Growth hormone (GH) is a 191 amino acid single-chain polypeptide secreted by somatotroph cells in the anterior pituitary gland [1]. Its name can be misleading as it suggests that its role is exclusively for promotion of postnatal growth since researchers originally discovered it to be responsible for growth advancement and regulation during childhood and adolescence [2]. Nevertheless, it is now known for nearly 90 years that GH exerts ‘anti-insulin’ effects, and less commonly known, some ‘insulinlike’ actions that modulates glucose homeostasis [3]. There is also increasing evidence that GH plays an important role in extracellular matrix (ECM) remodeling and fibrosis formation [4]. While the GH role in normally stimulating mitosis, cell differentiation, and growth has been progressively established, it has been suggested that it might be a contributor to carcinogenesis [5]. The Ecuadorian Laron and Brazilian Itabaianinha cohorts with congenital mutations in the growth hormone receptor (GHR) and growth hormone-releasing hormone (GHRH) receptor, respectively, provide a unique and arguably the purest models to evaluate the non-growth promoting effects of GH and insulin-like growth factor I (IGF-I). Intriguingly, despite their obese phenotype, these individuals display decreased risk of insulin resistance and type 2 diabetes mellitus (T2DM), normal cardiovascular risk, diminished incidence of cancer and, possibly, extended lifespan compared to local controls [6–11]. Herein, we review three important inter-related GH actions which have been reported in animal and human studies on key body functions, including glucose metabolism, fibrosis and cancer, and explore the possibility that varying GH levels, whether excessive, insufficient or aberrantly expressed GH action, might contribute to the development of commonly encountered age-related diseases such as T2DM, cardiovascular disease and cancer, ultimately, influencing longevity.

Almost 90 years ago, Houssay [3] first described the phenomenon of insulin hypersensitivity in hypophysectomized animals. Since then, other researchers have been intrigued by this phenomenon and have attempted to define the role of the GH/IGF-I axis on glucose metabolism. Early animal and human studies have shown that GH injection exerts both acute and chronic effects on glucose metabolism. The acute effects of GH injection are more of ‘insulin-like,’ as demonstrated in hypophysectomized animals, hypopituitary subjects, and in children with idiopathic GH deficiency (GHD) [12,13].

Using the human forearm as an experimental model, Rabinowitz et al. [14] described the physiologic and pathophysiologic interaction between the effects of GH and glucose metabolism on muscle and adipose tissue. These investigators found that intra-arterial administration of insulin alone increased skeletal muscle glucose uptake but abrogated the regional release of free fatty acids (FFA) from adipose tissue. By contrast, GH alone stimulated the release of FFA from adipose tissue and its uptake into muscle and decreased glucose uptake. Daughaday and Kipnis [15] then demonstrated early ‘insulin-like’ effects of GH following intravenous GH administration; however, this early effect was followed by an increase in non-esterified fatty acid levels reflecting the induction of lipolysis, and subsequently generation of insulin resistance in a time-dependent manner. In addition to the forearm model and using comparable methodologies, Moller et al. [16] found that muscle insulin resistance developed within 2 hours as evidenced by decreased glucose infusion rates and impaired forearm glucose uptake, along with decreased insulin-induced suppression of hepatic glucose output. In the same study, GH infusion also increased circulating levels of lipid intermediates and the forearm uptake of FFA. Nevertheless, these lipolytic effects were delayed compared with the immediate effects of GH on glucose fluxes. This temporal distinction suggests that GH initially alters glucose metabolism, via IGF-I, followed by its direct net effects on lipid metabolism at a later stage [17]. The overall chronic effects of GH can be characterized as ‘anti-insulin’ [12], and can be explained by the delayed lipolytic effects of chronic GH administration in decreasing adiposity and diminishing triglyceride accumulation [18]. Additionally, using the euglycemic, hyperinsulinemic clamp technique, Bratusch-Marrain et al. [19] demonstrated that intravenous GH infusions induced elevations in serum GH levels that generated impairment in hepatic and peripheral insulin sensitivity, and slightly mitigated the insulin suppressive effect of endogenous glucose production, suggesting that the primary site of insulin resistance resides in peripheral tissues.

