Management of Growth

Hormone Deficiency in Adult

Ketut Suastika
FK Unud, Denpasar
PP Perkeni

Round Table Discussion Ikatan Dokter Anak Indonesia

MANAJEMEN DEFISIENSI HORMON PERTUMBUHAN PADA MASA TRANSISI DAN DEWASA
Minggu, 19 Juni 2022 : 13.00 – 15.30 WIB.
Growth
Hormone:
Physiology
Growth Hormone Secretion Patterns in Adults
Melmed S. N Engl J Med 2019;380:2551-62.
Changes in GH Secretion With Age: The “Somatopause”
• 24-hr integrated concentration of GH significantly correlated with age (P <.0001)

Individual and Mean Integrated GH Concentrations

12
+
10 Men
+ (n = 89)
+
24-Hr IGHC (μg/L)
8 +
+ + Women
+ + + (n = 84)
+ +++
6 ++ + ++
++ +
+
++ + +
4 ++
+ + +
+ ++++ +++ +
+++++ + +++ +
+
2 +++++ + + +
++ + + + + ++
GH, growth hormone; + ++++ +
++ + ++ + +
IGHC, integrated growth hormone +
concentration.
0
0 10 20 30 40 50 60 70
Yr
Zadik. J Clin Endocrinol Metab. 1985;60:513.
Major physiologic actions of growth hormone and insulin-like growth
factor 1 (IGF1) action

Given that growth hormone uses signal transducer -

and activator of transcription 5 (STAT5) to induce
both IGF1 and for many of its direct actions, it is IGF-1 GH
difficult to attribute specific roles to growth
hormone or IGF1 for many biologic effects. +
However, those actions that involve more direct
growth hormone action are placed to the right,
whereas those involving induced IGF1 to the left, Immune
acknowledging that these assignments may Lipolysis
function Insulin resistance
change. Note that the growth hormone–IGF1
system is regulated by the tight negative feedback
Skeletal Renal Chondrocyte Bone, Insulin
loop between hepatic IGF1 production and proliferation
pituitary growth hormone secretion. muscle function tooth synthesis
hypertrophy
GH, growth hormone; IGF1, insulin-like growth
factor 1. Cardiovascular Gastro- Hepatic
Reproduction Neurogenesis
endothelium intestinal metabolism

William’s Textbook of Endocrinology, 14th Edition, 2020

Adult Growth Hormone
Deficiency (AGDH):
Clinical Features and
Diagnostic Tests
What is Adult Growth Hormone Deficiency (GDH)?

• Adult GHD is a well-defined clinical entity characterized by

decreased lean body mass and increased fat mass, dyslipidemia,
cardiac dysfunction, decreased fibrinolysis and premature
atherosclerosis, decreased muscle strength and exercise capacity,
decreased bone mineral density (BMD), increased insulin
resistance, and impaired QoL.
• GHD may present as childhood-onset GDH (CO-GHD) or adult-
onset GDH (AO-GHD) and may occur either as isolated GDH
(IGHD) or associated with multiple pituitary hormone deficiencies
(MPHD).
Yuen KCJ et al. AACE 2019 Guideline. Endo Pract 2019; 25: 1191
Prevalence and Incidence of Adult-Onset GHD

• Estimated prevalence: 2-3 per 10,000 population1

• Comparative incidence (all per 100,000)1
• Childhood-onset GHD
• Boys: 2.58 (95% CI: 2.30-2.88); girls: 1.70 (95% CI: 1.48-1.96)
• Adult-onset GHD
• Men: 1.90 (95% CI: 1.77-2.04); women: 1.42 (95% CI: 1.31-1.54)
• Phenotypic features differ between childhood-onset and adult-onset GHD2

1. Feldt-Rasmussen. Endotext. 2017. 2. Yuen. Endocr Pract. 2019;25:1191.

 Etiology of Adult GHD

• 57% of adult GHD cases are • Nontumoral disorders have

caused by pituitary adenomas increased in prevalence, including
and craniopharyngiomas1 traumatic brain injury and head
• Childhood-onset GHD2 trauma related to sports and
subarachnoid hemorrhage3,4
• Idiopathic, organic
• Sheehan syndrome is another cause
• Etiology of hypopituitarism1,3
of hypopituitarism and GHD in adult
• Pituitary adenoma, Cushing disease, women3
acromegaly, pituitary atrophy,
craniopharyngioma, benign tumor
or lesion, aggressive tumor
(including hematologic neoplasm)

