Recent study 2011 - Elevated levels of GH

[marcus300]

I posted this on another thread but thought it may make interesting reading for some.

There was a recent study conducted by Australian scientists what concluded that increased levels of growth hormone and IGF-1 are linked to prostate, colon and breast cancers. Humans and animals with low levels of growth hormone showed resistance to many types of cancers, while animals with an abundance of growth hormone receptors show an increased cancer risk. Adults who take a moderate dosages of growth hormone or IGF-1 do not appear to have an increased risk of cancer, however higher dosages could promote the disease..

[sgt2jay]

what would you define as a moderate dose to Higher dose?

[marcus300]

what would you define as a moderate dose to Higher dose?

Good question, let me do some searching for the study

[marcus300]

Looks like anything over a therapeutic dose for prolonged periods of time. But wouldnt we here of pro after pro falling down with cancers if the risk was huge?

There is no significant risk above that of the general population resulting from therapeutic replacement with GH. However, use of GH for prolonged periods at supraphysiologic levels could contribute to increased cancer risk, particularly colon and thyroid cancer, as it does in acromegaly.

[sgt2jay]

Thanks

[DeepDiver]

And this illustrates why it is so important with GH or AAS to have regular physicals and blood work to confirm how your body is responding. Both my GH and AAS is Dr proscribed, before during and after these cycles regular blood work and checkups are necessary. Before my doc would even consider GH or AAS he took a complete family history, including cancers, to ascertain my risks. If any family history indicated problems, I would not have been a candidate. Putting something in your body and only relying on what your friends or BB's tell you, is a sure fire way to become a statistic in on of those scientific studies.

[prop402]

I call BS. They do these studies on rats in cages and the levels are extremely high. If they did it on humans - the elevated growth hormone is just an attempt to stimulate the immune system .

[JohnnyVegas]

I call BS. They do these studies on rats in cages and the levels are extremely high. If they did it on humans - the elevated growth hormone is just an attempt to stimulate the immune system .

If it is the study I read, it was on a tribe of people that are very short because their bodies don't generate much (if any) GH. They are basically cancer free and it has been linked to the lack of GH.

I will look for the study.

[bjpennnn]

^^^pretty crazy. So i guess since i am a short ****er i am gtg ha.

[JohnnyVegas]

I found the study that I was thinking of. It is recent. It isn't what Marcus was talking about, but it reinforces whatever study he was referencing.

ScienceDaily (Feb. 16, 2011) — A 22-year study of abnormally short individuals suggests that growth-stunting mutations also may stunt two of humanity's worst diseases.

Published in Science Translational Medicine, the study raises the prospect of achieving similar protection in full-grown adults by other means, such as pharmaceuticals or controlled diets.

The international study team, led by cell biologist Valter Longo of the University of Southern California and Ecuadorian endocrinologist Jaime Guevara-Aguirre, followed a remote community on the slopes of the Andes mountains.

The community includes many members with Laron syndrome, a deficiency in a gene that prevents the body from using growth hormone . The study team followed about 100 such individuals and 1,600 relatives of normal stature.

Over 22 years, the team documented no cases of diabetes and one non-lethal case of cancer in Laron's subjects.

Among relatives living in the same towns during the same time period, 5 percent were diagnosed with diabetes and 17 percent with cancer.

Because other environmental and genetic risk factors are assumed to be the same for both groups, Longo and his team concluded that -- at least for adults past their growing years -- growth hormone activity has many downsides.

"The growth hormone receptor-deficient people don't get two of the major diseases of aging. They also have a very low incidence of stroke, but the number of deaths from stroke is too small to determine whether it's significant," Longo said.

Overall lifespan for both groups was about the same, with the abnormally short subjects dying more often from substance abuse and accidents. The study did not include psychological assessments that could have helped explain the difference.

"Although all the growth hormone deficient subjects we met appear to be relatively happy and normal and are known to have normal cognitive function, there are a lot of strange causes of death, including many that are alcohol-related," Longo said.

