Growth Hormone Deficiency I n Adults

1. Growth Hormone Deficiency In Adults Gita Majdi, M.D, MRCP(UK) Endocrinology Fellow Western University November 2013

2. Outline: • Physiology of Growth Hormone • Pathophysiology & Presentation of Growth Hormone Deficiency in Adults • Growth Hormone Replacement Therapy in Adults • Somatopause

3. Growth HormonePhysiology: Somatotroph cells 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.)

4. Biosynthesis of Growth Hormone 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)

5. THE HUMAN GROWTH HORMONE CLUSTER 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 • . Volume 26 Number 1 September 2010 www.GGHjournal.com ISSN 1932-9032

6. Growth Hormone 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.

7. Growth Hormone Assays • Plasma GH is measured by RIA (polyclonal or monoclonal) or by IRMA (dual monoclonal). • Measured GH concentrations are antibody dependent, and different antibodies bind to a heterogeneous spectrum of GH isoforms. • Monomeric 22-kd GH1, the most abundant circulating form, is the only GH standard of sufficient purity and quantity, and it is used as the basis for GH measurement; however, it accounts for only about 25% of circulating immunoreactivity. • Polyclonal antibodies, used in earlier RIAs, recognized several molecular forms of GH; newer immunometric assays employ highly specific monoclonal antibodies. • New GH assays based on measurement of GH bioactivity have been developed, including the eluted stain assay (ESTA) and the immunofunctional assay (IFA).

8. Growth Hormone Secretagogues and Ghrelin 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.

9. IGF1 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

10. Dopamine ? Reproduced from Rosenbloom A: Growth hormone insensitivity: physiologic and genetic basis, phenotype and treatment. J Pediatr. 1999;135:280-289.)

11. GH secretion • -GH secretion is normally episodic • two thirds of the total daily GH secretion produced at night • Major GH secretory pulses accounting for up to 70% of daily GH secretion • Normal GH secretion is characterized by secretary episodes separated by troughs of minimal basal secretion during which GH is undetectable • daily production of GH in the prepubertal state is 200 to 600 µg • daily production of GH 1000 to 1800 µg at the pubertal peak • In adulthood, production rates range from 200 to 600 µg/day with higher rates in women than in men • Adiposity that accompanies the aging process accounts for a significant component of declining GH output with increasing age. Source: Willams Textbook of Endocrinology 12th edition

12. Secretion of GH in Adults 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

13. GHBP • Circulating growth hormone–binding proteins (GHBPs) include a 20-kd low-affinity GHBP and a 60-kd high-affinity GHBP. • The high afinity GHBP corresponds to the extracellular domain of the hepatic GH receptor. • The GHBPs function to dampen acute oscillations in serum GH levels • Plasma GH half-life is prolonged by decreased renal GH clearance of bound GH. • GHBP concentrations are normal in hypopituitarism and acromegaly

14. Action of GH 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

15. GH Action 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.)

16. GH deficiency in Adults (1) • GH is the most abundant hormone in the adult pituitary gland • GHD in adults is recognized as a distinct entity. • GHD has negative effects on body composition, cardiovascular risk, quality of life, and physical functioning. • Life expectancy is reduced in hypopituitary patients with GHD,largely as a consequence of cardiovascular and cerebrovascular events, especially in female subjects. • Neither estrogen nor thyroid deficiency accounts for this increased risk and reduced survival.

17. GHD in Adults (2) • The diagnosis of adult GHD is established by provocative testing of GH secretion • Patients should receive adequate replacement for other pituitary hormonal deficits before testing. • Provocative tests include the insulin tolerance test (ITT), arginine, glucagon, clonidine, growth hormone–releasing peptide (GHRP), (GURP), and GHRH, alone or in combination with arginine or pyridostigmine. • GHRPs are synthetic analogs of ghrelin. • As provocative tests vary in their ability to evoke GH release, a single value cannot be applied as a diagnostic threshold across different tests . • ITT is a more potent stimulator of GH release than arginine, clonidine, or l-dopa, and combinations such as arginine plus GHRH, or GHRP plus GHRH are more potent than ITT alone .

18. Pathophysiology of Adult GHD • Congenital • Acquired causes: • 50% arise from pituitary tumors • 20% from extra pituitary tumors • 5% from inflammatory or infiltrative lesions • 15% of cases being idiopathic • Surgical or radiation treatment of pituitary and parasellar tumors is the most common cause of GHD, accounting for almost two thirds of cases.