1. Feldt-Rasmussen. Endotext. 2017. 2. Molitch. J Clin Endocrinol Metab. 2011;96:1587.

3. Boguszewski. F1000Res. 2017;6:2017. 4. Yuen. Endocr Pract. 2019;25:1191.

Clinical
Features of
GH Deficiency
in Adults
Rigorously documented adult
growth hormone deficiency is
associated with central obesity,
loss of lean muscle mass,
decreased bone mass, and a
variable effect on the quality of
life
Melmed S. N Engl J Med 2019;380:2551-62.
Brain
• Increased social isolation
• Decreased quality of life, energy and drive, self-
esteem
Hypothalamic-pituitary dysfunction
• Pituitary mass
• Secondary adrenal, thyroid, and gonad failure
Cardiovascular
• Abnormal cardiac structure and function
• Increased levels of lipid and inflammatory markers
• Decreased fibrinolysis, maximum O2 uptake,
exercise capacity
Glucose metabolism
• Insulin resistance
Adipose tissue
• Pincreased fat mass and truncal obesity
• Decreased lean body mass
Bone
• Increased skeletal fragility and vertebral fracture
• Decreased bone density
Skeletal muscle
• Decreased muscle mass
 What Are the Features of Adult GHD, and Why Treat?

­ Psychosocial issues
¯ Decreased ­ Central fat – Low self-esteem
lean body deposition
mass – Depression
– Mental fatigue
– Poor memory
¯ Bone mineral ­ Glucose
density intolerance – Impaired cognition
– Social isolation
– Dissatisfaction with
¯ Physical ­ Dyslipidemia body image
performance

¯ Cardiac ­ Intima-media
capacity thickness

Simpson. Growth Horm IGF Res. 2002;12:1. Slide credit: clinicaloptions.com

 Algorithm for testing transition patients with clinical
suspicion of GHD (AACE 2019 Guideline)
Adult patient with clinical suspicion of GHD

Congenital defects Organic GHD Idiopathic isolated GHD or

Genetic defects 0,1 or 2 hormones deficiencies suspected hypothalamic GHD
Organic disease Low IGF-1 (<0 SDS)
3 hormones deficiencies
Low IGF-1 (<-2.0 SDS)
High suspicion Low suspicion
Low IGF-1 (<0 SDS) Normal IGF-1 (>0 SDS)
No further testing Observe
required
Treat Further testing required Further testing required

Legend for GST

Treat if:
- Peak GH <3.0 ug/L in normal-weight (BMI <25 kg/m2) patient
ITT Macimorelin GST - Peak GH <3.0 ug/L in overweight (BMI 25-30 kg/m2) patient
Peak GH <5.0 µg/L Peak GH <2.8 µg/L (see Legend) with a high pre-test probability
Treat Treat - Peak GH <1.0 ug/L in overweight (BMI 25-30 kg/m2) patient
with a low pre-test probability
- Peak GH <1.0 ug/L in obese (BMI >30kg/m2) patient
Yuen KCJ et al. AACE 2019 Guideline. Endo Pract 2019; 25: 1191
 Algorithm for testing adult patients with clinical suspicion
of GHD (AACE 2019 Guideline)
Adult patient with clinical suspicion of GHD

Organic GHD Organic GHD History of hypothalamic-pituitary tumor, surgery,

>3 hormones deficiencies 0,1 or 2 hormones deficiencies cranial irradiation, empty sella, pituitary apoplexy,
Low IGF-1 (<-2.0 SDS) Low IGF-1 (<0 SDS) traumatic brain injury, subarachonoid hemmorrhage,
autoimmune hypophysitis or Rathke”s cleft cyst

No further testing High suspicion Low suspicion

required Low IGF-1 (<0 SDS) Normal IGF-1 (>0 SDS)
Treat Observe
Further testing required Further testing required

Legend for GST

Treat if:
- Peak GH <3.0 ug/L in normal-weight (BMI <25 kg/m2) patient
ITT Macimorelin GST - Peak GH <3.0 ug/L in overweight (BMI 25-30 kg/m2) patient
Peak GH <5.0 µg/L Peak GH <2.8 µg/L (see Legend) with a high pre-test probability
Treat Treat - Peak GH <1.0 ug/L in overweight (BMI 25-30 kg/m2) patient
with a low pre-test probability
- Peak GH <1.0 ug/L in obese (BMI >30kg/m2) patient
Yuen KCJ et al. AACE 2019 Guideline. Endo Pract 2019; 25: 1191
AGHD: Therapy
Recommendations for Starting GH Doses in Adults with GHD
§ Age <30 yr: 0.3–0.4 mg/day (higher for transition and younger patients)
§ 30-60 yr: 0.2–0.3 mg/day
§ Age >60 yr: 0.1–0.2 mg/day
§ DM, obesity, or previous GDM: 0.1–0.2 mg/day
§ Target IGF-I SDS between -2 and +2

Yuen. Endocr Pract. 2019;25:1191.

