts to amplify hypothalamic GHRH secretion and synergize with its pituitary GH-stimulating effects () (10). Interestingly, recently germline or somatic duplication of GPR101 has been shown to constitutively activate the cAMP pathway in the absence of a ligand, leading to GH release. Although the precise physiology of GPR101 is unclear, it is worth mentioning it since it clearly has an effect on GH pathophysiology (11).

In addition, a multitude of other factors may impact the GH axis, most probably due to interaction with GRHR, somatostatin, and ghrelin. Estrogens stimulate the secretion of GH, but inhibit the action of GH on the liver by suppressing GH receptor (GHR) signaling. In contrast, androgens enhance the peripheral actions of GH (12). Exogenous estrogens potentiate pituitary GH responses to submaximal effective pulses of exogenous GHRH (13) and mute inhibition by exogenous SST (14). Also, exogenous estrogen potentiates ghrelins action (15).

GH release correlates inversely with intraabdominal visceral adiposity via mechanisms that may depend on increased free fatty acids (FFA) flux, elevated insulin, or free IGF-I.

Factors that stimulate and suppress GH secretion under physiological conditions.

GHRH is a 44 amino-acid polypeptide produced in the arcuate nucleus of the hypothalamus. These neuronal terminals secrete GHRH to reach the anterior pituitary somatotrophs via the portal venous system, which leads to GH transcription and secretion. Moreover, animal studies have demonstrated that GHRH plays a vital role in the proliferation of somatotrophs in the anterior pituitary, whereas the absence of GHRH leads to anterior pituitary hypoplasia (16). In addition, GHRH up-regulates GH gene expression and stimulates GH release (17). The secretion of GHRH is stimulated by several factors including depolarization, 2-adrenergic stimulation, hypophysectomy, thyroidectomy and hypoglycemia, and it is inhibited by SST, IGF-I, and activation of GABAergic neurons.

GHRH acts on the somatotrophs via a seven trans-membrane G protein-coupled stimulatory cell-surface receptor. This receptor has been extensively studied over the last decade leading to the identification of several important mutations. Point mutations in the GHRH receptors, as illustrated by studies done on the lit/lit dwarf mice, showed a profound impact on subsequent somatotroph proliferation leading to anterior pituitary hypoplasia (18). Unlike the mutations in the Pit-1 and PROP-1 genes, which lead to multiple pituitary hormone deficiencies and anterior pituitary hypoplasia, mutations in the GHRH receptor lead to profound GH deficiency with anterior pituitary hypoplasia. Subsequent to the first GHRH receptor mutation described in 1996 (19), an array of familial GHRH receptor mutations have been recognized over the last decade. These mutations account for almost 10% of familial isolated GH deficiencies. An affected individual will present with short stature and a hypoplastic anterior pituitary. However, they lack certain typical features of GH deficiency such as midfacial hypoplasia, microphallus, and neonatal hypoglycemia (20).

SST is a cyclic peptide, encoded by a single gene in humans, which mostly exerts inhibitory effects on endocrine and exocrine secretions. Many cells in the body, including specialized cells in the anterior paraventricular nucleus and arcuate nucleus, produce SST. These neurons secrete SST into the adenohypophyseal portal venous system, via the median eminence, to exert effects on the anterior pituitary. SST has a short half-life of approximately 2 minutes as it is rapidly inactivated by tissue peptidase in humans.

SST acts via a seven trans-membrane, G protein coupled receptor and, thus far, five subtypes of the receptor have been identified in humans (SSTR1-5). Although all five receptor subtypes are expressed in the human fetal pituitary, the adult pituitary only expresses 4 subtypes (SSTR1, SSTR2, SSTR3, SSTR5). Of these four subtypes, somatotrophs exhibit more sensitivity to SSTR2 and SSTR5 ligands in inhibiting the secretion of GH in a synergistic manner (21). Somatostatin inhibits GH release but not GH synthesis.

Ghrelin is a 28 amino-acid peptide that is the natural ligand for the GH secretagogue receptor. In fact, ghrelin and GHRH have a synergistic effect in increasing circulating GH levels (7). Ghrelin is primarily secreted by the stomach and may be involved in the GH response to fasting and food intake.

With the introduction of dependable radioimmunological assays, it was recognized that circulating GH is blunted in obese subjects, and that normal aging is accompanied by a gradual decline in GH levels (22,23). It has been hypothesized that many of the senescent changes in body composition and organ function are related to or caused by decreased GH (24), also known as "the somatopause".

Studies carried out in the late 90s have uniformly documented that adults with severe GH deficiency are characterized by increased fat mass and reduced lean body mass (LBM) (25). It is also known that normal GH levels can be restored in obese subjects following massive weight loss (26), and that GH substitution in GH-deficient adults normalizes body composition. What remains unknown is the cause-effect relationship between decreased GH levels and senescent changes in body composition. Is the propensity for gaining fat and losing lean mass initiated or preceded by a primary age-dependent decline in GH secretion and action? Alternatively, accumulation of fat mass secondary to non-GH dependent factors (e.g. life style, dietary habits) results in a feedback inhibition of GH secretion. Moreover, little is known about possible age-associated changes in GH pharmacokinetics and bioactivity.

