hppl - precocious puberty all slides

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Location of Hypothalamus & Pituitary

Image: http://www.umm.edu/patiented/articles/hypothalamus_000337.htm



Hypothalamus

Mamillary Bodies

Control Feeding reflexes

(licking, chewing,

swallowing, etc).

Autonomic Centres

(Sympathetic/Parasympathe

tic)

Regulate heart rate & blood

pressure.

Tuberal Nuclei

Release peptide hormones

that targets the anterior

pituitary

(adenohypophysis).

Supraoptic

NucleusProduce & secretes

ADH via posterior

pituitary

Paraventricular

Nucleus

Produce & secretes

oxytocin via posterior

pituitary

Preoptic

area

Regulatebody

temperature.

Suprachiasma

tic nucleus

Coordinates

day-night

cycles of

activity.

Image: Frederic H. Martini, Anatomy & Physiology, 2 nd Edition, Pearson 2010, Figure 13-10,



Hypothalamus-Pituitary Axis

Anterior Lobe Pathway

1. Swelling near infundibulum,

allowing hypothalamus to release

regulatory factors into interstitial

fluids2. Factors travels and enters capillary

network at median eminence

region

3. Travels to the capillary network in

anterior lobe region via portal vein& flow from the superior

hypophyseal artery.

4. Bind to receptors of endocrine cells

5. Hormones released into circulation.Image: Frederic H. Martini, Anatomy & Physiology, 2 nd Edition, Pearson 2010, Figure 16-7, page 523.



Hypothalamus-Pituitary Axis

Posterior Lobe Pathway

1. Neurons of supraoptic &

paraventricular releases ADH &

Oxytoxin respectively.

2. Move along the axons in

infundibulum & gets released

at posterior pituitary capillary

network.

3. Hormones released into thecirculatory by the flow from

inferior hypophyseal artery.

Image: Frederic H. Martini, Anatomy & Physiology, 2 nd Edition, Pearson 2010, Figure 16-7, page 523.



Pituitary Gland

Thyroid-

stimulatingHormone (TSH)

Targets thyroid

gland and

release thyroid

hormones

Adrenocor ticotro

pic Hormone

(ACTH)Targets cells that

produce

glucocorticoids,

hormone that

affect glucose

metabolism

Gonadotropins

Regulates activitiesof gonads,

releasing..

Follicle-

stimulating

Hormone (FSH)

Luteinizing

hormone

(LH)

Important for

sexual maturation

Prolactin

(PRL)

Works with

other

hormones to

stimulate

mammary

gland

developmentGrowthHormone

(GH)

Stimulates cellgrowth and

replication, by

Melanocyte-

Stimulating

Hormone(MSH)

control skin

pigmentation

Antidiuretic

hormone (ADH)

Regulates

osmotic

concentration of

body fluids

Oxytoxin

(OX

T)Helps in

pregnancy,

promoting

labor and

delivery.

(posterior lobe)

Image: Frederic H. Martini,

Anatomy & Physiology, 2 nd

Edition, Pearson 2010, Figure16-6, page 522.



Hypothalamic-Pituitary HormonesAssociated with Growth & Maturation



Growth Hormone (GH)

Indirect Action

Stimulate growth by accelerating rate of protein synthesis by:1. GH acts on liver to release somatomedins

(aka insulin-like growth factors,IGFs)2. Somatomedins bind to receptor on

plasma membrane of skeletal musclefibers, cartilage cells and other targetcells.

3. Stimulate target cells to increase uptakerate of amino acids and their

incorporation into new proteins.4. Important after consumption of a meal as

blood contains high concentration of glucose and amino acids.

1. Glucose metabolism to obtain ATP

2. Amino Acids Used for protein synthesis.

Hypothalamus-Pituitary AxisAssociated with Growth & Maturation




Growth Hormone (GH)

Direct Action

More selective & only appear after

blood glucose and amino acid

concentration have returned back tonormal.

Mostly associated with metabolism.





Growth Hormone (GH)

Regulation by Negative Feedback

Production of GH is activated by

growth hormone releasing hormone

(GHRH) & inhibited by growth

hormone-inhibiting hormone (GHIH)

Somatomedins stimulate GHIH &

inhibits GHRH.





GonadotropinsRegulates activity of gonads and important for sexual maturation.

Two gonadotropins are:

1. Follicle-stimulating hormone (FSH)Male: stimulates nurse cells in testis to undergo physical maturation for sperm

development

Female: acts with luteinizing hormone to promote follicle development &

stimulates ovarian cells to secrete estrogens.

