Hypothalamus and Pituitary Hormones



Hypothalamus and Pituitary Hormones

I. Over view

a. Two Systems

i. Endocrine

1. releases hormones

2. can take from seconds to days

3. lasts for weeks to months

ii. Neuroendocrine

1. messages sent from the pituitary and the hypothalamus

2. Coordinates body functions

3. neuroendocrine system communicates locally with the muscles or glands in the form of electrical impulses or neurotransmitters

4. can act within milliseconds

5. can have a stimulatory or inhibitory effect on the release of hormones

b. Given IM, SQ, IV but not PO

c. Pituitary Gland

i. Posterior Pituitary

1. Hormones

a. Desmopressin

b. Oxytocin

c. Vasopressin (ADH)

2. Produced in the hypothalamus and stored in the posterior pituitary

3. Derived form neuroectoderm

ii. Anterior Pituitary

1. Glycoproteins/Hormones

a. Thyroid stimulating hormone (TSH)

b. Luteinizing hormone (LH)

c. Follicle stimulating hormone (FSH)

d. Corticotropin (ACTH)

e. Gonadotropin releasing hormone (GnRH)

f. Grow hormone releasing hormone (GHRH)

g. Luteinizing hormone releasing hormone (LHRH)

h. Somatostation

i. Somatotropin

j. Melanotropin and prolaction are derived from oral ectoderm

2. Alpha subunit is the common subunit to TSH, LH, FSH and hCG

3. Beta subunit determines hormone specificity

4. Hypothalamus sends a signal via the hypophyseal portal system to the anterior pituitary causing the release of hormones into the blood stream

a. Regulated by neuropeptide releasing or inhibiting factors

i. Used for diagnostic purposes to determine if there is a pituitary insufficiency

b. Hormones are bound to a low molecular weight peptide

5. The hormones are carried through in the blood until they reach the target tissue and can bind with the receptor

II. Hormones of Anterior Pituitary

a. Adrenocorticotropic hormone (ACTH or corticotropin)

i. The hypothalamus releases corticotropin releasing hormone

1. useful tool for Cushing’s syndrome and sctopic ACTH producing cells

ii. CRH causes the post-translational modification of pro-opiomelanocortin (POMC) to ACTH

iii. ACTH stimulates the cell’s receptors causing the release of a G-protein and an increase in camp leading to the conversion of cholesterol to pregnenolone (will later for cortisol)

1. this is the rate limiting step in the adrenocorticosteroid pathway

iv. Stimulated by CRH, it regulates adrenal cortical function. Stimuli that increase CRH release include fever, hypoglycemia, physical or emotional trauma and other stressors. It can stay high in spite of negative feedback in the case of stress.

v. It is the physiologic regulator of glucocorticoids (cortisol and corticosterone).

vi. Diuranl oscillation operates on top of this pulsatile rhythm. Glucocorticoid levels in the plasma begin to rise in the early morning, peak sometime before noon and then fall gradually to a low level round midnight. This pattern is reversed in individuals who sleep during the day and are awake at night.

vii. It promotes expression of genes involved in steriodogenesis

viii. NOT and important regulator of aldosterone

ix. Inhibited by feed back inhibition exerted by glucocorticoids. If an individual is chronically treated with large doses of glucocorticoids the level of ACTH drops so much that the adrenal gland can actually atrophy. This is why it is important to wean patients off of steroids to allow normal adrenal function to return

x. IN a situation of glucocorticoid deficiency, there is an increase in the concentration of ADH

xi. It is also made by some neurons in the paraventricular nuclei and it does stimulate production of ACTH and can amplify the ability of CRH to stimulate ACTH secretion

xii. Target organ: adrenal cortex

1. promotes the trelease4 of glucocorticoids and androgens (mineralocorticoids –to a lesser extent)

xiii. Hypersecretion

1. Cushing’s disease

xiv. Drugs:

1. Used for:

a. Primary adrenal insufficiency associated with adrenal atrophy such as Addison’s disease

b. Secondary adrenal insufficiency associated with inadequate secretion of ACTH fro the pituitary