Physiologically, during fasting when the liver is exposed to low intra-portal insulin levels, a state of hepatic GH resistance develops where GH levels increase and IGF-I levels decrease [20]. However, when insulin release is controlled with somatostatin, exogenous GH increases FFA levels [21], and when lipolysis is pharmacologically inhibited by acipimox, insulin sensitivity was shown to improve [22]. Alternatively, when partial suppression of GH action with a GHRH receptor antagonist is induced, lipolysis decreased resulting in increased insulin sensitivity [23]. During moderate intensity exercise in healthy subjects, normal physiological GH surge is mimicked, and FFA fluxes during and after exercise increase, whereas glucose and amino acid metabolism are unchanged [24]. Administration of high GH doses to athletes increases FFA levels and lipolysis in the basal state and in the peri-exercise period [25,26], whereas studies in adults with GHD have shown that withdrawal of GH for 3 months reduces FFA release during exercise [27]. Thus, the major metabolic effect of GH during moderate exercise appears to be caused by stimulation of lipolysis, and when high doses of GH are administered over a prolonged period, lipolysis prevails and protein oxidation decreases.

Conversely, in patients with type 1 diabetes mellitus (T1DM), especially when poorly controlled, hepatic GH resistance develops with increases in GH levels and decrease IGF-I levels [20] caused by the combination of negative nitrogen balance and intra-portal hypoinsulinemia [28,29]. When subjects with diabetes are optimally treated with insulin, modest amounts of GH serves as a beneficial metabolic regulator that preserves carbohydrate and protein at the expense of lipid consumption. Interestingly, low-dose GH replacement therapy for 6 months to hypopituitary patients with T1DM decreases asymptomatic hypoglycemic episodes despite increased insulin dosage requirements and unaltered glycemic control [30]. Additionally, antagonizing GH action with pegvisomant [31,32] and lowering GH levels by infusion of IGF-I in combination with insulin-like growth factor binding protein-3 (IGFBP-3) to T1DM patients similarly improves insulin sensitivity [33,34].

In adults with GHD, studies using GH doses generally exceeding 0.3 mg a day for 6–12 months induced worsening in glucose metabolism, whereas when GH treatment was continued for more than 12 months, these negative effects on glucose homeostasis parameters reversed and returned to baseline levels [35]. It has been postulated that the improvement of body composition and physical fitness with longer duration of GH therapy eventually outweighs its early negative effects on glucose metabolism, and that this temporal shift accounts for the attenuation of GH-related impairments in several measures of glucose homeostasis over time [36]. Based on these findings, clinical practice guidelines published by several professional societies have recommended using lower GH doses [37,38]. Indeed, several studies have reported that the administration of low GH doses (0.1 to 0.3 mg a day) improved insulin sensitivity in adults with GHD without inducing lipolysis seen with higher GH doses (Fig. 1) [39–41]. Conversely, acromegaly patients have increased FFA levels and other lipid intermediates along with increased lipid oxidation rates [42], despite compensatory hyper-insulinemia [42]. These patients also have decreased fat mass [43] and increased lean body mass [44] because of the direct GH antagonistic insulin effects and lipolysis generated by the excess chronic GH exposure.

Nevertheless, the exact molecular mechanisms of GH-induced insulin insensitivity remain elusive. Although GH does not directly regulate insulin receptor (IR) levels, and there is no direct interaction between the GHR and the IR, there are downstream signaling events following insulin and GH stimulation that may converge at a post-receptor level. GH promotes tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1) and IRS-2 proteins by activation of Janus kinase 2 (JAK2) [45,46], and like insulin, GH can stimulate phosphorylation of Shc [47], an adaptor protein that interacts with the IGF-I receptor and IR that activates the RAS-mitogen-activated protein kinase (MAPK) signaling pathway. GH is also known to activate the S6 kinase, p90RSK, most likely through MAPK [48]. Thus, the fact that both GHR and IR utilize some common signaling molecules might partly explain the anti-insulin effect of GH. Another mechanism by which GH can impair insulin sensitivity is by activating signal transducer and activator of transcription 5 (STAT5) and increasing the protein levels of suppressors of cytokine signaling (SOCS). In the liver, GH-mediated STAT5 activation is essential for normal hepatic function, and loss of this signaling pathway in mice has been reported to lead to enhanced peripheral and hepatic insulin sensitivity [49], suggesting that a key function of the normal GH/STAT5 pathway is to antagonize insulin action. This is achieved, in part, by inducing the expression of the SOCS proteins, whereby expression of SOCS-1, -3, and -6 has been shown to exert effects on insulin-induced IRS-1-p85 interactions and on activation of MAPK and protein kinase B (AKT) [50,51]. Additionally, SOCS-1–deficient mice develop a state of increased insulin sensitivity resulting in a prolonged IRS-1 phosphorylation following insulin treatment [52]. Conversely, adenoviral-driven expression of SOCS-1 in the liver of mice has been reported to result in a decrease in IRS-1 and -2 levels, leading to hyperglycemia, hyperinsulinemia and insulin resistance [53].