 AACE 2019: Parameters to Monitor in
Adults With GHD Receiving GH Replacement Therapy

• Metabolic variables
• Body composition (BMI, waist circumference), BMD (DXA scan), CV (BP, pulse
rate), fasting lipids, physical capacity, glucose metabolism
• Quality of life
• QoL-AGHDA questionnaires
• Assessment for adverse events and safety
• Including monitoring for potential tumor growth with MRIs*
• Serum IGF-I*
• Assessment and management of other pituitary hormone deficiencies
*Required for safety monitoring and should be assessed regularly.

Yuen. Endocr Pract. 2019;25:1191.

 AACE 2019: Monitoring GH Replacement Therapy in Adults
With GHD

• Monitor at 6- to 12-mo intervals after achieving maintenance dose

• Monitoring should include clinical evaluation and assessment of AEs
• If initial bone DEXA scan abnormal, repeat at 2- to 3-yr intervals
• If a pituitary lesion present, perform periodic MRIs
• Patients receiving thyroid and GC replacement may need dose adjustments
after starting GH therapy
• Patients not already receiving thyroid or GC replacement should be
monitored for deficiencies, with replacement given if needed

Yuen. Endocr Pract. 2019;25:1191.

Growth Hormone (GH) Replacement Therapy in Adult- Onset GH
Deficiency: Effects on Body Composition in Men and Women
• Methods:
• A randomized, double-blind, placebo-controlled, multicenter study in 166 subjects with AGHD as a result of
hypothalamic-pituitary disease (acquired at >18 yr of age) to assess the effects of GH on these outcomes.
• GH was initiated at 0.0125 mg/kg.d, increased to 0.025 mg/kg.d as tolerated, or decreased to 0.00625 mg/kg.d for
12 months.
• Outcomes:
• Primary measures of efficacy included body composition, strength and endurance, and quality of life.
• Additional parameters included serum IGF-I concentrations, serum lipids, and bone mineral density.
• Results:
• GH-treated men and women demonstrated significant decreases in total body and trunk fat and increases in lean
body mass over base-line.
• In GH-treated men, mean IGF-I SD scores exceeded age-adjusted normal ranges, whereas similar doses produced a
smaller response in women.
• GH treatment was associated with significant improvements in total cholesterol and low- density lipoprotein (P < 0.05
for all).
• No significant treatment effects were observed in strength and endurance, quality of life, or bone mineral density.
• GH treatment was generally well tolerated.
• Conclusions:
• Subjects with AGHD should receive individualized GH therapy to maintain IGF-I between the mean value and +2 SD
and improve body composition and cardiovascular risk factors.

Hoffman AR et al. J Clin Endocrinol Metab 89: 2048–2056, 2004)

 Effects of GH Replacement in Adults With GHD:
Body Composition, Lipids, BP, and Glucose
• Meta-analysis of blinded, randomized, placebo-controlled trials of GH treatment in adults with GHD
• Treatment had beneficial effects on lean and fat body mass, total and LDL cholesterol, and diastolic blood pressure but reduced
insulin sensitivity

Impact of Treatment on Treatment Weighted Mean (SD) Global Effect Size

Trials, n
CV Risk Factors GH Placebo Change (GH-Placebo) (95% CI)
Lean body mass 19 473 474 2.82 kg (2.68)
Fat mass 13 352 345 -3.05 kg (3.29)
BMI 8 134 134 -0.12 kg/m2 (1.40)
Triglycerides 11 202 203 0.07 mmol/liter (0.36)
HDL cholesterol 13 267 261 0.06 mmol/liter (0.09)
LDL cholesterol 13 255 248 -0.53 mmol/liter (0.29)
Total cholesterol 15 310 306 -0.34 mmol/liter (0.31)
Diastolic blood pressure 10 200 201 -1.80 mm Hg (3.77)
Systolic blood pressure 9 190 191 2.06 mm Hg (5.34)
Insulin 11 192 194 8.66 pmol/liter (6.98)
Glucose 13 254 257 0.22 mmol/liter (0.14)
-0.4-0.3-0.2-0.1 0 0.1 0.2 0.3 0.4
Maison. J Clin Endocrinol Metab. 2004;89:2192. Slide credit: clinicaloptions.com
 Effects of GH Replacement in Adults With GHD:
Bone Mineral Density
BMD Response to 2 Yr of GH Treatment in Adults With GHD According to Z Score at BL