Cross-sectional studies performed to assess the association between body composition and stimulated GH release in healthy subjects show that adult people (mean age 50 yr) have a lower peak GH response to secretagogues (clonidine and arginine), while females had a higher response to arginine when compared to males. Multiple regression analysis, however, reveal that intra-abdominal fat mass is the most important and negative predictor of peak GH levels, as previously mentioned (27). In the same population, 24-h spontaneous GH levels also predominantly correlated inversely with intra-abdominal fat mass () (28).

Correlation between intra-abdominal fat mass and 24-hour GH secretion.

A detailed analysis of GH secretion in relation to body composition in elderly subjects has, to our knowledge, not been performed. Instead, serum IGF-I has been used as a surrogate or proxy for GH status in several studies of elderly men (29-31). These studies comprise large populations of ambulatory, community-dwelling males aged between 50-90 yr. As expected, the serum IGF-I declined with age (), but IGF-I failed to show any significant association with body composition or physical performance.

Changes in serum IGF-I with age; modified from (32).

Considering the great interest in the actions of GH in adults, surprisingly few studies have addressed possible age-associated differences in the responsiveness or sensitivity to GH. In normal adults the senescent decline in GH levels is paralleled by a decline in serum IGF-I, suggesting a down-regulation of the GH-IGF-I axis. Administration of GH to elderly healthy adults has generally been associated with predictable, albeit modest, effects on body composition and side effects in terms of fluid retention and modest insulin resistance (33). Whether this reflects an unfavorable balance between effects and side effects in older people or the employment of excessive doses of GH is uncertain, but it is evident that older subjects are not resistant to GH. Short-term dose-response studies clearly demonstrate that older patients require a lower GH dose to maintain a given serum IGF-I level (34,35), and it has been observed that serum IGF-I increases in individual patients on long-term therapy if the GH dosage remains constant. Moreover, patients with GH deficiency older than 60 years are highly responsive to even a small dose of GH (36). Interestingly, there is a gender difference response to GH treatment with men being more responsive in terms of IGF-I generation and fat loss during therapy, most probably due to lower estrogen levels that negatively impact the GH effect on IGF-I generation in the liver (37).

The pharmacokinetics and short-term metabolic effects of a near physiological intravenous GH bolus (200g) were compared in a group of young (30 year) and older (50 year) healthy adults (38). The area under the GH curve was significantly lower in older subjects, whereas the elimination half-life was similar in the two groups, suggesting both an increased metabolic clearance rate and apparent distribution volume of GH in older subjects. Both parameters showed a strong positive correlation with fat mass, although multiple regression analysis revealed age to be an independent positive predictor. The short-term lipolytic response to the GH bolus was higher in young as compared to older subjects. Interestingly, the same study showed that the GH binding proteins correlated strongly and positively with abdominal fat mass (39).

A prospective long-term study of normal adults with serial concomitant estimations of GH status and adiposity would provide useful information about the cause-effect relationship between GH status and body composition as a function of age. In the meantime, the following hypothesis is proposed (): 1. Changes in life-style and genetic predispositions promote accumulation of body fat with aging; 2. The increased fat mass, leads to increased FFA availability, and induces insulin resistance and hyperinsulinemia; 3. High insulin levels suppress IGF binding protein (IGFBP)-1 resulting in a relative increase in free IGF-I levels; 4. Systemic elevations of FFA, insulin and free IGF-I suppress pituitary GH release, which further increases fat mass; 5. Endogenous GH is cleared more rapidly in subjects with a high amount of fat tissue.

At present it is not justified to treat the age-associated deterioration in body composition and physical performance with GH especially due to concern that the ensuing elevation of IGF-I levels may increase the risk for the development of neoplastic disease (For an extensive discussion of GH in the elderly see the chapter on this topic in the Endocrinology of Aging section of Endotext).

Hypothetical model for the association between low GH levels and increased visceral fat in adults.

A real-life model for GH effects in human physiology is represented by patients with life-long severe reduction in GH signaling due to GHRH or GHRH receptor mutations, combined deficiency of GH, prolactin, and TSH, or global deletion of GHR. They show short stature, doll facies, high-pitched voices, and central obesity, and are fertile (40). Despite central obesity and increased liver fat, they are insulin sensitive, partially protected from cancer and present a major reduction in pro-aging signaling and perhaps increased longevity (41). The decrease of cancer risk in life-long GH deficiency together with reports on the permissive role of GH for neoplastic colon growth (42), pre-neoplastic mammary lesions (43), and progression of prostate cancer (44) demands, at least, a careful tailoring of GH substitution dosage in the GH deficient patients.