Longo noted that any treatment for preventive reduction of growth hormone would have to show fewer and milder side effects than drugs used against a confirmed disease.

But he added that any preventive treatment would target adults with high growth hormone activity in order to bring it down to average, and not to the extremely low and potentially riskier state observed in Laron's subjects.

If high growth factor levels "become a risk factor for cancer as cholesterol is a risk factor for cardiovascular diseases," drugs that reduce the growth factor could become the new statins, Longo said.

Such drugs would be used at first only for families with a very high incidence of cancer or diabetes.

And because growth hormone activity decreases naturally with age, any preventive treatment would be appropriate only until the effects of advanced age took over, Longo explained.

Animal studies provide evidence for the health benefits of blocking growth hormone. Groups led by John Kopchick of Ohio University and Andrzej Bartke of Southern Illinois University achieved a record 40 percent lifespan extension with growth factor deficient mice in studies published in 2000 and 1996, respectively.
Later, the researchers linked growth factor deficiency to reduced tumor risk.

The Food and Drug Administration has already approved drugs that block growth hormone activity in humans. These are used to treat acromegaly, a condition related to gigantism.

Because studies have shown that growth hormone deficiency protects mouse and human cells against some chemical damage, Longo said his team would initially seek approval for a clinical trial to test such drugs for the protection of patients undergoing chemotherapy.

Growth hormone-blocking drugs such as pegvisomant appear to be well tolerated, Longo said. But even if chronic growth hormone blocking should come with a minor side effect, Longo predicted that societies and governments would make the trade in exchange for less chronic disease.

He called it the "square survival curve," where most of one's life is lived without major illness. "It's the dream of every administration, anywhere in the world. You live a long healthy life, and then you drop dead," Longo said.

Exactly how growth hormone deficiency might protect a person is not fully understood.

In test tube studies, Longo's team found that serum from Laron's subjects had a double protective effect: it protected DNA against oxidative damage and mutations but it promoted the suicide of cells that became highly damaged.

Laron's subjects tend to have very low insulin levels and low insulin resistance, which may explain the absence of diabetes.

In joint experiments with a group led by Rafael de Cabo at the National Institute on Aging, human cells exposed to the Laron's serum also showed surprising changes in the activity of genes linked to life extension in yeast and other model organisms. Although Longo and colleagues had identified such genes 15 years ago, they had not been shown to be important for disease prevention in humans.

Artificial hormone blocking is not the only way to reduce these hormones in humans.

A natural method appears to achieve the same effect: restriction of calories or of specific components of the diet such as proteins.

Several studies are underway to assess the effect of dietary restriction in humans and other primates. The results are not yet known, but a recent study by Longo's group showed that fasting induces rapid changes in growth factors similar to those caused by the Laron mutation.

However, because fasting or restriction in particular nutrients for long periods can lead to dangerous conditions including anorexia, reduced blood pressure and immunosuppression -- and because individuals with rare genetic mutations can suffer life-threatening effects from even short periods of fasting -- Longo emphasized that additional studies are needed and that any changes in diet must be approved and monitored by a physician.

The study in Science Translational Medicine began as an attempt by Longo to test evidence from animal studies that longevity mutations prevent progressive DNA damage and/or cancer.

Co-author Guevara-Aguirre wanted to understand the reasons for the stunted growth of children in the remote community, centered in the Loja province of southern Ecuador.

Initially, Longo said, the children "were more looked at in search of problems than solutions."

But as the study wore on, Guevara-Aguirre began to notice that the adults in the community were not dying of the usual chronic diseases.

That was the clue Longo had been seeking. After hearing of the Ecuador study, he invited Guevara-Aguirre to present at a symposium on aging and cancer in 2006 at USC's Leonard Davis School of Gerontology, where Longo is associate professor.

Together, they obtained funding from the Center of Excellence in Genomic Science in the USC College of Letters, Arts and Sciences, which sponsored part of the initial field research in Ecuador, and from the National Institute on Aging, which sponsored the cellular studies.