Lumbar Spine L2-L4 Femoral Neck Z score ≥-1

17.5
P <.01
17.5
P <.01 Z score ≤-1
1.5 1.5
12.5 12.5
10 10
7.5 7.5
Change From BL (%)

5 5
2.5 2.5
0 0
-2.5 -2.5
BL 6 12 18 24 BL 6 12 18 24

Femoral Trochanter Ward’s Triangle

17.5 17.5
1.5 NS 1.5 P <.001
12.5 12.5
10 10
7.5 7.5
5 5
2.5 2.5
0 0
-2.5 -2.5
BL 6 12 18 24 BL 6 12 18 24
Mo
Johannsson. J Clin Endocrinol Metab. 1996;81:2865. Slide credit: clinicaloptions.com
 Effects of GH Replacement in Adults With GHD:
QoL and Days of Sick Leave
QoL in Hypopituitary Patients With Adult-Onset GHD Change in Days of Sick Leave in Adult Patients
During 7 Yr of GH Replacement: QoL-AGHDA1 With GHD During 2 Yr of GH Replacement2

10 20
9 *P <.001. *P <.05. †P <.01. ‡P <.001 vs BL.

Sick Leave (Days/6 Mo)

8
QoL-AGHDA Score

7 * 15
6 *
* * †
5 10
4
3 *
‡
2 5
1 †
0 0
0 1 3 5 7 0 6 12 18 24
Yr Mo
§ Partners surveyed reported significant improvement in patient alertness, activity, endurance, and mood
with GH treatment but not placebo3
1. Elbornsson. Eur J Endocrinol. 2017;176:99. 2. Verhelst. Clin Endocrinol (Oxf). 1997;47:485.
3. Burman. J Clin Endocrinol Metab. 1995;80:3585. Slide credit: clinicaloptions.com
 FDA-Approved Long-Acting GH Therapies: Somapacitan
Phase III REAL 1 Trial of QW Somapacitan Vs Daily GH Vs Placebo in Untreated Adult GHD (N = 301)1
Placebo Somapacitan Daily Placebo/soma Soma/soma
Daily GH/daily GH Daily GH/soma
Truncal Fat Percentage
4 4
ETD -1.53
3 3 ETD 1.15
(95% CI: -2.68; -0.38)
Change week 34 (%)

Change week 86 (%)

(95% CI: -0.10; 2.40)
2 P = .0090 2 P = .0715
1 1
0 0
-1 -1
-2 -2
-3 -3
-4 -4

• Once-weekly SC injection
• Approved 2020 for use in adult GHD2
1. Johannsson. J Clin Endocrinol Metab. 2020;105(4):e1358. 2. Somapacitan PI. Slide credit: clinicaloptions.com
 All-cause mortality in studies on hypopituitarism with or
without growth hormone replacement therapy (GHRT)

Data are given as standardized mortality ratios (SMRs) with 95% confidence intervals (CIs) and numbers of observed (Obs.) and expected (Exp.) deaths for
studies with GHRT (upper) and without (lower) GHRT.

van Bunderen CC and Olsson DS. Reviews in Endocrine and Metabolic Disorders (2021) 22:125–133
 AEs of GH Replacement Therapy in Adult GHD

• Short term • Long term

• Related to sodium and
water-retaining properties
• Insulin-antagonizing effects
• Usually dose related:
edema, arthralgias,
myalgias, hyperglycemia
• Potential induction of cell
growth and proliferation
• Possible increased risk
of tumor recurrence and
de novo neoplasia

AEs can be minimized by avoiding overtreatment and maintaining serum IGF-I

levels within the age-adjusted reference range

Yuen. Endocr Pract. 2019;25:1191.