2. Luteinizing hormone (LH)

Male: Stimulates testis to produce androgen, such as testosterone.

Female: induces ovulation, leading to production of reproductive cells & stimulates

ovaries to secrete estrogens and progestins, such as progesterone.




Regulation of Gonadotropins (FSH & LH)

Production of FSH & LH is activated by

Gonadotropin-releasing hormone (GnRH) as a

releasing hormone (RH)

FSH & LH - Hormone 1 - binds to receptors of

respective target organ

Binding leads to maturation of sexual

organs/tissues & release of various secondary

hormones Hormone 2 which sends a

negative feedback, inhibiting production of gonadotropins.

± FSH production is inhibited by inhibin

± LH production is inhibited by estrogens, progestins and

androgens.





Thyroid Hormone

Development of the skeletal,muscular and nervous system ingrowing children.

T4 important for skin development

before puberty.

Regulation by Negative Feedback

± Production & release of TSH isactivated by TRH.

± TSH binds to membrane receptors andby stimulating adenylate cyclase,activates key enzymes involved inthyroid hormone production.

± Circulating thyroid hormones (T3 & T4)

inhibits production of TRH & TSH.


Image (edited): Frederic H. Martini, Anatomy & Physiology, 2 nd Edition, Pearson 2010, Figure 16-8, page 524.



Mechanism of ThyroidHormone synthesis, storage and secretion:

1. Iodine ions (I-) absorbed from diet at the digestive tract travels via

bloodstream to the thyroid gland, transported into cytoplasm viacarrier proteins in the basal membrane of follicle cells.

2. Iodine ions diffuse to the apical surface of each follicle cells,

converted to activated form of iodide (I+) by enzyme thyroid

peroxidase.

3. Tyrosine molecules to which iodide ions have been attached

become linked covalently, forming molecules of thyroid hormones

(Thyroxine aka tetraiodothyronine T4 and triiodothyronine T3).Process is (probably) by thyroid peroxidase, remain incorporated

into thyroglobulin.

4. Follicle cells remove thyroglobulin from follicle cells by

endocytosis.

5. Lysosomal enzymes breaks down thyroglobulin allowing amino

acids and thyroid hormones to enter cytoplasm. (amino acids

recycled to synthesize more thyroglobulin)

6. T3 & T4 diffuse across basement membrane and enters

bloodstream.

7. Approx. 70% of T3 and 75% of T4 gets attached to transport

proteins called thyroid-binding globulins (TBGs). The rest are

attached to thyroid-binding prealbumin (TBPA) or to albumin.

Only small amount (0.3% of T3 and 0.03% of T4) are circulating

freely.





Prolactin (PRL) Works with other hormones in

stimulating mammary glanddevelopment

Stimulates milk production bymammary glands

Regulation by negative feedback

± Production of PRL is stimulated byprolactin-releasing factors (PRF)

± Circulating PRL Inhibits PRF

stimulates prolactin-inhibiting hormone

(PIH), which inhibits PRL production





Insulin ± Growing cells need adequate supply of energy and

nutrients. Without insulin, passage of glucose andanimo acids across plasma membrane will be

drastically reduced or eliminated

Parathyroid Hormone (PTH) & Calcitriol

± Promote absorption of calcium salts for

subsequent deposition in bone. Without adequatelevel of both hormones, bones can still enlarge,but will be poorly mineralized, weak and flexible.(e.g. rickets)

Other HormonesAssociated with Growth & Maturation



Insulin Regulation

Respond to level of glucose

Elevated level

± Insulin released, glucose enters cells.

Declined level

±Glucagon released, liver releasedglucose in blood.

Image: http://www.endocrineweb.com/conditions/diabetes/normal-regulation-blood-glucose



Parathyroid Hormone (PTH) &

Calcitriol Regulation

Respond to levels of calcium

Elevated calcium

± Release of calcitonin, blood

calcium level falls.

Declined calcium

± PTH released, blood level rises.




Image: Boron and

Boulpaep, Medical

Physiology, 1st edition,Saunders 2003, Figure



References

Boron and Boulpaep, Medical Physiology, 1st edition,Saunders 2003.

Frederic H. Martini, Anatomy & Physiology, 2nd Edition,Pearson 2010.

Igor Mitrovic (MD), Introduction to the Hypothalamo-Pituitary-Adrenal (HPA) Axis.

F. Rastinejad, Hypothalamic/Pituitary Axis: Adrenals andThyroid, Medical Pharmacology.

A.D.A.M., Inc.