[Pac Man]

I read that study not too long ago, I believe they also showed them on discovery. I'd rather be a little bigger with an increased risk personally

[Twist]

I found the study that I was thinking of. It is recent. It isn't what Marcus was talking about, but it reinforces whatever study he was referencing.

ScienceDaily (Feb. 16, 2011) — A 22-year study of abnormally short individuals suggests that growth-stunting mutations also may stunt two of humanity's worst diseases.

Published in Science Translational Medicine, the study raises the prospect of achieving similar protection in full-grown adults by other means, such as pharmaceuticals or controlled diets.

The international study team, led by cell biologist Valter Longo of the University of Southern California and Ecuadorian endocrinologist Jaime Guevara-Aguirre, followed a remote community on the slopes of the Andes mountains.

The community includes many members with Laron syndrome, a deficiency in a gene that prevents the body from using growth hormone . The study team followed about 100 such individuals and 1,600 relatives of normal stature.

Over 22 years, the team documented no cases of diabetes and one non-lethal case of cancer in Laron's subjects.

Among relatives living in the same towns during the same time period, 5 percent were diagnosed with diabetes and 17 percent with cancer.

Because other environmental and genetic risk factors are assumed to be the same for both groups, Longo and his team concluded that -- at least for adults past their growing years -- growth hormone activity has many downsides.

"The growth hormone receptor-deficient people don't get two of the major diseases of aging. They also have a very low incidence of stroke, but the number of deaths from stroke is too small to determine whether it's significant," Longo said.

Overall lifespan for both groups was about the same, with the abnormally short subjects dying more often from substance abuse and accidents. The study did not include psychological assessments that could have helped explain the difference.

"Although all the growth hormone deficient subjects we met appear to be relatively happy and normal and are known to have normal cognitive function, there are a lot of strange causes of death, including many that are alcohol-related," Longo said.

Longo noted that any treatment for preventive reduction of growth hormone would have to show fewer and milder side effects than drugs used against a confirmed disease.

But he added that any preventive treatment would target adults with high growth hormone activity in order to bring it down to average, and not to the extremely low and potentially riskier state observed in Laron's subjects.

If high growth factor levels "become a risk factor for cancer as cholesterol is a risk factor for cardiovascular diseases," drugs that reduce the growth factor could become the new statins, Longo said.

Such drugs would be used at first only for families with a very high incidence of cancer or diabetes.

And because growth hormone activity decreases naturally with age, any preventive treatment would be appropriate only until the effects of advanced age took over, Longo explained.

Animal studies provide evidence for the health benefits of blocking growth hormone. Groups led by John Kopchick of Ohio University and Andrzej Bartke of Southern Illinois University achieved a record 40 percent lifespan extension with growth factor deficient mice in studies published in 2000 and 1996, respectively.
Later, the researchers linked growth factor deficiency to reduced tumor risk.
Correlation does not mean causation. See below

The Food and Drug Administration has already approved drugs that block growth hormone activity in humans. These are used to treat acromegaly, a condition related to gigantism.

Because studies have shown that growth hormone deficiency protects mouse and human cells against some chemical damage, Longo said his team would initially seek approval for a clinical trial to test such drugs for the protection of patients undergoing chemotherapy.

Growth hormone-blocking drugs such as pegvisomant appear to be well tolerated, Longo said. But even if chronic growth hormone blocking should come with a minor side effect, Longo predicted that societies and governments would make the trade in exchange for less chronic disease.

He called it the "square survival curve," where most of one's life is lived without major illness. "It's the dream of every administration, anywhere in the world. You live a long healthy life, and then you drop dead," Longo said.

Exactly how growth hormone deficiency might protect a person is not fully understood.

