Growth Hormone Deficiency
In 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
Growth Hormone
Physiology: 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.)
• 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.
Biosynthesis of Growth Hormone
Nature Reviews Endocrinology 6, 562-576 (October 2010)
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
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.
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).
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.
IGF1
The IGFs (somatomedins) are a family of
peptides that are, in part, GH dependent and
mediate many of the anabolic and mitogenic
actions 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 ?
Reproduced from Rosenbloom A: Growth hormone insensitivity: physiologic and
genetic basis, phenotype and treatment. J Pediatr. 1999;135:280-289.)
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
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; 1992:221310
Interval
Young Adult
Fasting
Obesity
Middle Age
24-hr
Secretion 540 ± 44
(µg/24 hr)
2171 ± 333
77 ± 20
196 ± 65
Secretory
bursts (no. 12 ± 1
in 24 hr)
32 ± 2
3 ± 0.5
10 ± 1
GH burst
45 ± 4
(µg)
64 ± 9
24 ± 5
10 ± 6
GHBP
• Circulating growth hormone–binding proteins (GHBPs) include a 20-kd lowaffinity 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
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 IGFbinding protein 3 (IGFBP-3) and the acidlabile 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.
Endocrinol Metab Clin North Am. 1996;25:615-631
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), cfos, cell proliferation genes, glucose metabolism, and
cytoskeletal proteins.
GHR internalization and translocation (dotted lines)
induce nuclear proproliferation genes via importin α/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.)
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.
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 ldopa, and combinations such as arginine plus GHRH, or GHRP plus GHRH
are more potent than ITT alone .
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.
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.
GHD
Clinical Consequence
Body Composition
General and central adiposity
Reduced lean mass
Reduced bone mass
Function
Reduced exercise capacity
Muscle weakness
Impaired cardiac function
Hypohidrosis
Quality of Life
Low mood
Fatigue
Low motivation
Reduced satisfaction
Cardiovascular Risk Profile
Abnormal lipid profile
Insulin resistance
Increased inflammatory markers
Intimal media thickening
Effect of GH Replacement
Decrease
Increase
Increase
Improve
Increase
Improve
Increase
Improve
Improve
Improve
Improve
Improve
No change
Decrease
Decrease
Adult GHD
Laboratory
Effect of GH Replacement
Blunted peak GH to stimulation
Increase
Low IGF1
Increase
Hyperinsulinemia
Improve
High LDL- and low HDL-cholesterol
Improve
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 panhypopituitarism or a defined genetic or
developmental abnormality that causes complete and irreversible
GHD.
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
-
Test
Insulininduced
hypoglycemia*
ArginineGHRH*
GHRP6GHRH*
GHRP2GHRH*
GHRP2
Glucagon*
No. Subjects
(Normal/Deficient)
GH Threshold
(µg/L)
35/23
<5
74/49
<9
125/125
<15
30/36
<17
77/58
46/73
<15
<3
GH, growth hormone; GHRH, growth hormone–releasing hormone; GHRP, growth hormone–releasing
peptide.
Recommended by the Growth Hormone Research Society and the Endocrine Society.
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 levels are 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 GHD in 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.
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.
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.)
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.)
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 Clin Endocrinol Metab.
2008;93:331-338.)
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.)
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.
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.
Side Effects of GH
•
Edema
•
Arthralgias
•
Myalgias
•
Muscle stiffness
•
Paresthesias
•
Carpal tunnel syndrome
•
Atrial fibrillation
•
Headach
•
Benign intracranial
hypertension
•
Increase in melanocytic nevi
•
Hyperglycemia
•
Iatrogenic acromegaly
• 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 radiationinduced 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.
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.
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.)
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.
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.
Effects of Growth Hormone
(GH) Administration in
Healthy Older Men with
Low Levels of Insulin-Like
Growth Factor Type 1
(IGF1)
MEAN CHANGE IN VARIABLE
Parameter
IGF1 (ng/mL)
P Value
GH (n = 26)
Placebo (n = 26)
119.2
7.6
<.0001
Body Weight and Composition
Weight (kg)
0.5
1.0
>.2
Lean mass (%)
4.3
−0.1
<.001
Fat mass (%)
−13.1
−0.3
<.001
Bone mineral content
(%)
0.9
−0.1
.05
Skin thickness (%)
13.4
1.1
.09
Knee extension
3.8
1.3
>.2
(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.)
Muscle Strength (%)
Knee flexion
10.0
8.2
>.2
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.
Hand grip
−1.5
3.8
.11
Maximum Oxygen
Consumption (%)
2.5
−2.0
>.2
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.
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 Clin
Endocrinol Metab. 94:1198, 2009.)
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)
• Arthralgias in 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
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 GHIGF1 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.