4. growth hormone and IGF

what tissues can GH affect?

1. Liver: IGF1 is produced in response to GH; glucose uptake is increased

2. Skeletal muscle: anabolism (when growing); glucose uptake; metabolism

3. Bones: linear growth; remodeling

4. Pancreas: effects insulin secretion (by dec tissue sensitivity to insulin); glycemic status is affected

5. Adipose Tissue: lipolysis (young and old)

6. Cardiac: remodeling; inotropy increased; chronotropy increased

7. Kidneys: impacts total body water; RAAS; water retentive

8. Endocrine: induces thyroid hormone synthesis; impacts reproductive endocrine function

what is SRIF?

stands for somatotroph release inhibiting factor, AKA somatostatin

what is released in the hypothalamus (relating to GH secretion) (3)?

1. GHRH

2. GH secretagogue

3. somatostatin/SRIF

what receptors do somatotrophs express in anterior pituitary (relating to GH secretion) (4)?

1. GHRH-R

2. GH secretagogue-R

3. SRIF-R

4. Dopamine-R

what increases GHRH secretion (6)?

1. hypoglycemia

2. arginine

3. ghrelin (hunger hormone)

4. dopamine

5. serotonin

6. sleep and exercise*

how does exercise stimulate GHRH (4)?

1. inc neuromuscular input

2. inc neural input (brain aware of inc activity)

3. inc core body temp

4. lactate production

**all are signs of increased metabolic activity

GH stimulates — production in the liver

GH stimulates IGF1 production in the liver

what else is produced in liver relating to GH? why?

production of binding proteins

• GHBP

• IGFBP

these BP inc half-life and decrease renal clearance

what inhibits GH release?

1. somatostatin → inhibits somatotrophs from releasing GH

2. glucose

3. IGF-1 → provides negative feedback to GHRH

what time does GH secretion rate spike?

during sleep → hypoglycemia, promote tissue repair and growth

what are the basic metabolic effects of GH?

GH is important for muscle repair so it prevents protein breakdown, creates energy through fat breakdown and maintains glycogen energy stores

1. inc lipolysis: promotes TG → FFA

2. dec proteolysis: inhibits protein → AA

3. dec glycogenolysis: inhibits glycogen → glu

how does GH affect blood glucose? and why?

1. increase plasma glucose

2. prevent glucose uptake (via insulin)***

***risk of insulin resistance

GH wants to maintain adequate blood sugar so there is enough carbohydrates present for muscle and bone use

what are the anabolic effects of GH and IGF1?

1. bone → inc deposition/mineralization

2. fat → inc lipolysis

3. skeletal muscle → shift from glycogenlysis to beta oxidation; anabolism; myocyte proliferation

aspects of bone affected by GH and IGF1 (5)?

1. Chondrocytes: longitudinal growth; IGF1 expression

2. Osteoblast: deposition (mineralization); IGF1 expression

3. Trabecular: site for chronic remodeling; inner surface (androgens, E2, GH, and IGF1)

4. Cortical: dense (mineral and ECM) structure for shape and structure; less remodeling; outer surface (androgens, E2, GH, and IGF1)

5. Growth plate: epiphysis; longitudinal growth (estrogen, GH, and IGF1)

age related changes in serum GH?

peak at puberty

decline after 20 y/o

can GH reverse/stop aging?

within normal/expected range for an age, NO it can’t

pituitary macroadenoma

tumor above or within pituitary gland → XS GH

mass effect → visual defects (temporal hemianopia or optic nerve obstruction)

what kind of visual defects can be observed in pituitary macroadenoma?

temporal hemianopia

optic nerve obstruction

gigantism vs acromegaly

gigantism → XS GH pre-growth plate closure

acromegaly → XS GH post-growth plate closure

in adult, when would you see sxs of XS GH?

chronic → 10 years

clinical features of chronic XS GH (7, 4)?

1. insulin resistance

2. HA

3. double vision, loss of visual fields

4. resistant HTN

5. ventricular hypertrophy

6. sexual dysfunction, problems with menstruation, infertility

7. bone changes (delayed, 9 yrs)

   1. frontal bossing

   2. cranial ridging

   3. wide hands, feet, nose

   4. mandibular overgrowth

explain CV pathophysiology of acromegaly

INC contractility, hypertrophy, HR, CO → biventricular hypertrophy → heart overworked leading to heart failure → acromegalic cardiomyopathy

how does acromegaly cause HTN?

1. GH inc lean body mass by inc skeletal m. and H20 retention

2. inc aldosterone

3. 1 and 2 inc effective circulating volume (ECV)

4. inc vascular smooth muscle tone

all of these cause HTN

[+high ECV inhibits RAAS]

what test do you use to determine GH excess? how does it work?

oral glucose tolerance test (OGGT)

theory:

1. if give oral glucose load, high glucose should inhibit GH release

2. draw blood GH at intervals following OGGT

3. if GH >=2ng/mL → EXCESS (ref: 0.5-1.7)*

*can also check for abnormally elevated IGF-1

tx of XS GH (not pituitary adenoma)?

1. somatostatin analogue → octreotide, lanreotide

2. GH-R antagonist → pregvisomant

tx of XS GH due to pituitary adenoma?

adenoma causes inc GH and PRL

normally dopamine inc GH, but in adenoma it can block PRL secretion and inhibit GH

1. dopamine receptor agonists → bromocriptine and cabergoline

what is Laron syndrome?

form of GH deficiency caused by mutations in GH-R → insensitivity to GH

• normal or elevated GH

• low IGF-1

pt will have short stature/dwarfism

testing for GH deficiency?

stimulate GH release

• arginine → inc GHRH

• exogenous GHRH

• exercise → inc metabolism → inc GHRH

• insulin → hypoglycemia → inc GH

clinical consequences of adult GH deficiency?

1. skeletal m.: dec lean body mass → dec muscle mass

2. bone: bone demineralization → osteoporosis

3. CV: reduced CO, reduced exercise capacity

4. adipocytes: dyslipidemia

5. insulin resistance + DM → central obesity

effects of GH doping

inc in lean body mass but ONLY due to H2O retention