Growth Hormone And Insulin Like Growth Factor-1

Tissue Responsiveness To Growth Hormone

Although a decline in the amplitude of growth hormone pulses is an important determinant of the decrease in plasma IGF-1, more recent studies demonstrate that growth hormone induced IGF-1 secretion is diminished in elderly individuals and suggest that resistance to the action of growth hormone may be a secondary contributing factor in the low plasma IGF-1 concentrations . In rodents, a two-fold increase in growth hormone receptors has been observed with age but this increase fails to compensate for the reduction in growth hormone secretion . A more detailed investigation revealed that the KD and apparent size of the growth hormone receptor were not altered with age whereas the capacity of growth hormone to induce IGF-1 gene expression and secretion was 4050% less in old than in young animals.

Gh Ghr And Follicular Growth

GH has been reported by many studies to modify the growth of developing ovarian follicles . In vitro studies using caprine preantral follicles have demonstrated the stimulatory effect of GH on antral follicle development particularly during the initial antral phase . GH exposure over 18 days increased the diameter of caprine preantral follicles, and using in vitro maturation protocols, led to the generation of healthy oocyte-cumulus complexes, production of more metaphase II oocytes, and better fertilization ability . The same investigators showed that GH exposure over a similar period functioned synergistically with Follicle Stimulating Hormone in supporting canine follicular growth, increasing the follicular diameter, promoting viability, and it was suggested that this was due to GH-induced production of antral follicle fluid and consequential antrum formation . This response was largely observed in a separate study in secondary bovine follicles exposed to GH for 32 days, where the follicle diameter, antrum formation and E2 release were all increased .

What Is A Gh Stimulation Test

GH stimulation tests help to diagnose GH deficiency and hypopituitarism. For a stimulation test, a sample of blood is drawn after 10-12 hours of fasting. Then, under close medical supervision, you are given an intravenous solution of a substance that normally stimulates the release of GH from the pituitary. Blood samples are then drawn at timed intervals and GH levels are tested in each to see if the pituitary gland was stimulated to produce the expected levels of GH. Since exercise normally causes an increase in GH, vigorous exercise may also be used as the stimulant for GH release.

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What Is It Used For

An IGF-1 test is used to diagnose growth hormone disorders, including:

• GH deficiency. In children, GH is essential for normal growth and development. A GH deficiency can cause a child to grow more slowly and be much shorter than children of the same age. In adults, GH deficiency can lead to low bone density and reduced muscle mass.
• GH insensitivity, also known as Laron syndrome. This is a rare genetic disorder in which the body is unable to use the growth hormone it produces. It also causes slowed growth rate and shorter than normal height in children.
• Gigantism. This is a rare childhood disorder that causes the body to produce too much growth hormone. Children with gigantism are very tall for their age and have large hands and feet.
• Acromegaly. This disorder, which affects adults, causes the body to produce too much growth hormone. Adults with acromegaly have thicker than normal bones and enlarged hands, feet, and facial features.

Epidemiological Studies Of High Igf

Epidemiological studies in adults have suggested that high IGF-I concentrations could potentially be associated with certain cancers however, opposite effects have been reported for high IGFBP-3. Hypothetically, assessment of possible risk can be identified using tertiles of IGF-I SDS and IGFBP-3 SDS. Patients with levels in the possible risk area of high IGF-I SDS with concomitant low IGFBP-3 SDS may require a reduction in GH dose in order to avoid any potential risk of adverse events .

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Consideration And Diagnosis Of Ghd

2.1. Conditions where GH provocative testing is not required to diagnose GHD.

Of note, for patients who do not meet the following criteria yet present a high index of suspicion, GHD can be diagnosed by the conventional approach.

2.1.1. We suggest establishing a diagnosis of GHD without GH provocative testing in patients possessing all of the following three conditions: auxological criteria, hypothalamic-pituitary defect , and deficiency of at least one additional pituitary hormone.