In test tube studies, Longo's team found that serum from Laron's subjects had a double protective effect: it protected DNA against oxidative damage and mutations but it promoted the suicide of cells that became highly damaged.
It seems to me that this is the key. That these subjects have the ability to kill off cells that are damaged while also protecting them from mutations. I am guessing that the mutation part can be enhanced by GH, so that is where they see GH causing issues. What if it is that this ability to get rid of damaged cells is the key? I hope more comes out about this

Laron's subjects tend to have very low insulin levels and low insulin resistance, which may explain the absence of diabetes.

In joint experiments with a group led by Rafael de Cabo at the National Institute on Aging, human cells exposed to the Laron's serum also showed surprising changes in the activity of genes linked to life extension in yeast and other model organisms. Although Longo and colleagues had identified such genes 15 years ago, they had not been shown to be important for disease prevention in humans.

Artificial hormone blocking is not the only way to reduce these hormones in humans.

A natural method appears to achieve the same effect: restriction of calories or of specific components of the diet such as proteins.

Several studies are underway to assess the effect of dietary restriction in humans and other primates. The results are not yet known, but a recent study by Longo's group showed that fasting induces rapid changes in growth factors similar to those caused by the Laron mutation.

However, because fasting or restriction in particular nutrients for long periods can lead to dangerous conditions including anorexia, reduced blood pressure and immunosuppression -- and because individuals with rare genetic mutations can suffer life-threatening effects from even short periods of fasting -- Longo emphasized that additional studies are needed and that any changes in diet must be approved and monitored by a physician.
I can tell you what they will find. Super low calories (below 1,000), made of fruits, vegetables and nuts; protein intake about once or twice per week, will promote longevity.

The study in Science Translational Medicine began as an attempt by Longo to test evidence from animal studies that longevity mutations prevent progressive DNA damage and/or cancer.

Co-author Guevara-Aguirre wanted to understand the reasons for the stunted growth of children in the remote community, centered in the Loja province of southern Ecuador.

Initially, Longo said, the children "were more looked at in search of problems than solutions."

But as the study wore on, Guevara-Aguirre began to notice that the adults in the community were not dying of the usual chronic diseases.

That was the clue Longo had been seeking. After hearing of the Ecuador study, he invited Guevara-Aguirre to present at a symposium on aging and cancer in 2006 at USC's Leonard Davis School of Gerontology, where Longo is associate professor.

Together, they obtained funding from the Center of Excellence in Genomic Science in the USC College of Letters, Arts and Sciences, which sponsored part of the initial field research in Ecuador, and from the National Institute on Aging, which sponsored the cellular studies.

Very interesting info here. I hope more comes out about it soon. I read a study where older people were given hgh and NO new cancers developed (odd because statistically it certainly should have occurred), and people with current tumors DID NOT experience any new growth or worsening whatsoever.

At this current time I do not believe that HGH is the cause of anything that this suggests. I am sure there is another variable that is lying hidden for now. I will try to get in touch with someone about this and respond back later.

[layeazy]

wow its just good to read us Aussies are researching also an interesting discussion on the abc radio was talking about testosterone therapy for females is helping At low doses the patients reported no side effects increase energy levels and well being...

[layeazy]

Wanted: 100 women aged 35–55 who are taking antidepressants and experiencing low libido, for a medical trial.

They will need to make visits to the Alfred Hospital in Melbourne, where Professor Susan Davis, an endocrinologist, wants to give them—or some of them—testosterone .

Testosterone is more important to women than is widely realised, as Professor Davis's earlier research has demonstrated.

http://www.abc.net.au/rn/lifematters...11/3183796.htm thats the link for the audio might interest the women on the forum...

