Growth Hormone Deficiency I n Adults. Gita Majdi, M.D, MRCP(UK) Endocrinology Fellow Western University November 2013. Outline:. Physiology of Growth Hormone Pathophysiology & Presentation of Growth Hormone Deficiency in Adults Growth Hormone Replacement Therapy in Adults Somatopause.
Gita Majdi, M.D, MRCP(UK)
Somatotrophs are located predominantly in the lateral wings of the anterior pituitary gland
Comprise between 35% and 45% of pituitary cells .
These ovoid cells contain prominent secretory granules up to 700 µm in diameter.
The gland contains a total of 5 to 15 mg of GH.
From Asa SL. Tumors of the pituitary gland. In: Rosai J, ed. Atlas of Tumor Pathology, Series III, Fascicle 22. Washington, DC: Armed Forces Institute of Pathology, 1997:14.)
The human GH locus spans approximately 66 kilobases (kb) on the long arm of chromosome 17q22-24.
It contains a cluster of five highly conserved genes, each consisting of five exons separated by four introns.
Encode the various forms of human growth hormone (hGH) and human chorionic somatomammotropin.
Nature Reviews Endocrinology 6, 562-576 (October 2010)
The human growth hormone gene cluster consists of the genes that code for:
placental lactogen (PL; also known as chorionic somatomammotropin, CS),
growth hormone variant (GH-V; also known as placental growth hormone)
and growth hormone normal (GH-N; also known as pituitary growth hormone)
The cluster contains five genes, three PL and two GH genes that evolved from a common ancestral precursor by recombination events involving moderately repeated sequences
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Human GH is produced as a single chain, 191 amino acid, 22-kd protein.
The GHBPs function to dampen acute oscillations in serum GH levels associated with pulsatile pituitary GH secretion, and plasma GH half-life is prolonged by decreased renal GH clearance of bound GH.
Hypothalamic somatostatin ( SRIF, Somatotropin release-inhibiting factor) and GHRH are secreted in independent waves and interact together with additional GH secretagogues to generate pulsatile GH release.
Ghrelin is a 28-amino-acid peptide that binds the GHS receptor to induce hypothalamic GHRH and pituitary GH.
Ghrelin administration dose-dependently evokes GH release and also induces food intake.
The IGFs (somatomedins) are a family of peptides that are, in part, GH dependent and mediate many of the anabolic and mitogenicactions of GH.
Structure of the insulin-like growth factor IGF-1 peptide.
(Reproduced from Yakar S, Wu Y, Setser J, et al. The role of circulating IGF-1. Endocrine. 2002;19:239-248
Dopamine ? Biosynthesis of Growth Hormone
Reproduced from Rosenbloom A: Growth hormone insensitivity: physiologic and genetic basis, phenotype and treatment. J Pediatr. 1999;135:280-289.)
Source: Willams Textbook of Endocrinology 12th edition
From Thorner MO, Vance ML, Horvath E, et al. The anterior pituitary. In: Wilson JD, Foster D, eds. Williams Textbook of Endocrinology, 8th ed. Philadelphia, PA: Saunders; 1992:221-310
Integrated model of the GH-IGFBP-IGF axis in the growth process.
Three mechanisms are proposed.
1- growth hormone (GH) stimulates production of insulin-like growth factor 1 (IGF-1); circulating IGF-1 (endocrine IGF-1) then acts at the growth plate.
2- GH regulates hepatic production of IGF-binding protein 3 (IGFBP-3) and the acid-labile subunit (ALS) of the IGFBP complex; IGF-1 binds to IGFBP-3 and with ALS, forming the 150-kd ternary complex. Proteases then cleave this complex into fragments that release IGFBP-3 and IGF-1 in the intravascular space and at the growth plate.
3- GH induces differentiation and local IGF-1 production, and IGF-1 acts via autocrine and paracrine mechanisms to stimulate cell division. T3, triiodothyronine.
EndocrinolMetabClin North Am. 1996;25:615-631
GH binds to the growth hormone receptor (GHR) dimer, which undergoes internal rotation, resulting in Jak2 phosphorylation (P) and subsequent signal transduction.
Ligand binding to a preformed GHR dimer results in internal rotation and subsequent phosphorylation cascades.