2.1.2. We suggest that GHD due to congenital hypopituitarism be diagnosed without formal GH provocative testing in a newborn with hypoglycemia who does not attain a serum GH concentration above 5 µg/L and has deficiency of at least one additional pituitary hormone and/or the classical imaging triad .

Technical Remark: A low GH concentration at the time of spontaneous hypoglycemia is alone insufficient to diagnose GHD.

2.2. GH provocative testing.

2.2.1. We recommend against reliance on GH provocative test results as the sole diagnostic criterion of GHD.

Technical Remark: Very low peak GH levels on provocative testing are consistent with severe GHD, and patients with such results are expected to benefit greatly from GH treatment. However, the threshold test result that distinguishes normal from partial GHD that responds to treatment has not been well established.

Technical Remark: Best available evidence exists for boys evidence is extrapolated to girls.

Growth Hormone Feedback To Insulin

Acromegaly is characterized by unrestrained growth hormone secretion and subsequent elevated insulin-like growth factor -1 resulting from a benign somatotroph GH-secreting adenoma in the pituitary. In healthy individuals, the negative feedback loop regulating GH secretion is modulated in part by IGF-1, which inhibits basal GH secretion as well as GH secretion mediated by hypothalamic growth hormone releasing hormone . IGF-1 also suppresses basal and GHRH-induced gene transcription and downregulates GH receptors in the periphery to limit local GH action. In acromegaly, somatotroph proliferation and transformation may lead to disrupted GH feedback regulation, leading to tonically elevated GH and IGF-1 levels that remain unrestrained.

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Contributions Of Circulating Vs Peripherally Secreted Igf

Additional knockout of the IGFALS gene inhibited linear growth indicating that serum IGF-I, not just locally produced IGF-I, is important to maintain bone growth and deficiency of ALS in children is associated with growth retardation . Mice deficient in liver-specific IGF-I also had a large increase in serum GH, which could have contributed to maintain postnatal growth . Thus, GH and IGF-I appear to act synergistically, with both involved in bone growth and remodelling, to influence longitudinal growth and bone strength.

Why Do I Need An Igf

Your provider may order an IGF-1 test if you or your child has symptoms of a GH disorder.

Symptoms of GH deficiency or GH insensitivity in children include:

• Slowed growth rate compared with children of the same age
• Shorter height, arms, and legs, and lower weight than children of the same age
• Poor nail growth

Adults with GH deficiency may have symptoms such as fatigue and decreased bone density and muscle mass. But IGF-1 testing isn’t common for adults, as other disorders are much more likely to cause these symptoms.

Symptoms of GH excess in children include:

• Excessive growth compared with children of the same age
• Overly large head
• Larger than normal hands and feet
• Mild to moderate obesity

Symptoms of GH excess in adults include:

• Deep, husky voice
• Larger than normal facial features such as lips, nose, and tongue
• Excessive sweating and body odor
• Thickening of bones
• Erectile dysfunction in men

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Gh And Ovarian Cell Proliferation Differentiation And Gonadotropin Response

Interaction of FSH and LH with their complementary gonadotropin receptors induces downstream signaling that is critical for steroidogenesis, proliferation, and differentiation, and both signal through the cyclic adenosine monophosphate/protein kinase A pathway to enhance production of E2 and P4 . FSHR and LHR are both G-protein coupled receptors that transmit the intracellular cascade via adenylate cyclase activity, cAMP accumulation, with subsequent activation of PKA, which then phosphorylates the transcription factor CREB . CREB binds cAMP response elements in genomic DNA causing the transcription of various genes including those encoding for steroidogenic enzymes and cholesterol transport, the precursor substrate for sex steroid synthesis .

Transitional Care After Childhood Gh Treatment

5.1. We recommend that patients with multiple pituitary hormone deficiencies regardless of etiology, or GHD with a documented causal genetic mutation or specific pituitary/hypothalamic structural defect except ectopic posterior pituitary, be diagnosed with persistent GHD.