[marcus300]

Numerous epidemiological studies have provided evidence that GH/IGF-1 is likely to be a driver of major human cancers. First, there is a link between tall stature, cancer risk and GH/IGF-1 levels. With the use of final height as a marker for GH and IGF-1 action, a review of over 300 case–control and cohort studies [12] found that taller individuals have a higher incidence of breast cancer (22% increase), prostate cancer (20% increase) and colon cancer (20–60% increase) relative to shorter individuals. A Danish study of 14-year-old children in the top quintile of height showed that they have an adjusted relative risk of over 1.5 for breast cancer, which surpasses other risk factors examined including BMI and age of first menarche [13]. A carefully controlled twin study from Scandinavia also found that tallness associates with increased breast cancer risk [14]. An anthropometric analysis revealed an association between rapid childhood growth during adolescence with the risk of developing several cancers, particularly of the breast, prostate and colon [3]. For breast cancer risk, a major prospective meta-analysis of patients in 12 countries concluded that not only are serum IGF-1 concentrations positively associated with height, but they are also positively associated with breast cancer risk in women (high vs low serum IGF-1; OR: 1.28), but only in estrogen receptor-positive tumors [15]. Moreover, higher levels of free and total plasma IGF-1 have been reported in breast cancer patients [16]. In relation to the restriction of risk to estrogen receptor-positive women, synergistic interaction between estrogen action and IGF-1 action has been shown in vitro for epithelial cell proliferation [17]. IGF-1 levels are also positively related to high mammographic density, which is an indicator of increased breast cancer risk [18]. Of further relevance, loss of BRCA1 function associates with overactivation of the IGF-1 signaling axis [19].

There have been reports that genetic variants in the GH–IGF system can determine relative tumor risk. A genome-wide association study (GWAS) in UK Caucasians has identified 64 SNPs that influence susceptibility for lung cancer, of which 11 were mapped to genes of the GH–IGF-1 axis, including GH1, GHR, GH-releasing hormone (GHRH) and IGFBP5 [20], and genetic variation at many genes in the GH–IGF pathway have been shown to associate with a variety of cancers [20,21]. A recent GWAS of over 1000 breast cancer cases matched with a similar number of controls concluded that the GH signaling pathway was the third most highly enriched pathway in breast cancer, but found insulin signaling intermediates rather than IGF-1 intermediates to co-associate with GH/JAK2 signaling in this analysis [22]. However, polymorphisms in the IGF-1 gene or in the GH synthesis pathway were not significantly associated with breast cancer [23]. Four IGFBP-3 SNPs have been reported to be associated with IGF-1 and IGFBP-3 levels in one study [24], and a strong association between a specific BP-3 promoter polymorphism and mammographic density, a known risk factor for breast cancer development, in another study [25]. However a larger cohort and a recent multi-ethnic cohort study reported no direct association of BP3 with breast cancer [23,26]. While IGFBP-3 polymorphic alleles were modestly associated with risk of colorectal cancer [27], there were contrasting associations between IGFBP-3 polymorphisms and the risk of prostate cancer in other studies [28,29]. It remains to be seen if these genetic variations could determine a higher cancer risk in susceptible individuals receiving GH treatment.

Elevated levels of IGF-1 have also been shown to confer an increased risk for other cancers such as colorectal cancer and prostate cancer. A recent systematic review of 42 published studies concluded that raised circulating IGF-1 is positively associated with prostate cancer risk, with little evidence for a role of IGF-2, IGFBP-1, IGFBP-2, and inconclusive evidence for involvement of IGFBP-3 [30]. For colon cancer, the relative risk for IGF-1 (RR: 1.07; 95% CI: 1.01–1.14) is modest compared with that seen in acromegaly [31]. This may be a consequence of the elevated insulin levels associated with acromegaly acting together with elevated IGF-1 and, of course, GH itself [31–33].