Gene deletion studies in mouse models have also provided important information for understanding the differential effects of IGF-I and GH on glucose metabolism. In an elegant study by Yakar et al. [54], these investigators used the liver IGF-I–deficient (LID) mouse model to understand the role of circulating IGF-I in glucose metabolism. These LID mice demonstrated a 75% reduction in circulating IGF-I levels, a 4-fold increase in GH levels and developed insulin resistance without significant increases in circulating FFA levels. At the age of 8 to 10 weeks, these LID mice showed increased insulin secretion and insulin insensitivity in muscle at the level of phosphorylation of the IR and post-receptor substrates. Treatment of LID mice with exogenous IGF-I inhibited GH and insulin secretion and improved insulin sensitivity. Inhibiting GH action by treating LID mice with a GHR antagonist improved insulin sensitivity, but this did not return to normal levels. These investigators then crossed the LID mice with GH antagonist transgenic mice to inactivate GH actions in the LID mice [55]. These dwarf mice demonstrated marked reductions in circulating IGF-I levels, increased FFA levels, and improved insulin sensitivity due to increased insulin-stimulated glucose uptake in the liver, muscle, and white adipose tissue. These data reveal that, despite low circulating IGF-I levels, insulin sensitivity in LID mice can be enhanced by inactivating GH action indicating that chronic elevation of GH levels plays an important role in promoting insulin resistance, whereas differentially, IGF-I is more involved in maintaining the fine balance between GH and insulin in modulating glucose metabolism and adipogenesis by initiating acute metabolic changes and safeguarding against hypoglycemia [56].

The term fibrosis refers to the development of fibrous connective tissue as a reparative response to injury or damage. The process of fibrosis is characterized by excessive ECM accumulation within tissues that occurs as a pathological process that can lead to organ dysfunction and failure [57,58]. The intricate relationship between GH and fibrosis and the excessive accumulation of fibrous connective tissue in response to injury, is multifaceted and context-dependent. A strong link exists between GH exposure and collagen production as evidenced by in vitro studies showing GH enhancement of collagen gene expression in various cell type studies which demonstrate higher collagen expression in GH-treated rodents [59,60]. Lach et al. [61] recently elegantly analyzed fibrosis in young (3 months) and aged (12–15 months) bovine GH (bGH) transgenic mice and found that aged bGH mice had more collagen than wild-type in kidney, liver, spleen and quadriceps of both males and females, and heart in males. These data demonstrate that GH activity positively correlates with fibrosis across multiple tissues with increasing severity with aging and suggest that fibrosis is a common factor in organ dysfunction caused by excessive GH.

Similarly in humans, both acute and chronic GH treatment in older men results in increases in collagen expression in tendon and muscle [62]. Acromegaly patients are exposed to chronic GH excess that induces increased collagen turnover, which decline upon disease remission [63]. Besides increased collagen synthesis, other factors are also influenced by GH that contribute to fibrosis (e.g., ECM-modifying proteins, transforming growth factor-β [TGFβ] pathway and MAPK pathways implicated in fibrosis, senescence, immune cell function, and fibroblast activation or plasticity) that are preceded by and closely associated with inflammation [64]. These fibrotic effects of GH are frequently context- and tissue-specific but are not always pro-fibrotic. For example, an ECM-degrading endopeptidase, matrix metalloproteinase 2, is decreased after GH treatment of individuals with GHD [65], but is increased in patients with active acromegaly [66]. Conversely, GH action itself might also be influenced by ECM-modifying proteins. Tissue inhibitor of metalloproteinase 3 (TIMP3), which has a high affinity for ECM proteoglycans, modulates the GHR on the cell surface in human cell lines that express GHR and JAK2, and dampens the GH-induced intracellular signaling cascade, thereby providing evidence of an interplay between GH and the ECM [67].

Cellular senescence, characterized by irreversible cell cycle arrest and a senescence-associated secretory phenotype (SASP), also positively correlates with GH and IGF-I levels [68], further contributing to a pro-fibrotic milieu. Nonetheless, senescence might be beneficial in preventing fibroblast differentiation and the ability of these fibroblasts to contribute to hepatic fibrosis [69], but can also be detrimental, as removal of senescent cells in rodents pharmacologically or genetically reverses fibrosis in some tissues such as lung [70], and prolong lifespan [71]. However, GH treatment attenuated senescence of primary human endothelial progenitor cells [72], and IGF-I overexpression in rats improved stress-induced senescence in the liver [73].