 Safety Concerns Associated With Long-term GH
Replacement
• DM and glucose intolerance: use low GH doses, optimize antidiabetic
therapy
• History of active malignancy and proliferative diabetic retinopathy:
contraindicated
• Strong family history of cancer: careful consideration
• Previous history of cancer: careful consideration, discuss with oncologist,
initiate >5 yr after cancer remission, use low GH doses
• History of CVD: GH replacement exerts positive effects on some CV risk
markers
• Recurrence of pituitary adenoma: no increase in relative risk
• Cancer risk: no increased risk
• Mortality risk: no increased risk

Boguszewski. Pituitary. 2021;24:810. Yuen. Endocr Pract. 2019;25:1191. Slide credit: clinicaloptions.com
Majority view of the effect of GH treatment for approved
indications on cancer risk in children and adults
Age at onset of New primary cancer Recurrence of the primary Second or subsequent
GH treatment cancer in survivors neoplasm in survivors
Child No evidence for GH No evidence for GH Risk present but diminishes
treatment effect Level: treatment effect Level: with time from onset of GH
robust robust treatment Level: suggestive
Adult No evidence for GH Insufficient data available Insufficient data available
treatment effect Level:
suggestive

The term ‘robust’ is used when there are multiple independent published sources supporting the
statement (see Supplemental References). The term ‘suggestive’ is used when there are less than three
sources supporting the statement. The term ‘insufficient’ is used when available publications provide
inadequate evidence to support the statement.

Alen DB et al. European Journal of Endocrinology (2016) 174, P1–P9

Health Care Transition
Health Care Transition (HCT)
• HCT is the “purposeful, planned movement of adolescents and young adults with and without chronic
physical, behavioral, and developmental conditions from child-centered to adult-oriented healthcare
systems.”
• It not only represents the passage from one developmental stage to another (dependence to independence
to interdependence), but also represents the passage from one type of care to another (pediatric/family-
centered care to adult/patient-centered care) and often the change to a different healthcare setting.

• Child-centered healthcare • Adult-oriented healthcare

• Pediatric/family-centered care • Adult/patient-centered care

White PH. https://www.clinicaloptions.com/diabetes/programs/2022/adult-g...Qnl863imgWFZfvNNO9BcYL5iK_4ziIA1CNoqBfRukCD4M1o0-tCr2Oiz-Uaaw

Health Care Transition (HCT)
• Although all youth transition to adult-focused care, usually between the ages of 18 and 21, youth with chronic conditions such as
those with GHD typically require a more explicit process of transition planning and integration into adult healthcare, to address
barriers to continuity of care, lack of disease education about the need for continued GH replacement, and lack of knowledge about
managing their own health.
• A structured transition process should include three components: (1) planning, (2) transfer, and (3) integration into adult healthcare.
These steps should occur over time, beginning in early adolescence around the age of 12-14 years in a pediatric approach to care
and continuing into young adulthood in an adult approach to care.

Planning Transfer Integration

12-14 years 18-21 years into adult

White PH. https://www.clinicaloptions.com/diabetes/programs/2022/adult-g...Qnl863imgWFZfvNNO9BcYL5iK_4ziIA1CNoqBfRukCD4M1o0-tCr2Oiz-Uaaw

 Optimizing Transition of Care from Pediatric to
Adult Growth Hormone Deficiency Care: Unmet Needs

Patient/ Caregiver Pediatric Endocrinologist Adult Endocrinologist

§ Lack of disease education (eg,
need for continued GH
replacement)*
§ Lack of expectations for
managing disease as an adult*
§ Lack of treatment options
§ Lack of adherence*
§ High cost
§ Inconsistencies in lab
§ Lack of communication and
planning*
§ Lack of effective model for
transferring young adults to
adult endocrinologist*
§ Lack of lab standardization of
IGF-I and GH assays
§ Lack of education awareness
about treatment of adults with
GHD
§ Lack of knowledge of how to
manage/engage young adults
with pediatric-onset
conditions*
§ Lack of standardization of
assays and consistent
retesting and treatment
monitoring

*Addressed by structured HCT process recommended by AAP/AAFP/ACP Clinical Report.

Yuen. Growth Horm IGF Res. 2021;56:101375.

 The ideal patient journey for patients with childhood-onset growth
hormone deficiency
Pediatric care
GH stimulation testing
Diagnosis of GHD
GH treatment
Ongoing communication about the benefits of GH therapy throughout the life span

Transition care
Either the pediatric or adult endocrinologist could take the lead in completing the testing, depending on their confort level and
accessibility to the tests
Communication and coordination between pediatric and adult care providers
Reassess etiology of GHD and indications for GH replacement
Retesting:
Suspend GH replacement
IGF-1/GH stimulation

Resume/adjust GH dose Discontinue GH replacement

Adult care
Continue GH replacement as needed
Retest via IGF-1 and/or GH stimulation as needed
Recommend monitoring for clinical effectiveness and safety
Yuen. Growth Horm IGF Res. 2021;56:101375.
Assure that age-appropriate screening test are obtained