2. Corticotropin: synthetic adrenocorticosteroid

a. Extract of the anterior pituitary of domestic animals

b. Antibodies can form

3. Cosyntropin

a. Synthetic human ACTH

b. Less side effects

c. Used as for diagnostic purposes to determine if the patient has primary or secondary adrenal insufficiency as well as infantile spasms and adrenal insufficiency

b. Growth Hormone (somatotropin)

i. Large polypeptide

ii. Have a synthetic from made from recombinant DNA technology

1. somatotropin from animal sources is ineffective

iii. The hypothalamus secretes growth hormone releasing hormone (GHRH) which causes the release of growth hormone (GH) from the anterior pituitary

1. an infusion of sermorelin (i.e. GHRH) can be used in people with a GH deficiency

iv. GH can then stimulate protein synthesis, increase cell proliferation and bone growth and increase the formation of hydroxyproline from proline (i.e. make cartilage)

v. GH is used in the treatment of growth hormone deficiency in children (if they have a normal thyroid)

1. use is contraindicated if patient has closed epiphyses or an enlarging intracranial mass

vi. stimulated by GHRH release which is triggered by low blood levels of GH as well as by a number of secondary triggers including estrogens, hypoglycemia, an increase in blood level of the amino acids arginine and leucine, low levels of fatty acids, exercise, L-DOPA, alpha-2 adrenoceptor agonists (clondine), and othe rtypes of stresssors such as fever and pain

vii. inhibited by feed back inhibition exerted by GH and IGFs (somatomedians) and by hyperglycemia, hyperlipidemia, obesity, beta-2 adrenoceptor agonist and emotional deprivation, wall of which elicit GHIH (somatostatin) release. The release of somatostatin is suppressed by serotonin, nonselective beta blocker antagonists and slow wave sleep

viii. target organs and effects

1. liver, muscle, cartilage and other tissues

2. anabolic hormone that stimulates somatic growth and mobilizes fats and spares glucose

3. most effects are mediated indirectly by IGFs

ix. hyposecretion

1. causes pituitary dwarfism in children

2. in sever cases progeria ensues (premature aging)

x. hypersecretion

1. gigantism in children and acromegaly in adults

a. protrusion of the lower jaw (prognathism) and overgrowth of the facial bones

xi. Used in the treatment of Dwarfism

1. Etiology

a. GHRH deficiency

b. GH deficiency

c. Insensitivity to GH and IGFs

d. Other causes: congenital hypothyroidism, Cushing’s syndrome in children, type 1 DM, precocious puberty, rickets, chronic malnutrition

2. Diagnosis

a. Slow growth velocity

b. Low plasma levels of both GH and IGFs

c. Test: measure GH plasma level during sleep and exercise or used L-DOPA, clonidine, propanolol or insulin to try and promote GH secretion

xii. Drugs:

1. Somatotropin: hGH

2. Somatrem

a. Has extra methionyl group

b. Short half life (25 min)

c. Causes somatomedin (IGF-1) induction from the liver

i. Like growth hormone

d. Uses:

i. Childhood GH deficiency

ii. Adult GH deficiency

iii. osteoprosis

e. Abuses:

i. Athletes

ii. To slow the aging process (somatopause)

f. Adverse reactions:

i. Allergic reaction, iatrogenic acromegaly, hyperglycemia, increased risk of prostate cancer

c. Growth hormone inhibiting hormone (Somatostatin)

i. Released from the hypothalamus

ii. Small polypeptide

iii. Acts on the intestine pancreas and neurons

iv. Drug:

1. Octreotide

a. Longer half life than somatostatin

b. Used to treat acromegaly caused by hormone secreting tumors and secreting diarrhea associated with tumors producing VIP

c. Adverse effects:

i. Flatulence, nausea, secretory diarrhea, gallstones and steatorrhea

ii. Does not elicit rebound hypersecretion

d. Gonadotropin releasing hormone (GnRH) and Luteinizing hormone releasing hormone (LHRH)

i. Hypothalamus releases GnRH

1. used to treat hypogonadism as it stimulates gonadal hormone production

2. Step can be blocked by the used of the synthetic analogs leuprolide, goserelin, nafarelin and histrelin

a. Used for prostatic cancer, endometriosis and precocious puberty

ii. GnRH acts on the anterior pituitary to cause the release of FSH and LH

iii. Drugs

1. Gonadotropin

a. Used for infertility

b. Two forms

i. Menotropin (hMG)