5.2. We recommend re-evaluation of the somatotropic axis for persistent GHD in persons with GHD and deficiency of only one additional pituitary hormone, idiopathic isolated GHD , IGHD with or without a small pituitary/ectopic posterior pituitary, and in patients after irradiation.

Technical Remark: Testing can be performed after a trial of at least 1 month off GH treatment.

5.2.1. We suggest that measurement of the serum IGF-I concentration be the initial test of the somatotropic axis if re-evaluation of the somatotropic axis is clinically indicated.

5.2.2. We recommend GH provocative testing to evaluate the function of the somatotropic axis in the transition period if indicated by a low IGF-I level.

5.3. We suggest that GH treatment be offered to individuals with persistent GHD in the transition period. There is evidence of benefit however, the specifics of the patient population that benefits, the optimal time to re-initiate treatment, and the optimal dose are not clear.

Technical Remark: The transition period is the time from late puberty to establishment of adult muscle and bone composition, and encompasses attainment of AH.

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Gh Treatment Of Patients With Iss

6.1. In the USA, for children who meet FDA criteria, we suggest a shared decision-making approach to pursuing GH treatment for a child with ISS. The decision can be made on a case-by-case basis after assessment of physical and psychological burdens, and discussion of risks and benefits. We recommend against the routine use of GH in every child with height SDS -2.25.

Technical Remark: While studies have shown GH treatment increases the mean height of treated cohorts, there is marked interindividual variability in responses, including some individuals who do not respond to treatment.

6.2. We suggest a follow-up assessment of benefit in HtSDS and psychosocial impact 12 months after GH initiation and dose optimization.

6.3. Because there is overlap in response between dosing groups, we suggest initiating GH at a dose of 0.24 mg/kg/week, with some patients requiring up to 0.47 mg/kg/week.

Physiological Roles Of Igf

IGF-I is a relevant hormone both in embryological and postnatal states. Although it is mainly produced by the liver, virtually every tissue is able to secrete IGF-I for autocrine/paracrine purposes.

Pituitary and liver establish negative feedback mechanisms common to any other endocrine gland. The pituitary somatotrophs are under a delicate controlled balance between stimulatory growth horomone-releasing hormone and inhibitory somatostatin, both generated by the hypothalamus as a result of systemic and cortical neurogenic, metabolic, and hormonal factors. In another hand, IGF-I inhibits GH secretion acting on the hypothalamus by two feedback mechanisms: firstly, inhibiting GH gene expression and secondly by stimulating the secretion of somatostatin, that inhibits GH production.

Secreted GH can exist in both free and bound states by the GHBP . Also, activation of liver GH receptor, promotes IGF-I synthesis which, in turn, is released to the circulation and can be found in its free form but mainly bound to IGFBPs .

In an attempt to provide a coherent and integrated review of certain physiological conditions where the role of IGF-I has been well established, we have summarized them in this review .

Figure 2

GH/IGF-I axis and targets. Pituitary GH interacts with GH receptors in hepatocytes increasing IGF-I secretion for endocrinological purposes in different organs, although an autocrine/paracrine IGF-I production by those organs is also present.

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Safety Issues Of Gh Treatment For Patients With Ghd

4.1. We recommend that prospective recipients of GH treatment receive anticipatory guidance regarding the potential adverse effects of intracranial hypertension, slipped capital femoral epiphysis , and scoliosis progression.

4.2. We recommend monitoring of GH recipients for potential development of intracranial hypertension, SCFE, and scoliosis progression by soliciting pertinent history and performing a physical examination at every follow-up clinic visit further testing should be pursued if indicated.

4.3. We recommend re-assessment of both the adrenal and thyroid axes after initiation of GH therapy in patients whose cause of GHD is associated with possible multiple pituitary hormone deficiencies .

Technical Remark: Evaluate for possible central adrenal and thyroid insufficiencies in those not yet diagnosed, and consider increasing hydrocortisone and/or levothyroxine doses in those already on these hormone replacement.