[marcus300]

The risk of developing cancer is determined by genetic elements and by environmental conditions including diet and lifestyle. Recent evidence suggests that the GH–IGF-1 axis might provide a link between these factors and the disposition to cancer through its effects on normal cell proliferation, differentiation and apoptosis. The GH–IGF-1 axis influences several stages and aspects of cancer development and behaviour: cellular proliferation, cell survival, angiogenesis and metastasis, and even resistance to chemotherapy [3]. Being a potent and ubiquitous mitogen, IGF-1 can act on many cell types to bring about increased proliferation via the MAPK signaling pathway. Its anti-apoptotic actions are mediated via the PI3K/Akt pathway and can disrupt the tight control between cell proliferation and death leading to hyper-proliferation [4]. Carcinogenesis is a multistep process which involves accumulation of a number of genomic ‘hits’ leading to complete transformation and/or survival of partially transformed cells with one or a few hits [5]. In such a case, IGF-1 would increase the pool of transformed/damaged cells that are available for undergoing subsequent hits. This implies that higher levels of IGF-1 can bring about increased proliferation and survival and hence promote carcinogenesis even though not being directly responsible for initiating cancer development. Hence, individuals with relatively high levels of IGF-1 may be at an increased risk as the anti-apoptotic actions of IGF supports partially transformed cells to provide an increased pool of cells for subsequent damaging hits. It is important to note that the IGF-1 activity in a given tissue is not merely a function of its circulating levels but also the local expression of genes encoding for IGFs, IGF-1 receptor (IGF-1R), IGFBPs and proteases that cleave the IGFBPs to regulate the release of IGF-1 (particularly for IGFBP-3). There is considerable heterogeneity in the levels of IGF-1 and IGFBP-3 between normal individuals as a result of genetic and non-genetic determinants [6,7].

Recent evidence suggests a complex cross-talk between the GH–IGF-1 axis and estrogen receptor signaling that can stimulate mammary epithelial proliferation under normal conditions and increase the risk of breast cancer [8], as well as positive crosstalk with the ErbB1 receptor [9]. The latter also undergoes direct tyrosine phosphorylation by the GHR [10], which itself is able to activate the classic oncogenic pathways directly through JAK2 and Src [11]. Thus, the combination of GH and IGF-1 signaling, together with their interactions with other potentially oncogenic signaling proteins such as estrogen receptor and ErbB1 would lead one to expect involvement in cancer initiation or progression for this key growth-promoting axis (Figure 1).

[marcus300]

Six decades of research have established that growth hormone (GH) plays a crucial role in promoting proportionate postnatal growth, and that this is largely mediated through the induction of IGF-1. This action is supported by important roles of GH in the regulation of metabolism, and of cardiovascular, renal, reproductive and immune functions. These roles are accomplished through ubiquitously expressed GH receptors (GHRs) which, similar to receptors for many other growth factors, signal through a tyrosine kinase (JAK2) able to activate STAT, Ras/ERK and PI3K/Akt pathways. The ability of GH to also induce IGF-1, both locally in a paracrine/autocrine manner [1,2] and in an endocrine manner via action on the liver, results in a particularly potent growth stimulus that requires tight control. This comprises feedback inhibition of GH secretion by pituitary somatotropes by hepatic (endocrine) IGF-1, as well as a set of negative regulators common to other growth factor/cytokine signaling factors: suppressors of cytokine signaling (SOCS), protein inhibitors of activated STAT (PIAS) proteins, phosphatases, receptor downregulation, and transcriptional regulation of receptor expression. Given the ability of GH and IGF-1 to promote cell proliferation, cell movement and angiogenesis, and to suppress apoptosis, it is not surprising that dysregulation of the tightly controlled GH–IGF-1 axis promotes neoplasia. As discussed here, converging data from recent epidemiologic, animal and in vitro studies indicate that the state of the GH–IGF-1 axis has important influences on cancer biology, cancer risk and carcinogenesis.