20. Presentation Of GHD in Adults • Symptoms of GHD are nonspecific and include fatigue, lack of energy, social isolation, low mood, poor concentration, and reduced physical capacity. • The signs are also nonspecific and include general and central adiposity, reduced lean tissue, and bone mineral density along with unfavorable biochemical changes such as hyperlipidemia and glucose intolerance. • Some patients have established evidence of macrovascular disease, such as increased carotid intimal thickness. • GHD may also be associated with heart abnormalities including reduced left ventricular mass.

21. GHD

22. Adult GHD

23. Diagnosis of GH deficiency in Adults • Isolated GHD may be complete or partial • Up to 67% of children initially diagnosed with idiopathic GHD had normal GH responses when subsequently retested as adults for GHD after cessation of GH treatment • Therefore, children with GHD should be retested before GH treatment is continued into adulthood unless they have clearly documented panhypopituitarismor a defined genetic or developmental abnormality that causes complete and irreversible GHD.

24. - 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 -

26. Growth Hormone–Responsive Markers • Growth hormone–responsive markers include IGF1, IGF binding protein 3 (IGFBP3), and the acid-labile subunit of the IGFBP complex. • Serum IGF1 concentrations are useful for diagnosis only when age-adjusted normal ranges are used. • Normal concentration of IGF1 does not exclude the diagnosis. • Reduce IGF1 levelsare associated with malnutrition, liver disease, poorly controlled diabetes mellitus, and hypothyroidism. • A subnormal IGF1 level in an adult patient with coexisting pituitary hormone deficits is strongly suggestive of GHD. • The separation of IGF1 values between GH-deficient and normal subjects is greatest in the young. • IGF1 levels decline with aging in normal subjects. • IGF1 measurements become less reliable as a biochemical marker of GHDin patients older than 50 years. • Measurement of IGFBP3 or the acid-labile subunit does not offer any advantage over that of IGF1. • In patients with organic hypothalamic-pituitary disease, the prevalence of GHD is strongly linked to the number of pituitary hormone deficits, ranging from approximately 25% to 40% in those with no other deficit to 95% to 100% when more than three pituitary hormone deficiencies are present. • Patients with three or more pituitary hormone deficiencies and an IGF1 level lower than the reference range have a greater than 97% chance of being GH deficient and therefore do not require GH stimulation testing.

27. GH Therapy • GH replacement improves exercise capacity and performance in cardiac output and diastolic function. • Quadriceps or hip muscle strength improves significantly after 6 months of treatment, but muscle strength normalized after 2 years, without further significant change at 5 years. • A large survey in 304 patients showed improved quality of life and also significant reduction in the numbers of sick leave and doctor visits during 12 months of GH therapy. • A latency period up to 3 months is required before patients recognize benefits of hGH replacement, and these benefits are most obvious in those patients with the most profound symptoms and signs of GHD.

28. Growth Hormone Replacement Therapy 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.)

29. GH Therapy 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.)

30. GH Therapy 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.)

31. GH Therapy 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.)

32. Growth Hormone Administration • GH secretion is greater in the young, and greater in women than in men. • It is recommended that the starting dose of GH should be 0.2 mg/day in young men, 0.3 mg/day in young women, and 0.1 mg/day in older individuals. • These doses are then titrated according to serum IGF1 concentrations and at a rate that minimizes side effects. • If side effects occur, the dose should be reduced, and if no side effects are reported, the therapeutic goal is to maintain IGF1 levels in the normal age- and gender-matched range while avoiding levels in the upper quintile or above. • Dose determination based on body weight is not recommended due to large interindividual variation in absorption, insensitivity to GH, and lack of evidence that a larger replacement is required for heavier adults. • GH is administered by nightly subcutaneous injection to mimic the greater secretion of GH at night. • Side effects of GH in children are considerably fewer than those observed in adults.