Previous studies have also shown that GH and/or IGF-I influence the differentiation and proliferation of fibroblasts [74,75]. For example, GH was identified as an inhibitor of TGFβ-induced myofibroblast differentiation in the skin of bGH transgenic mice [76]. Fibroblast activation protein (FAP), a cell surface protease that plays a critical role in the degradation of ECM [77], has been linked to GH action in humans [63]. The expression of FAP is limited in conditions associated with notable ECM remodeling, such as liver fibrosis [78], where FAP levels are elevated in active acromegaly that decreases upon disease remission [63]. Further studies are needed to determine if GH directly influences FAP abundance and action to influence ECM remodeling, as well as the ability of FAP to act as a biomarker for GH-induced fibrosis.

Acromegaly patients also frequently display multi-organ fibrosis affecting the skin, liver, thyroid [79–82] and most notably the heart [83] resulting in acromegalic cardiomyopathy. Similarly, bGH mice develop widespread multi-organ fibrosis impacting the heart, kidney, liver, spleen and quadriceps with males and age exhibiting a more robust and severe phenotype [61]. Conversely, several mouse lines with decreased GH action, such as GHR antagonist mice [60], mice with GHR disruption in adipocytes [84] or mice deficient in GH [85] exhibit decreased fibrosis in their adipose tissue. Collectively, these data in humans with acromegaly and GH transgenic mice support the critical role of fibrosis as an important component of the organ dysfunction seen in diseases associated with GH-related disorders.

The benefits of GH in promoting collagen deposition are best illustrated by its effect on promoting longitudinal growth and bone acquisition [86,87]. However, GH might also have therapeutic potential related to normalized GH levels in deficient states or indirect influences on other disease pathologies or severe conditions. Studies have shown that the dysregulation of the GH/IGF-I axis in obese individuals and adults with GHD can contribute to the development of metabolic dysfunction-associated steatotic liver disease and the progression of hepatic fibrosis, and that GH replacement therapy can ameliorate these liver-related changes [88]. In a rat model with intestinal inflammation, GH has been shown to improve intestinal fibrosis [89], and in children with severe burns, GH therapy promoted healing without the scarring caused by tissue fibrosis [90]. However, the use of GH for fibrotic diseases faces limitations, as many beneficial studies restore GH to normal levels in deficient individuals, focus on acute or short-term treatment, and involve non-approved uses.

Nonetheless, available data suggest an intricate balance between having sufficient GH action to promote favorable ECM remodeling and avoiding excess GH action that promotes ECM deposition and scarring that results in organ dysfunction. Furthermore, sufficient GH action and normalization of GH levels are necessary for ECM remodeling, but excessive GH action and levels can lead to detrimental ECM deposition, scarring, and organ dysfunction. More studies are needed to determine whether GH and IGF-I are the primary drivers of fibrosis or if fibrosis arise secondarily because of underlying organ dysfunction.

There is accumulating evidence in recent years implicating the role of GH on cancer promotion. Indeed, there are experimental, epidemiological, genetic, and clinical studies, both in animal models and humans that suggest such an association [5,91]. In the general population, relatively high IGF-I levels and low IGFBP-3 levels have been associated with greater risk of common cancers (e.g., prostate, breast, colon, and lung) [92], while several components of the GH-IGF signaling system exhibit correlations with clinical, histopathological, and therapeutic parameters in cancer patients [5]. Conversely, organisms including humans that lack GHR activity are virtually devoid of cancer [93,94]. Besides the pituitary, GH is locally expressed in colon, prostate, lung, and breast, where it binds to the GHR to initiate signaling in a paracrine/autocrine fashion (Fig. 2) [95], subsequently promoting growth and survival of a tumor by affecting the tumor microenvironment (TME) (Fig. 3) [96]. Elegant studies by Chesnokova et al. [97] have elucidated the role of autocrine and/or paracrine GH in modulating the TME, thereby supporting the notion of tumor growth and survival through the ‘field cancerization’ paradigm. Notably, aging leads to activation of the tumor suppressor p53, resulting in apoptosis or induction of p53–p21 senescent pathway or a DNA damage repair (DDR) pathway [98]. Chromatin immunoprecipitation assays reveal GH as a target for p53 binding, whereas transcriptomic and proteomic analyses confirm DNA damage that induces local GH production in normal colon and tumor cells [97,99]. Locally produced GH in turn exerts a feedback inhibition on p53 expression and diverts cellular commitment from senescence or apoptosis to proliferative survival [97]. Autocrine and/or paracrine GH signaling abrogates the DDR pathway, as is observed in human colonic epithelial transformation [100]. Crossing GHR knockout mice with mice predisposed to cancers slowed down tumor progression [101], whereas GH-deficient rats crossed with rats predisposed to prostate cancer showed reduced tumor incidence and burden [102]. Concordantly, GH-deficient female rats are resistant to chemical induction of mammary carcinogenesis, and GH replacement restores the risk of tumor development [103]. Intracellular (autocrine) GH promotes breast cancer cell transformation [104–106] and induces an invasive phenotype by triggering an epithelial-mesenchymal transition (EMT), cell motility and increased cell survival [95,105,107].