4.4. We recommend discussion about and monitoring of glucose metabolism of GH recipients who are at increased risk for diabetes due to insulin resistance.

4.5. Counseling prospective recipients of GH treatment regarding the risk of neoplasia.

4.5.1. We recommend informing at-risk patients about available data and encourage long-term follow-up with their oncologist.

4.5.1.1. For children with acquired GHD due to effects of a primary malignancy:

Can You Use Igf To Treat Diabetes

Mecasermin is an artificial version of IGF. Its a prescription medication doctors use to treat growth failure in children. One of the potential side effects of mecasermin is hypoglycemia. If you have hypoglycemia, that means you have low blood glucose.

Research shows that IGF is capable of suppressing type 1 diabetes in mice. In type 1 diabetes, the bodys immune system turns on itself, attacking beta cells in the pancreas that produce insulin. IGF may be able to defend against the bodys own attack.

Some studies have shown that treatment with IGF may help control diabetes. It hasnt been developed for treatment of diabetes due to severe side effects, including:

• swelling of the optic nerve

While promising research exists, the relationship between IGF and diabetes is complicated. More research is necessary before doctors can use IGF to treat this complex disease.

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Study Selection And Data Extraction

All studies were screened on title, abstract, and keywords. For selected studies, full text articles were studied and checked against the in- and exclusion criteria. For all included full text articles, study characteristics were summarized in a data extraction form. This form consisted of general study characteristics, information on the study design, the used biomarkers, analytical assay, and the reported summary statistics. An overview of all variables documented in this data extraction form can be found in Online Resource 2.

Role Of Igf In Testes

Interestingly, GH-induced IGF secretion by Sertoli cells was reported to increase the number of LH receptors in Leydig cells, meaning that IGF could increase testicular androgen production , and both IGF-1 and IGF-2 were shown to enhance testosterone production . IGF also has proliferative actions on Sertoli cells in the same autocrine manner . As stated before, GH-induced effects on seminiferous tubules are mainly accomplished through IGF action . IGFR expression has been shown in porcine Leydig and Sertoli cells . The majority of the IGF-1 effects on Leydig cells was found by examining knock-out mice. IGF-1 knock-out mice exhibited significant stunting in the development of vas deferens, seminal vesicles and prostate, along with developmental delay of Leydig cells, which were fewer than normal . In addition, testosterone levels were reduced by 82%, and LH-stimulated testosterone production was decreased . However, capacitated sperm from these mice were able to fertilize oocytes . Interestingly, IGF regulates Leydig cell differentiation and stimulates hCG-dependent cAMP synthesis in order to stimulate steroidogenesis . hCG was also shown to upregulate the expression of IGFR in rat Leydig cells suggesting cross-talk between both pathways . Furthermore, IGF was demonstrated to increase responsiveness of porcine Leydig cells to physiological hCG concentrations and to pharmacological steroidogenesis activators .

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What Do The Results Mean

If your child’s results show lower than normal levels of IGF-1, it probably means he or she has a GH deficiency or insensitivity to GH. In a child, this may be caused by a genetic disorder or brain disease. Your child may benefit from treatment with GH supplementation. GH supplementation is an injected medicine that contains manufactured human growth hormone. When GH deficiency is diagnosed and treated early, some children can grow several inches in the first year of treatment. Others grow less, and more slowly, but still benefit from treatment.

If your results show lower than normal IGF-1, it may be due to a normal age-related decrease in the hormone or other condition. Your provider may order more tests to help make a diagnosis.

Higher than normal levels of IGF-1 may mean gigantism in children or acromegaly in adults. Gigantism and acromegaly are most often caused by a tumor in the pituitary gland, a small organ in the base of the brain that controls many functions, including growth. Treatment for the tumor may include radiation therapy, surgery, and/or medicine. If the disorder was not caused by a tumor, you or your child may need more tests.