[marcus300]

Acromegaly is an important disease state for assessment of cancer risk because of the presence of persistently elevated levels of IGF-1. This is a result of hypersecretion of GH by pituitary somatotropes, particularly as a result of activating mutations in the GHRH signaling cascade. A number of studies have been carried out to assess whether this condition is associated with cancer risk. The most recent meta-analysis by Renehan and Brennan across three population studies concluded that acromegaly is associated with a 2.46-fold (95% CI: 1.79–3.38) increased risk of colon cancer [34]. Adenomatous lesions tend to be larger and more dysplastic in acromegaly, and are often multiple [35]. Acromegaly was also associated with an increased risk for thyroid cancer (3.64-fold; 95% CI: 1.63–8.11) in this meta-analysis. However, there is no statistical association between serum IGF-1 and presence of colorectal neoplasia in the three existing studies [34], so one is left with the possibility of direct GH action on the colon, or elevated plasma insulin as a driving factor, consequent to the diabetogenic action of elevated GH [36]. In relation to the other cancers, which showed a relationship to circulating IGF-1 in large population studies, in acromegaly there has been no confirmed association with breast cancer, although the limited sample number of untreated female acromegalics may have prevented small effects being observed [35]. This could also be a consequence of impaired ovulation in acromegalic women; hence, a lack of progesterone and estrogen, which together can promote breast cancer. Likewise, prostatic cancer shows no evident association with acromegaly, although benign prostatic hyperplasia with calcifications is evident across different studies [35]. A number of other cancers have been reported to be associated with acromegaly, but insufficient numbers are available for definite conclusions. These include various lympho-hematopoietic neoplasms (e.g., lymphoma, multiple myeloma, chronic myeloid or lymphocytic leukemia), brain tumors including meningiomas, adrenal tumors and melanomas [35].

These studies indicate a low but significant risk for certain cancers, particularly of epithelial origin, in relation to elevated circulating IGF-1. What of the converse situation, that is, GH and/or IGF-1 deficiency? In the sole published study to date, a worldwide survey of 222 individuals with GHR mutation or isolated GH deficiency, not a single case of malignancy was reported. Conversely, 338 first- and second-degree relatives reported a 10–24% incidence of a range of malignancies [37]. The difference in average age between the two groups (32 vs 55 years, respectively) probably contributed to this disparity, but the apparent resistance of GH-deficient and/or IGF-1-deficient individuals to cancer is supported by extensive animal studies. These will be discussed in the following sections, but at face value, the above findings imply that IGF-1–GH signaling is permissive for cancer but that beyond its essential role at low IGF-1 concentrations, has only modest effects in cancer promotion.

[marcus300]

Many human prostate cancers overexpress GH1 or GH2 and GHR transcripts as evidenced in the Oncomine database (Table 2) [201]. Furthermore, an immunohistochemical study of 20 prostate cancers and 17 controls reported a fourfold increase in human GH expression in prostatic carcinoma Gleason scores 6–8. Co-expression of GH and GHR isoforms has also been reported at protein and mRNA levels in prostate cancer cell lines (e.g., ALVA-41, PC-3, DU 145) [71,79], with van Garderen and Schalken reporting six of seven prostate cancer lines expressing GH1 transcripts, and all expressing GHR transcripts [77]. Association of autocrine GH expression with prostate cancer contrasts with clinical studies show that acromegaly is associated with prostate hypertrophy but not malignancy [80], and the observation that GH replacement in GHD patients increases prostate size to normal without any increase in neoplasia [81]. As previously noted, absence of GH or GHR signaling results in resistance to T-antigen induced prostate cancer in mice and rats [55,82]. Loss of GH/IGF1 activity is also associated with impaired development of the prostatic ductal branching architecture that results from IGF-1 deficiency [83]. A reasonable hypothesis to explain these findings is that autocrine GH acts in a different manner from endocrine GH to promote cancer formation, whereas endocrine GH promotes hypertrophy in an IGF-1-dependent manner. This situation may apply to other cancers overexpressing GH1 and GH2 evident in the Oncomine database, such as chronic adult T-cell leukemia, ovarian mucinous carcinoma, endometrioid and clear-cell adenocarcinomas, and bladder urothelial cancers (Table 2) [201]. The GHR itself is also reported as overexpressed in a range of neoplasias (see earlier). Moreover, since human GH can activate the human prolactin receptor [84], the presence of overexpressed prolactin receptor in prostate cancer, T-cell leukemias and ovarian adenocarcinomas [201] raises the possibility that autocrine GH may also drive oncogenesis in these cancers.