Mc Graw Hill Companies Inc, Ganongs Review of MedicalPhysiology, 23rd Edition, 2010.

Rang & Dale, Pharmacology, 5th Edition, 2003.



Gigantism

a rare childhood condition caused by

hyper-secretion of growth hormones (usually causedby pituitary adenoma) prior to epiphyseal closure.Increased amounts of GH results in overgrowth of bones and abnormally tall stature.

Treatments

Surgery- removal of tumors with well-defined

borders

Drugs

Somatostatin analogs- Inhibits the release of growth hormones and thyroid stimulating hormonesfrom the anterior pituitary.

Ex: Octreotide, Lanreotide

Dopama

Pegvisomant- Growth hormone blocker; blocks theeffects of growth hormones

Radiation is used to bring GH levels to normal;takes time and may cause low levels of otherpituitary hormones

Congenital Adrenal Hyperplasia

an inherited disorder that causes

enzyme deficiency resulting in the inability of adrenal glands to produce hormones necessary tolife. In the non-salt wasting form of this disorder, theadrenal glands are unable to produce cortisol andinstead, are shifted away to produce other hormonessuch as androgens. Excessive androgen results inprecocious puberty, rapid growth, bone aging, andambiguous genitalia for females.

Treatment

Hydrocortisone- Cortisol replacement



If left untreated,

Gigantism

Abnormally large stature- Increased metabolic state resulting in faster degeneration of

cells which results in a decrease in life expectancy.

May also cause emotional stress and low self esteem.

CAH

Early maturation of bones- Once bones reach maximum maturity, growth stops and

results in a short adult stature.

Untreated CAH may result in precocious puberty wherein sexual and physical

characteristics mature earlier than normal.



Q 1bPhysical examination

Tall, well proportioned and markedly muscular. Mild facial acne, fine pubic hair, adult-likedistribution pattern.

Large penis, but normal testes size.

Hormone levels: ± Testosterone: 172 ng/dl

± 17-OH-progesterone: 12,000 ng/dl (basal) and 22,000ng/dl (ACTH stimulation)

± Cortisol: 5 µg/dl (basal) and 10 µg/dl (ACTH

stimulation) Normal neurological signs.

What is Jims problem?



Gigantism

Gigantism ± Increased skeletal growth

velocity

± Increased body size withdisproportionately long arms

and legs ± Delayed puberty

± Hypogonadotropichypogonadism

± Headache and visual changes

Not the cause of Jimsproblem



Precocious puberty

Definition: onset of sex maturation before age 8

in girls or age 9 in boys.

2 types:

± GnRH-dependent

± GnRH-independent



GnRH-dependent The hypothalamic-pituitary-gonad axis is

activated.

Cause: CNS disorders

Symptoms:

± Enlargement of gonads

± Enlargement of penis

± Pubic hair appearance

± Facial acne

± Neurological symptoms, including developmental

delay

Not the cause of Jims problem



GnRH-independent

Congenital adrenal hyperplasia

21-hydorxylase deficiency

impaired biosynthesis of cortical steroids

steroidogenesis channeled to androgen

production

Sex-enhancing symptoms - virilisation.

The true cause of Jims problem



Q n 2

Pathology of CAH (diagram)

Normal values of various hormones listed

compare with Jims values

explain diagnosis



Q uestion 3

Initial Treatment for Jims Adrenal Hyperplasia

and its mechanism



Q uestion 4

What happens upon 21-hydroxylase

deficiency?



ACTH

Adrenal Gland

Stimulation

Cholesterol

Mineralocorticoids Glucocorticoids Sex Steroids

Aldosterone Cortisol Testesterone

Pregnenolone

17-Hydroxypregnenolone Dehydroxyepiandrosterone

17-Hydroxyprogesterone

11-Deoxycortisol

Androstenedione

Progesterone

11-Deoxycorticosterone

Corticosterone

17

17

21

21

11



What other treatment is available for thecorrection of this deficiency?

Severe 21-hydroxylase deficiency salt-wasting

75% requires aldosterone replacementMineralocorticoid alpha fludohydrocortisonetherapy & NaCl

Aromatase inhibitors slow its maturation

Suppress precocious puberty long acting GnRHagonists while simultaneously stimulating growthwith GH



Conclusion

The Hypothalamic-Pituitary-Adrenal axis plays a

vital role for growth and maturation especially

for normal puberty. As seen in Jims case who

suffers from Congenital Adrenal Hyperplasia, the

condition in which one of the enzymes

important for hormone synthesis in the adrenal

gland is deficient leading to precocious puberty.

hppl - precocious puberty all slides

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