Growth Hormone and puberty

Learning Objectives

• Intra uterine and Post natal Growth• Growth hormone release and its regulation• Direct and Indirect actions of Growth

hormone• Applied aspect• Puberty- role of nutrition and hormones• Growth periods

Intrauterine Growth

• Genetic factors determine early growth; maternal factors more important later in gestation

• Important roles for Growth hormone, IGF-II (early in gestation), IGF-I(later in gestation) and insulin

• Poor maternal nutrition and smoking - lowers birth weight.

Postnatal Growth

• Growth hormone, insulin, and thyroid hormone play major roles.

• Replacement of hormone deficiencies creates a period of catch-up growth, but it is soon replaced with a normal growth rate.

• There is no major role for gonadal sex steroids or for glucocorticoids on prepubertal growth but glucocorticoid excess will slow growth.

Growth hormone/ Somatotrophin

• The somatotrope produces growth hormone (GH, also called somatotropin) and is part of the hypothalamus-pituitary-liver axis .).

• GH is a protein that is similar to prolactin (PRL) and human placental lactogen (HPL).

• It is the single most important hormone for growth to adult stature.

• Large diurnal variation. The largest burst occurs with peak secretion occurring in the early morning just before awakening.

CONTROL OF GH SECRETION

Primarily by hypophysiotrophic hormones of hypothalamus-

Growth hormone releasing hormone [GHRH]Growth hormone release inhibiting hormone

[GHRIH]

Stimulate Growth hormone secretion Inhibit Growth hormone secretion

• Decrease blood glucose• Decrease blood FFA• Starvation/Fasting• Increase in circulating

levels of amino acids• Trauma, Stress ,excitement• Exercise• Deep Sleep (Stage III and

IV)• Growth hormone releasing

Hormone

• Increase blood glucose• Increase blood FFA• Obesity• Cortisol• GHIH and IGF-I• Growth hormone

Which of the following inhibits the secretion of growth hormone by the anterior pituitary?

(A) Sleep(B) Stress(C) Puberty(D) Somatomedins(E) Starvation(F) Hypoglycemia

The secretion of growth hormone is increased by

a. Hyperglycemiab. Exercisec. Somatostatind. Hypothermiae. Free fatty acid

• Secretion of GH requires the presence of normal plasma levels of thyroid hormones. GH secretion is markedly reduced in hypothyroid individuals.

Pulsatile GH secretion in an adolescent boyand in an adult. In the adult, GH levels are reducedas a result of smaller pulse width and amplitude rather thana decrease in the number of pulses.

GH secretion

• About 50% of GH in serum is bound to GH-binding protein (GHBP).

• GHBP reduces renal clearance and thus increases the biological half-life of GH, which is about 20 minutes.

• The liver and kidney are major sites of GH degradation.

Direct versus Indirect Actions of Growth Hormone

• GH acts directly on the liver, muscle, and adipose tissue to regulate energy metabolism

• GH is a protein anabolic hormone • GH is a lipolytic hormone• GH alters carbohydrate metabolism. Many of its

actions may be secondary to increased fat mobilization and oxidation

• GH antagonizes the action of insulin at the postreceptor level in skeletal muscle and adipose tissue (but not the liver)

Indirect Effects of Growth Hormone on Growth

• Most of the anabolic actions of growth hormone are an indirect result of increased production of growth factors, which are called somatomedins, or insulin-like growth factors (IGFs).

• A major growth factor is somatomedin C, also called IGF-I

Specific Properties of the IGFs

• IGF-I is a major anabolic growth factor-- increases the synthesis of cartilage (chondrogenesis) in the epiphyseal plates of long bones, thereby increasing bone length.

• Similar in structure to proinsulin and has some insulin-like activity• Because it has a long half-life, plasma IGF-I serves as a reflection of

24-hour growth hormone secretion. Growth hormone secretion is difficult to measure directly because it is secreted in pulses and mainly at night.

• It is also hypothesized that circulating IGFs increase lean body mass.

• IGF-II is another somatomedin, the importance of which is not well understood but may have a role in fetal development.

Complementary regulation of GH and insulin secretion coordinates availability of nutrients with

anabolism and either caloric storage or mobilization

Correct statements about human growth hormone include which of the following?

a. It is synthesized in the hypothalamusb. It stimulates production of somatomedins by

the liverc. Its release is stimulated by somatostatind. It causes a decrease in lipolysise. It is deficient in acromegaly

The basic effects of growth hormone on body metabolism include

a. Decreasing the rate of protein synthesisb. Increasing the rate of use of carbohydratec. Decreasing the mobilization of fatsd. Increasing the use of fats for energye. Inhibition of insulin-like growth factor 1

APPLIED PHYSIOLOGY

¯ GH SECRETION-DWARFISM

Stunted growth Delayed skeletal growth Normal intelligence. Well proportioned

• Normal growth requires not only normal levels of GH but also normal levels of thyroid hormones, insulin, and sex steroids

Relative importance of hormones in human growth at various ages.