The oncogenic actions of forced autocrine expression of human GH in immortalized human breast lines has been extensively studied by Lobie’s group. Thus, Zhu et al. have reported that overexpression of autocrine GH in mammary epithelial cell lines (particularly MCF-7 cells) results in increased cell proliferation, transformation and invasion, with an epithelial to mesenchymal transition [85]. This is associated with an altered transcript expression profile, with a number of oncogenic genes being upregulated by autocrine GH overexpression [86]. Autocrine GH led to increased expression of the oncogenic homeobox protein Hox-A1 and telomerase protein together with downregulation of junctional plakoglobin and increased DNA methyltransferase-3 activity resulting in methylation of the plakoglobin promoter [87]. Human GH overexpression also resulted in increased activity of matrix metalloproteases-2 and -9, redistribution of E-cadherin to the cytoplasm and increased secretion of trefoil factor 3 (TFF3), proposed to mediate the oncogenic actions of autocrine GH by Lobie’s group by paracrine actions on adjacent cells (Figure 2) [87]. Autocrine production of human GH was associated with increased angiogensis in xenografts, in accord with its ability to recruit endothelial cell precursors and to induce VEGF [88]. Of interest, autocrine human GH-driven proliferation of MCF-7 cells, transcriptional activation and cell spreading was reported to be completely blocked by the addition of exogenous human GHR-specific antagonist B2036/pegvisomant [89]. These studies indicate that overexpression of human GH in transformed cells is oncogenic. Is there, then, a difference between autocrine and endocrine GH signaling? van den Eijnden and Strous examined this question in ts20 cells, finding that GHR signaling in cells with autocrine GH does not manifest before the Golgi, and is associated with a very low level of chronic STAT5 and GHR tyrosine phosphorylation, but robust induction of a STAT5-responsive luciferase reporter [90]. Sustained GHR signaling would be associated with induction of negative-feedback regulators such as SOCS proteins, hence the pulsatile nature of pituitary GH secretion. It would appear that sustained autocrine GH stimulation does something different, for example, results in the gain of a phenotype characteristic of oncogenic transformation, yet sustained endocrine GH stimulation (as in acromegaly) results in only a modest increase in cancer susceptibility. One is driven to the conclusion that intracellular signaling events are important in the transformation process, particularly since Strous’ group found that autocrine GH-expressing cells are insensitive to external (endocrine) GH [90]. Conversely, Lobie’s group have reported that exogenous B2036/pegvisomant blocks autocrine growth, implying that autocrine GH is secreted and acts externally (or that the antagonist is internalized at high concentrations). It may be that both a hormone-induced signal from the plasma membrane and an intracellular signal are necessary for full autocrine action by GH.

[marcus300]

Given the animal and human data supporting critical involvement of the GH–IGF-1 axis in cancer incidence and progression, the development of GH antagonists for use alone or in conjunction with IGF-1R blockers, is of key importance. While pegvisomant is partially effective in suppressing cancer in animal models, it is disadvantaged by high cost and likely impairment of its action by elevated plasma GH resulting from lowered IGF-1 feedback. Therefore, other means of suppressing GH secretion or action would be most useful. Nevertheless, clinical trials of pegvisomant in cancer in conjunction with other adjuvant therapies appear warranted. The ability of GH and IGF-1 to confer resistance to radiotherapy [144,145] and chemotherapy [146] is a further reason for use of GH antagonists.

Given the potential role of GH in promoting stem cell activation [136,147], we can expect to see studies relating GH action to cancer stem cells and GH in the future.

Finally, while no activating clinical mutations in the GHR have been identified to date, this is a reasonable probability based on other activating mutations in cytokine receptors. Screening for activating mutations in GH/IGF-1-dependent cancers such as prostate cancer and lymphoma would appear warranted.

[marcus300]

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• An authoritative and comprehensive review describing the cancer promoting actions of IGF-1.

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