1. partially broken down FSH and LH obtained from the urine of menopausal women

2. human menopausal Gn

ii. Human Chorionic Gn (hCG)

1. placental hormones (LH analog)

c. Adverse effects

i. Ovarian enlargement

ii. Hypovolemia

iii. Multiple births

iv. Gynecomastia in men

d. Given IM

i. hMG/FSH can be given for 5-12 days for ovarian follicular maturation and growth

ii. hCG injection leads to ovulation

iii. hMG injection is used fro external sexual maturation in men and spermatogenesis

2. Gonadorelin: used to stimulate the secretion of FSH and LH from the anterior pituitary when given in a pulsatile fashion. Also used for diagnosis for gonadotropin deficiency

3. Leuprolide, Nafarelin, Histrelin and Goserelin

a. Long acting synthetic GnRH analogs which are used to inhibit the release of FSH and LH from the anterior pituitary in a continuous fashion

4. GnRH antagonists:

a. Prevent premature LH surges in women undergoin controlled ovarian stimulation via FSH administration in order to enlarg ovarian follicles

b. Cetrorelix an Ganirelex

e. Thyroid Stimulating Hormone (TSH or thyrotroph)

i. Stimulated by TRH and indirectly by pregnancy and cold temperature

ii. It regulates the function of the follicles of the thyroid gland

iii. Inhibited by feedback inhibition exerted by thyroid hormones on anterior pituitary and hypothalamus and by GHIH (somatostatin) and dopamine. Cortisol decreases both TRH and TSH secretion. GHE also reduces TSH secretion. Fasting decreases the responsiveness of thyrotrophs to TRH and may decrease the release of TRH as well. This coincides with a decrease in metabolic rate which would be useful in a fasting state

iv. Target organ:

1. Thyroid gland

2. stimulates the thyroid gland to release thyroid hormone

v. Hyposecretion

1. cretinism in children and myxedema in adults

vi. Hypersecretion

1. Graves’ disease and exopthalmos

f. Follicle Stimulating Hormone

i. Stimulated by GnRH (gonadotrophs in the anterior pituitary). The pulsatile release of GnRH prevents down regulation of gonadotroph receptors

ii. Inhibited by feed back inhibition exerted by estrogen in females and testosterone inhibition in males

iii. Target organ: ovaries and testes

1. in females it stimulates ovarian follicle maturation and estrogen production

2. in males it stimulates sperm production

iv. Hyposecretion: failure of sexual maturation

g. LH

i. Stimulated by GnRH

ii. Inhibited by feedback inhibition exerted by estrogen and progesterone in females and testosterone in males

iii. Target organ: Ovaries and testes

1. in females it triggers ovulation and stimulates ovarian production of estrogen and progesterone

2. in males it promotes testosterone production

iv. Hyposecretion leads to failure to come to sexual maturation

v. Drugs:

1. Urofollitorpin (FSH)

2. Placental hCG (LH)

a. Given IM

3. Menotropins (FSH and LH)

a. Given IM

4. used for hypogonadal states (infertility)

h. Prolactin (PRL)

i. Stimulated by PRH

1. PRH’s release is enhanced by estrogens, TRH, birth control pills, opiates and brest feeding

ii. Prolactin secretion is promoted by pregnancy, nursing, DA2 antagonists, H2 antagonists, opioids, intensive exercise, primary hypothyroidism and lactotropic cell adenoma

iii. Inhibited by PIH (dopamine)