GH targets include insulin-like growth factor 1 (IGF1), c-fos, cell proliferation genes, glucose metabolism, and cytoskeletal proteins.
GHR internalization and translocation (dotted lines) induce nuclear proproliferation genes via importinα/β (Impα/Impβ) coactivator (CoAA) signaling.
IGF1 may also block GHR internalization, acting in a feedback loop.
ERK, extracellular signal-related kinase; IRS, insulin receptor substrate; JAK 2, Janus kinase 2; MEK, dual specifying mitogen-activated kinase 2.
J Clin Invest. 2009;119:3189-3202.)
- Biosynthesis of Growth Hormone Validated Stimulation Tests for the Diagnosis of GH Deficiency in Adults
-Insulin induced hypoglycemia is the gold standard test for GHD.
-Normal subjects respond to insulin-induced hypoglycemia with peak GH concentrations of more than 5 µg/L
Effects of recombinant human growth hormone (rhGH) replacement on lean body mass and fat mass in adults with GH deficiency.
GH replacement induces profound effects on protein, fat, and energy metabolism, resulting in increased lean body mass and decreased fat mass without a significant change in body weight
(Reproduced with permission from Salomon F, Cuneo RC, Hesp R, et al. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med. 1989;321:1797-1803.)
Computed tomographic scan through the abdomen before (top) and after treatment with human growth hormone (hGH) (bottom) in a GH-deficient patient. (Figures provided by B.A. Bengtsson.)
Ten-year growth hormone (GH) therapy in 87 GH-deficient adults. CI, confidence interval; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; TC, total cholesterol.
(Modified from Melmed S. Update in pituitary disease. J ClinEndocrinolMetab. 2008;93:331-338.)
Mean concentrations of insulin-like growth factor 1 (IGF-1) before and during incremental doses of growth hormone (GH)—0.5, 1.0, and 2.0 IU/day, equivalent to approximately 0.25 to 1.0 mg daily—during oral and transdermal estrogen therapy in eight GH-deficient women.
(From Wolthers T, Hoffman DM, Nugent AG, et al. Oral estrogen therapy impairs the metabolic effects of growth hormone (GH) in GH deficient women. Am J Physiol. 2001;281:E1191-E1196.)
Management of Biosynthesis of Growth Hormonesomatotropin deficiency in adults. Patients older than 60 years require lower maintenance doses. Women receiving transdermal estrogen require lower doses than those receiving oral estrogen preparations.
GH, growth hormone; IGF-1, insulin-like growth factor 1; Rx, treatment.
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Benign intracranial hypertension
Increase in melanocytic nevi
Elderly men and women secrete GH less frequently and at lower amplitude than do young people. GH secretion declines approximately 14% per decade in normal individuals.
serum levels of IGF1 are 20% to 80% lower in healthy elderly individuals than in healthy young adults.
The course of serum insulin-like growth factor 1 (IGF-I) concentrations in 131 healthy women (E) and 223 healthy men (F) during aging. Note the difference in the distribution of ages in the different panels.
(Adapted from Corpas E, Harman SM, Blackman MR. Human growth hormone and human aging. Endocr Rev. 14:20, 1993.)
(From Papadakis MA, Grady D, Black D, et al. Growth hormone replacement in healthy older men improves body composition but not functional ability. Ann Intern Med. 1996;124:708-716.)
GH, 30 µg/kg three times a week, was administered for 6 months to 52 healthy 69-year-old men with well-preserved functional ability but low levels of IGF1.
In one exercise trial enrolling frail nursing home residents, stair climbing improved by 23% to 34% after 10 weeks of high-intensity resistance training, but only a modest 7% improvement in stair climbing was seen after 2 years of treatment with capromorelin.
Change in power stair climb in elderly individuals (aged 65 to 84 years) with mild functional limitations after 6 and 12 months of therapy with placebo or one of four doses of the oral growth hormone secretagogue/ghrelin memetic, capromorelin. *, P < .05 in comparison with placebo group.
(Reproduced from White HK, Petrie CD, Landschulz W, et al. Effects of an oral growth hormone secretagogue in older adults. J ClinEndocrinolMetab. 94:1198, 2009.)
( GH administered subcutaneously at an initial dose of 30 µg/kg three times per week and then reduced to 20 µg/kg for 26 weeks was associated )