Key pathways across cancer types that are involved in chemotherapy response include apoptosis inhibition, active drug efflux via ATP-binding cassette (ABC) transporters and a phenotype switch via EMT. GH expression imparts resistance against apoptosis in mammary and endometrial tumor cells following irradiation [108] and induces resistance against several chemotherapy regimens (e.g., mitomycin-C, doxorubicin, cisplatin, arsenic trioxide, and ruxolitinib) [109]. Similar effects of GH in driving refractoriness against chemotherapy (e.g., doxorubicin, cisplatin, and paclitaxel) and targeted (e.g., vemurafenib) therapies have also been observed in melanoma, liver and pancreatic cancers [109–112]. The mechanistic validation is derived from the identification that tumoral GHR activation that induces a STAT5–SRC–extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated upregulation of multidrug ABC transporters in human melanoma [113]. The ABC transporters promote resistance to a wide range of chemotherapy agents by limiting their cytosolic retention through active efflux. Studies in human melanoma cells have shown autocrine GH signaling-induced upregulation of multidrug efflux transporters of the ABCB, ABCC, and ABCG subtypes, which could be effectively blocked by GHR suppression [110]. Chemically induced mammary tumor establishment was possible in spontaneous dwarf rats with GHD when treated with exogenous GH; however when GH supplementation was discontinued and treated with doxorubicin, tumors regressed in these animals but not in GH-sufficient wild-type animals, implying a GH-dependent chemoresistance state [114].

In breast [115], colon [100], liver [116], and pancreatic [117] cancers, GH promotes metastasis from the primary tumor by an EMT process [118]. In addition to its angiogenic and lymphangiogenic effects, GH also promotes EMT in the overlapping pathways of tissue fibrosis and cancer metastases [119]. Suppression of the epithelial marker E-cadherin and upregulation of the mesenchymal markers N-cadherin and vimentin, and transcription factors such as zinc finger E-box binding homeobox 1 (ZEB1) and SLUG by exogenous GH, occur in melanoma [104,113] and pancreatic [117] cancer cells and by autocrine GH actions in colon [120] and breast cancer cells [105], while attenuating the GHR reverses these effects. In Dj1-knockout mice which incidentally have high production of GH in the lungs, local GH enhances the metastasis of disseminated melanoma cells [121]. The pronounced effect of GH in inducing fibrosis further emphasizes its unique and critical role in promoting cancer therapy resistance [122].

In intestinal organoids closely recapitulating normal human intestinal mucosa, GH treatment resulted in p53 suppression and increased Wnt/β-catenin signaling [123], leading to the downregulation of E-cadherin, which controls cell adhesion and prevents tumor cell dissemination [124]. This interesting JAK-STAT3 and Wnt–β-catenin pathway connection suggested that this cooperative interaction fuels the enhanced growth of intestine tumors. Thus, this study provides evidence that partial suppression of systemic JAK-STAT3 signaling sufficiently limits tumor growth by reducing Bmi-1–dependent repression of p21 and p16. This connection potentially provides a route to use the GHR-STAT3 pathway as a therapeutic target to inhibit adenomatous polyposis coli mutant cancers.

Intriguingly, epidemiological studies of short stature individuals with Laron syndrome in Ecuador who, by definition have congenital GH insensitivity due to inactivating mutations in the GHR gene [94], and individuals in Brazil with congenital isolated GHD caused by mutations in the GHRH receptor gene [6], have revealed lower cancer incidence rates compared to local controls, highlighting that congenitally absent or reduced GH action is cancer-protective. However, although these two syndromes appear similar phenotypically, there are also subtle differences. The key difference between individuals with Laron syndrome is the resistance to insulin and protection from cancer and diabetes observed in this cohort [94], while the individuals with congenital isolated GHD demonstrate that despite similar cancer protection, they still have some adverse cardiovascular risk factors and, unlike Laron syndrome individuals, present with reduced neonatal size (Table 1) [6]. Nonetheless, these landmark clinical studies in both cohorts serve as compelling examples of suppressed malignancy stemming from decreased GH and IGF-I levels and suppression of GH action that collectively imply that GH might be a critical factor in modulating cancer risk.