1. unique to the is hormone

2. there is also feedback inhibition by PRL on itself

3. Pergolide, bromocrptine and Cabergoline

a. Used for hyperprolactinemia, amenorrhea, galactorrhea, and infertility secondary to prolactienmia

iv. Target organ: breast secretatory tissue

1. promotes lactation

v. Hyposecretion: poor milk production in nursing women

vi. Hypersecretion: galactorrhea (inappropriate production of milk), cessation of menses in females, impotence (decreased sperm count and testosterone levels) and gynecomastia in males

1. amenorrhea suppresses normal pulsatile pattern of GnRH release and prevents positive feed back effects of estrogen and subsequent LH surge

III. Hormones of the Posterior Pituitary

a. Vasopressin

i. Also know as ADH (antidiuretic hormone)

ii. Released from the hypothalamus and stored in the posterior pituitary (supraoptic)

iii. Important for increasing plasma osmolarity

iv. Nonapeptide

v. Disulfide bonds

vi. Circular in structure

vii. Susceptible to proteolytic degradation

viii. Very short half life

ix. Structurally related to oxytocin

x. Antidiuretic and vasopressor activity

xi. Acts on the kidney V2 receptor to increase water permeability and resorption as well as the V1 receptor found on the VSM, liver and other tissue

xii. Stimulated by impulses from hypothalamic neurons (supraoptic and paraventricular nuclei) in response to increased osmolarity of blood (morphine, nicotine and barbiturates) or decreased blood volume. Also stimulated by pain, some drugs and low blood pressure. The results are decreased water excretion and formation of an osmotically concentrated urine. IN situations of glucocorticoid deficiency, there is an increase in the concentration of ADH

xiii. It is also made by some neurons in the paraventricular nuclei and it does stimulate the production of ACTH and can amplify the ability of CRH to stimulate ACTH secretion

xiv. Inhibited by adequate hydration of the body and by alcohol and weightlessness

xv. Target organ: Kidneys

1. stimulates the kidney tubule cells to reabsorb water

xvi. Hyposecretion: causes diabetes insipidus

xvii. Hypersecretion: syndrome of inappropriate ADH secretion (SIADH)

xviii. Should be used with caution in patients with asthma, epilepsy and CAD

xix. Adverse effects:

1. water intoxication, hyponatremia, headache, bronchoconstriction and tremor

xx. Used to control bleeding due to esophageal varices or colonic diverticula as well as for diabetes insipidus, hemophilia A and von Willebrand disease

xxi. Drug:

1. Desmopressin

a. Used for diabetes insipidus and nocturnal enuresis

b. Given intranasally for a local reaction

c. May cause ANF secretion (leads to hyponatremia)

b. Oxytocin

i. Also released from the hypothalamus and stored in the posterior pituitary (paraventricular nuclei)

ii. Important for parturition

iii. Stimulated by impulses from hypothalamic neurons in response to cervical/uterine (IV) stretching and suckling of infant at brest (nasal spray). It helps in milk ejection.

iv. Inhibited by lack of the appropriate neural stimule

v. Target organ:

1. uterus

a. stimulates uterine contractions and initiates labor

2. breast

a. initate milk production

vi. Used to cause uterine contraction of myeoepithelial cells, labor, to enhance milk ejection reflex and to control postpartum uterine bleeding

1. often used in combination with a prostaglandin such as dinoprostone

vii. Promotes brest mild ejection

viii. Very low antidiuretic ad pressor

ix. Given as a nasal spray

x. Adverse effects (uncommon)

1. hypertensive crises

2. uterine rupture

3. water retention

4. fetal death

xi. Contraindications:

1. abnormal fetal presentation

2. fetal distress and premature births

IV. Hypothalamus is important for:

a. T: thirst and water balance (supraoptic nucleus)

b. A: adenohypophysis control via releasing factors

c. N: neurohypophysis release of hormones synthesized in the hypothalamic nuclei

d. H: hunger (lateral nucleus) and satiety (ventromedial nucleus)

e. A: autonomic regulation (anterior hypothalamus regulates parasympathetic activity) and circadian rhythms (suprachiasmatic nucleus)

f. T: temperature regulation (posterior hypothalamus is responsible for heat conservation and production when cold and the anterior hypothalamus coordinates cooling when hot)

g. S: sexual urges and emotions (septate nucleus)