33. Management of somatotropin 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.

34. Side Effects of GH • Patients with active malignancies should not be treated with GH. • The possibility that hGH might initiate new cancers or stimulate growth of preexisting benign tumors is an important theoretical issue. • When comparing the relative risk of brain tumor recurrence in 180 children treated with hGH versus 891 who did not receive hGH, the risk of recurrence after a mean of 6.4 years was lower in the treated group than in those not receiving hGH. • GH treatment does, however, increases the risk of radiation-induced second tumor, especially meningiomas. • Nevertheless, long-term surveillance with adequate control groups and avoidance of high IGF1 levels in adults being treated for adult GHD are required to ensure that adult GH replacement does not increase the incidence of new cancers or growth of existing benign tumors. Edema Arthralgias Myalgias Muscle stiffness Paresthesias Carpal tunnel syndrome Atrial fibrillation Headach Benign intracranial hypertension Increase in melanocytic nevi Hyperglycemia Iatrogenic acromegaly

35. GH Therapy in GHD Adults • GH replacement therapy in GH-deficient adults increased muscle mass, muscle strength, bone mass, and quality of life. • A beneficial effect on the lipid profile and an important decrease in fat mass were also observed in these patients.

36. Somatopause 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.)

37. Somatopause • As in hypogonadal individuals, adult GH deficiency can be considered a model of normal aging because a number of catabolic processes that are central in the biology of aging can be reversed by GH replacement. • Randomized, controlled trial enrolling healthy men 61 to 81 years old with serum IGF1 concentrations in the lower third for their age, reported in 1990 that GH treatment (30 µg/kg three times weekly for 6 months) restored the men's IGF1 levels to normal. • In the treatment group, lean body mass rose by 8.8%, and lumbar vertebral density increased by 1.6%. • The magnitudes of these initial changes were equivalent to a reversal of the age-related changes by 10 to 20 years. • However, during continuation of this study to 12 months, the significant positive effect on bone mineral density at any site was lost.

38. Somatopause • GH administration in healthy elderly individuals frequently caused acute adverse effects, such as carpal tunnel syndrome, gynecomastia, fluid retention, and hyperglycemia, which were severe enough for an appreciable number of individuals to drop out of these studies. • The most disappointing aspect, however, was that no positive effects of GH administration were observed on muscle strength, maximal oxygen consumption, or functional capacity. • In contrast, when GH was administered in combination with resistance exercise training, a significant positive effect on muscle mass and muscle strength was recorded that did not differ from that seen with placebo treatment, which suggests that GH does not add to the beneficial effects of exercise.

39. Effects of Growth Hormone (GH) Administration in Healthy Older Men with Low Levels of Insulin-Like Growth Factor Type 1 (IGF1) (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.

40. Somatopause • In a systematic study of 31 articles describing 18 unique, well-defined study populations the safety and efficacy of GH in the healthy elderly were reviewed. • A total of 220 participants who received GH for 107 person-years completed their studies. • The mean age was 69 years, and they were overweight (mean BMI, 28 kg/m2). • Initial daily GH dose (mean, 14 µg/kg of body weight), and treatment duration (mean, 27 weeks) varied. • Overall fat mass decreased by 2.1 kg, and lean body mass increased by 2.1 kg in those treated with GH; total cholesterol levels decreased by 0.29 mmol/L. • Disappointingly, no consistent changes in muscle strength, physical activity, or psychosocial outcomes were observed.

41. 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.)

42. Somatopause: • GH is associated with substantial adverse effects. • One particularly well-conducted, placebo-controlled study enrolling healthy women (n = 57) and men (n = 74) aged 65 to 88 years showed: ( 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 ) • Carpal tunnel syndrome in 38% of women (versus 7% for placebo) and in 24% of men (0% for placebo) • Edema in 39% of women (0% for placebo) and 30% of men (12% for placebo) • Arthralgiasin 46% of women (7% for placebo) and 41% of men (0% for placebo). Eighteen men treated with GH developed glucose intolerance or diabetes, compared with only seven men in the nontreatment group

43. Somatopause: Summary • During the aging process, GH-IGF1 axis activity declines. • GH administration in older adults causes an increase in lean body mass and an appreciable loss of fat mass. However, does not improve muscle strength and functional capacity in elderly people, despite restoration of circulating IGF1 concentrations to young adult levels. • Most dose regimens of GH cause appreciable adverse effects, and long-term safety with regard to tumor development and progression remains uncertain. • Oral ghrelin mimetics are also capable of restoring GH and IGF1 levels in the elderly population, together with an increase in appetite. Modest functional improvement was observed in one study after 2 years' administration. • There is no evidence to support recommending medical intervention in the GH-IGF1 axis as an anti-aging effort, to prolong life, or to rejuvenate healthy elderly people. Only elderly patients with GH deficiency caused by organic diseases, such as pituitary adenomas, benefit from GH replacement therapy.