Although the majority of data on the relation between GH and the immune system are from animal studies, it seems that GH may possess immunomodulatory actions. Immune cells, including several lymphocyte subpopulations, express receptors for GH, and respond to its stimulation (45). GH stimulates in vitro T and B-cell proliferation and immunoglobulin synthesis, enhances human myeloid progenitor cell maturation, and modulates in vivo Th1/Th2 (8) and humoral immune responses (46). It has been shown that GH can induce de novo T cell production and enhance CD4 recovery in HIV+ patients. Another study with possible clinical relevance showed that sustained GH expression reduced prodromal disease symptoms and eliminated progression to overt diabetes in mouse model of type 1 diabetes, a T-cellmediated autoimmune disease. GH altered the cytokine environment, triggered anti-inflammatory macrophage (M2) polarization, maintained activity of the suppressor T-cell population, and limited Th17 cell plasticity (46). JAK/STAT signaling, the principal mediator of GHR activation, is well-known to be involved in the modulation of the immune system, so is tempting to assume that GH may have a role too, but clear data in humans are needed.

GHR signaling is a separate and prolific research field by itself (47), so this section will focus on recent data obtained in human models.

GHRs have been identified in many tissues including fat, lymphocytes, liver, muscle, heart, kidney, brain and pancreas (48,49). Activation of receptor-associated Janus kinase (JAK)-2 is the critical step in initiating GH signaling. One GH molecule binds to two GHR molecules that exist as preformed homodimers. Following GH binding, the intracellular domains of the GHR dimer undergo rotation, which brings together the two intracellular domains each of them binding one JAK2 molecule. This, in turn, induces cross-phosphorylation of tyrosine residues in the kinase domain of each JAK2 molecule followed by tyrosine phosphorylation of the GHR (48,50). Phosphorylated residues on GHR and JAK2 form docking sites for different signaling molecules including signal transducers and activators of transcription (STAT) 1, 3, 5a and 5b. STATs bound to the activated GHR-JAK2 complex are subsequently phosphorylated on a single tyrosine by JAK2 allowing dimerization and translocation to the nucleus, where they bind to DNA and activate gene transcription. A STAT5b binding site has been characterized in the IGF-I gene promoter region (51). Attenuation of JAK2-associated GH signaling is mediated by a family of cytokine-inducible suppressors of cytokine signaling (SOCS) (52). SOCS proteins bind to phosphotyrosine residues on the GHR or JAK2 and suppress GH signaling by inhibiting JAK2 activity and competing with STATs. For example, it has been reported that the inhibitory effect of estrogen on hepatic IGF-I production seems to be mediated via up regulation of SOCS-2 (53).

Data on GHR signaling derive mainly from rodent models and experimental cell lines, although GH-induced activation of the JAK2/STAT5b and the mitogen activated protein kinase (MAPK) pathways have been recorded in cultured human fibroblasts from healthy human subjects (54). STAT5b in human subjects is critical for GH-induced IGF-I expression and growth promotion as demonstrated by the identification of mutations in the STAT5b gene of patients presenting with severe GH insensitivity in the presence of a normal GHR (55). Activation of GHR signaling in vivo has been reported in healthy young male subjects exposed to an intravenous GH bolus vs. saline (56). Significant tyrosine phosphorylation of STAT5b was recorded after GH exposure at 30-60 minutes in muscle and fat biopsies, but there was no evidence of GH-induced activation of PI 3-kinase, Akt/PKB, or MAPK (56).

GH impairs the insulin mechanism but the exact mechanisms in humans are still a matter of debate. There is no evidence of a negative effect of GH on insulin binding to the receptor (57,58), which obviously implies post-receptor metabolic effects.

There is animal and in vitro evidence to suggest that insulin and GH share post-receptor signaling pathways (59). Convergence has been reported at the levels of STAT5 and SOCS3 (60) as well as on the major insulin signaling pathway: insulin receptor substrates (IRS) 1 and 2, PI 3-kinase (PI3K), Akt, and extracellular regulated kinases (ERK) 1 and 2 (61-63). Studies in rodent models suggest that the insulin-antagonistic effects of GH in adipose involve suppression of insulin-stimulated PI3-kinase activity (59,64). In 2001 it was demonstrated that GH induces cellular insulin resistance by uncoupling PI3K and its downstream signals in 3T3-L1 adipocytes (65)]. A follow up study has shown that GH increased p85 expression and decreased PI3K activity in adipose tissue of mice, supporting the previous report of a direct inhibitory effect of GH on PI3K activity (64). However, a study performed in healthy human skeletal muscle showed, as expected, that the infusion of GH induced a sustained increase in FFA levels and subsequently insulin resistance as assessed by the euglycemic clamp technique, but was not associated with any change in the insulin-stimulated increase in either IRS-1/PI3K or PKB/Akt activity (66). It was subsequently showed that insulin had no impact on GH-induced STAT5b activation or SOCS3 mRNA expression (67).

Because GH and insulin share some common intracellular substrates, a hypothesis arose claiming that competition for intracellular substrates explains the negative effect of GH on insulin signaling (59). Furthermore, studies have shown that SOCS proteins negatively regulate the insulin signaling pathway (68). Therefore, another possible mechanism by which GH alters the action of insulin is by increasing the expression of SOCS genes.

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Normal Physiology of Growth Hormone in Adults - Endotext - NCBI Bookshelf