In a large population-based prospective study, IGF-I levels in the highest percentiles of the normal range is associated with an increased risk of prostate and breast cancer in premenopausal and postmenopausal women [125], whereas Wang et al. [126] reported in a large meta-analysis of 20 studies that serum IGF-I levels are an independent prognostic factor for the progression and survival of patients with hepatocellular carcinoma. Most importantly, studies with cells, tissues and animals show that GH and IGF-I stimulate growth of the same cancer types, whereas absent malignancy growth is observed without GH and IGF-I activity [127]. Additionally, studies in acromegaly patients estimating the risks of cancer and benign neoplasia have shown elevated risks for specific cancer types [5]. However, many confounding factors exist, including surveillance bias, normalization of circulating levels of IGF-I from treatment and difficulty in adequately comparing the cause of death in individuals with well-controlled acromegaly versus healthy controls. Such observations have posed the question of whether direct pharmacological suppression of GH action might retard oncogenicity and decrease cancer risk. Interestingly, pegvisomant, a GHR antagonist, has been successfully tested in several cancer-derived cell lines [107,128,129], but whether it can inhibit the autocrine/paracrine actions of GH in cancer patients requires further clarification, particularly on the assessment of its effects on intracellular GH/GHR signaling [130]. At present, there are no clinical data to determine the usefulness of pegvisomant in human cancer due to bioavailability issues, short half-life, rapid renal clearance, and lack of in vivo stability due to proteolytic degradation [5]. Accordingly, despite its promising results in pre-clinical studies, the utility of pegvisomant in treating human cancer remains yet to be fully proven.

It is now apparent that, beyond its role in growth promotion, GH exerts other important but less evident effects, particularly on key body functions such as glucose metabolism, fibrosis and the initiation and progression of cancer. GH acutely exerts ‘insulin-like’ effects followed by glucose disposal inhibition in skeletal muscle. The insulin-antagonistic effects of GH are clinically significant because subjects with active acromegaly are predisposed to glucose intolerance, whereas the opposite is true for individuals with lifelong impairment of GH action and GHD. Observational data and clinical studies in adults with GHD do not indicate that long-term GH replacement exerts significant deterioration of glucose metabolism. Nonetheless, it is recommended to avoid overdosing of GH replacement and to use lower GH doses in individuals predisposed to glucose intolerance. Notably, GH has also been shown to stimulate collagen synthesis and turnover in adult humans to such an extent that quantification of IGF-I and type III procollagen peptide in serum is now approved as biomarkers used to detect GH doping in sport [131]. While GH is critical for growth promotion, after completion of longitudinal growth and somatic maturation, the primary anabolic effect of GH appears to shift towards collagen rather than muscle fibers. When GH is present in excess, fibrosis is triggered in a tissue-specific manner [61] and the subsequent alterations to normal tissue function represent an added caution when utilizing GH replacement in adults with GHD although arguably, GH replacement in these patients is aimed towards physiological normalization of IGF-I levels. On the other hand, data from acromegaly patients have shown a correlation with excess cardiovascular comorbidities with fibrosis likely contributing to this risk, while adults with GHD exhibit a proinflammatory state but generally do not develop significant tissue fibrosis. Taken together, these data suggest that maintaining ‘physiological’ GH and IGF-I levels is important to mitigate the negative consequences of GH on glucose metabolism and fibrosis. However, in cancer, the effects of GH on fibrosis and endothelial cells make it an important factor towards the development of detrimental TME. Although cancer risk is not elevated with GH replacement in adults with GH [132], experimental and animal data have suggested the possible mechanistic links of GH and IGF-I on the development, progression, chemotherapy resistance and metastases of cancers, prompting the hypothesis that GHR antagonists could be beneficial in the treatment of cancers with highly functional GHR expression. Ultimately, both excessive and insufficient GH exposure or aberrant GH action can lead to diverse adverse health outcomes that may impact longevity, thus highlighting the importance of balanced GH and IGF-I levels and signaling, and the need to differentiate between endocrine and local autocrine/paracrine GH and IGF-I actions.