OTHER CAUSES OF DWARFISM • It can be due to GHRH deficiency, growth hormone deficiency,

or deficient secretion of IGF-I. • African pygmies—normal serum GH levels, but they do not

exhibit the normal rise in IGF that occurs at puberty. They also may have a partial defect in GH receptors .Normal GH & somatomedin IGF-1

• Laron dwarf—genetic defect in expression of the GH receptor such that the response to GH is impaired. Thus, although serum GH levels are normal to high, Laron dwarfs do not produce IGFs in response to GH. Treating patients afflicted by Laron dwarfism with GH will not correct the growth deficiency

• Kwashiorkor-- GH, but retarted growth following protein deficiency- somatomedin

• Juvenile diabetes• Cretinism

• It is also part of the syndrome of gonadal dysgenesis seen in patients who have an XO chromosomal pattern

• Chronic abuse and neglect can also cause dwarfism in children, independent of malnutrition. This condition is known as psychosocial dwarfism or the Kaspar Hauser syndrome, named for the patient with the first reported case

• Achondroplasia, the most common form of dwarfism in humans, is characterized by short limbs with a normal trunk. It is an autosomal dominant condition caused by a mutation in the gene that codes for fibroblast growth factor receptor 3 (FGFR3). This member of the fibroblast growth receptor family is normally expressed in cartilage and the brain

Growth hormone excess

• Before puberty: causes gigantism (excess linear growth) because of excessive stimulation of epiphyseal plates.

• After puberty causes: increases organ size, increased hand and foot size, enlarged tongue, facial coarseness, insulin resistance

• Treatment is with somatostatin analogues (octreotide)

INCREASED GH SECRETIONGIANTISM OR GIGANTISM

Secretion of GH before epiphysial closure

Tall stature > 8 feet Large hands & feet Bilateral gynaecomastia, loss

of libido, impotence, amenorrhea & infertility

Excessive growth of internal organs

Hyperglycemia

ACROMEGALY - SECRETION -AFTER THE CLOSURE OF EPIPHYSIS

Acral-distal parts, Megaly-enlargement It is almost always due to macroadenoma (> 1 cm dia)

of the anterior pituitary and second in frequency to prolactinomas.

Ectopic GHRH secretion occurs but is rare Some tumors contain lactotrophs, and elevated

prolactin can cause hypogonadism and galactorrhea. Measurement of IGF-I is a useful screening measure

and confirms diagnosis with the lack of growth hormone suppression by oral glucose (not somatostatin).

A patient is diagnosed with acromegaly. Patients with this disease typically have

a. Decreased gluconeogenesisb. Hypoglycemiac. Insulin resistanced. Decreased protein synthesise. Decreased lipolysis

There is characteristic proliferation of cartilage, bone and soft tissue, visceral, and cardiomegaly.

Enlargement of flat bones- skull,Hands & feet Prognathism, frontal bossing, kyphosis, Thickening of skin- acromegalic facies Hypertrophy of int.Organs—cardiomegaly,

hepatomegaly, renomegaly, splenomegaly, enlarged tongue

• growth hormone excess directly causes the hyperglycemia and insulin resistance.

Which treatment would provide the greatest therapeutic benefit in patients with acromegaly?

(A) Glucocorticoid(B) Somatostatin(C) Growth hormone(D) Insulin(E) GHRH(F) Thyroid hormone

Puberty

Rate of growth in boys and girls from birth to age 20

Growth of different tissues at various ages as a percentage of size at age 20

Relative importance of hormones in human growth at various ages.

PULSATILE SECRETION OF GNRH, FSH, AND LH

• The primary event at puberty is the initiation of pulsatile secretion of GnRH.

• This new pattern of GnRH secretion drives a parallel pulsatile secretion of FSH and LH

• InitiationGenetically programmed

Neuronal maturationNutrition and stress

Melatonin

Reproductive Changes

• Hypothalamic pulse generator increases activity just before physical changes at puberty.

• First noted sign in a female is breast development; first by estrogen(promotes duct growth) then progesterone (promotes development of milk-producing alveolar cells).

• First noted sign in a male is enlargement of the testes. Mainly FSH stimulating seminiferous tubules

• Pubic hair development in males and females is dependent on androgen

CHARACTERISTICS OF PUBERTY• In males:• Leydig cell proliferation in the testes, and

increased synthesis and secretion of testosterone • There is growth of the testes, prostate. • There is a pronounced linear growth spurt, and

the epiphyses close when adult height is attained. • pubic and axillary hair appears, and there is

growth of the penis, lowering of the voice, and initiation of spermatogenesis.

Changes in plasma hormone concentrations during puberty in boys and girls

• In females:• Synthesis of estradiol by the ovaries. • The first event is thelarche, the development

of breasts, followed by pubarche, the development of axillary and pubic hair, and then by menarche, the first menstrual period..

• The growth spurt and closure of the epiphyses typically begin and end earlier in girls than in boys.

Growth Changes• During puberty, androgens promote the secretion in the

following anabolic sequence: At puberty, if T4 is normal, ↑ androgens drive ↑ growth

hormone, which drives ↑ IGF-I.• In males, the increased androgen arises from the testes

(testosterone); in females, from the adrenals (adrenarche).• Near the end of puberty, androgens promote the

mineralization (fusion or closure) of the epiphyseal plates of long bones. Estrogen can also cause plate closure, even in men.

• In females, the growth spurt begins early in puberty and is near completion by menarche.

• In males, the growth spurt develops near the end of puberty.