V. The major hypothalamic hormones and their targeted pituitary hormones

a. These hormones bind to receptors on cells of the anterior pituitary and modify the secretion of pituitary hormones. When there is damage to the pituitary stalk, secretion of all anterior pituitary hormones decreases with the exception of prolactin.

b. Sheehan’s syndrome: the pituitary in pregnancy is enlarged and therefore more vulnerable to infarction. Sometimes when deliver is associated with sever blood loss, the ensuing shock causes arteriolar spasm in the pituitary with subsequent ischemic necrosis. Some degree of hypopituitarism has been reported in 32% of women with sever postpartum hemorrhage.

c. These hormones are primarily used for diagnostic purposes.

VI. Effects of Hypothalamic hormones on the anterior pituitary

a. TRH stimulates the release of TSH

b. CRH stimulates the release of ACTH

c. GnRH stimulates the release of LH and FSH

i. Drugs: leuprolide and nafarelin

1. used for endometrosis, prostate carcinoma and precocious puberty

d. GHRH stimulates the release of GH

e. Somatostatin inhibits the release of GH

f. PIF (platelet inhibitory factor) inhibits the release of prolactin

VII. Hierarchy of Hormone Action

a. TRH to Anterior Pituitary to TSH to THYROID to T4, T3 and calcitonin

b. GnRH to AP to FSH and LH to Testes or Ovaries

i. Men: FSH to sertoli cells to sperm

ii. Women: LH/FSH to ovaries, corpus luteum and placenta

1. estradiol, progesterone, HCG, HPL, and estriol

c. CRH to AP to ACTH to Adrenal Cortex to Cortisol

d. GHRH to AP to GH to liver to IGF

e. Somatostatin to AP inhibits GH

f. Posterior pituitary releases:

i. Oxytocin which increase milk production

ii. ADH

g. Adrenal medulla releases NE and Epi

h. Pancreas releases insulin and glucagons

VIII. Feed back control of Hormone secretion

a. Negative feedback

i. Short loop: high levels of hormone from the anterior pituitary inhibits the hypothalamus

ii. Long loops

1. high levels of the hormone inhibits both the anterior pituitary and the hypothalamus

iii. Brings activation down

b. Positive feedback

i. Also called the hypothalamopituitary adrenal axis

ii. Hormone stimulates the anterior pituitary to release more hormone

IX. Diabetes Insipidus

a. Two types

i. Central neurogenic

1. sufficient ADH is not available to affect the renal collecting tube

ii. Nephrogenic

1. due to the inability of the kidneys to respond to ADH

b. Differential diagnosis of diabetes insipidus

i. In diabetes insipidus the individual continues to for m large quantities of glucose free dilute urine in spite of an elevated extracellular osmolarity. This is now considered diagnostic for diabetes insipidus. And injection of ADH will reduce urine flow in the central form but not in the nephrogenic form.

X. Syndrome of Inappropriate ADH secretion

a. Excessive secretion of ADH causes excessive reabsorption of water in the renal collecting duct

Drugs related to the hypothalamus and pituitary hormones:

|Hormone |Pharmacological agent |Clinical uses |

|GH |Somatrem or Somatropin |Pituitary dwarfism, osteoporosis |

|Somatostatin |Octreotide |Acromegaly, carcinoid and secretory GI tumors |

|ACTH |Cosyntropin |Infantile spasms, adrenal insufficiency |

|GnRH |Leuprolide and nafarelin |Endometrosis, prostate carcinoma (respiratory |

| | |form) and precocious puberty |

|FSH an dLH |Urofollitropin, Placental hCG and Menotropins |Hypogonadal states |

|PIH (DA) |Pergolide, bromocrptine |hyperprolactinemia |

|Oxytocin and vasopressing |Oxytocin an ddesmopression |Labor induction (oxy) |

| | |Neurogenic DI, hemophilia A, von Willebrand |

| | |disease and nocturnal enuresis (v) |

................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download