Hypothalamic- Pituitary Relationships Lecture (Dr. Lopez) Flashcards
The Hypothalamus and Pituitary Gland Function in Coordinated Fashion
- Hypothalamic- Pituitary unit regulates the Function of Thyroid, Adrenal, and Gonads
a) HTP Axis
b) HPA Axis
c) HPG Axis - Their concerted actions control:
a) Growth
b) Milk Production and Ejection
c) Osmoregulation
The Pituitary Gland is a Complex Endocrine Structure
Pituitary Gland = Hypophysis
Composed of:
1) ANTERIOR PITUITARY (Adenohypophysis)
- Oral Ectodermal portion
2) POSTERIOR PITUITARY (Neurohypophysis)
- Neural Portions
HYPOPHYSIAL STALK:
- Physical Connection between the Hypothalamus and the Pituitary Gland
- Generally, Cancers of the Pituitary expand up into the Brain and against the OPTIC NERVE
a) INCREASE in Pituitary Size often associated with DIZZINESS and VISION PROBLEMS, or Both
The Connections between the Hypothalamus and Posterior Lobe of the Pituitary are NEURAL
- Posterior Pituitary is a Collection of Axons whose Cell Bodies are located in the HYPOTHALAMUS
a) SUPRAOPTIC Nucleus
b) PARAVENTRICULAR Nucleus
- Secrete Neuropeptides (Ex: ADH and Oxytocin)
- ADH is Primarily associated with SUPRAOPTIC NUCLEI
- OXYTOCIN is Primarily associated with PARAVENTRICULAR NUCLEI
The Relationship between the Hypothalamus and the Anterior Lobe of the Pituitary is BOTH Neural and Hormonal
- ANTERIOR PITUITARY is a collection of Endocrine Cells
Secrete Hormones:
1) Thyroid Stimulating Hormone (TSH)
2) Follicle Stiulating Hormone (FSH)
3) Luteinizing Hormone (LH)
4) Growth Hormone
5) Prolactin
6) Adrenocorticotropic Hormone (ACTH)
- Connected to the Hypothalamus by HYPOTHALAMIC-HYPOPHYSIAL PORTAL VESSELS!!!!!!
The Hypothalamic-Hypophysial Portal Vessels provide most of the Bloody Supply to the Anterior Pituitary
Two Important Implications:
1) HYPOTHALAMIC Hormones can be DELIVERED to the Anterior Pituitary DIRECTLY and in HIGH CONCENTRATION
2) The HYPOTHALAMIC Hormones do not appear in the Systemic Circulation in High Concentration
Hypothalamus Controls the Pituitary by Both Neural and Hormonal Mechanisms
1) The Connections between the Hypothalamus and Posterior Lobe are NEURAL
2) The Connections between the Hypothalamus and Anterior Lobe are BOTH NEURAL and ENDOCRINE
Remember: Hypothalamic- Pituitary relationships are all about the Axes!
- Activity of Endocrine Axes are maintained at a Set Point (NEGATIVE FEEDBACK MECHANISM)
- Hypothalamic Hypophysiotropic Neurons are often secrete in a PULSATILE MANNER and are Entrained to CIRCADIAN RHYTHMS
- A Deep Understanding of the Endocrine AXES allows will allow you to Determine where Defects in HORMONAL Secretion lies!
a) PRIMARY ENDOCRINE DISORDER: - Low or High Levels of Hormone due to DEFECT in the PERIPHERAL ENDOCRINE GLAND (Thyroid Gland)
b) SECONDARY ENDOCRINE DISORDER:
- Low of High Levels of Hormone due to DEFECT in the PITUITARY GLAND
c) TERTIARY ENDOCRINE DISORDER:
- Low or High Levels of Hormone due to DEFECT in the HYPOTHALAMUS
Anterior Lobe Hormones
Peptide Hormones:
- TSH
- FSH
- LH
- ACTH
- Growth Hormone
- Prolactin
- Each Hormone Secreted by Different Cell Types (Except FSH and LH)
a) CORTICOTROPH: Releases ACTH
b) THYROTROPH: Releases TSH
c) GONADOTROPH: Releases FSH and LH
d) SOMATOTROPH: Releases GROWTH HORMONE
e) LACTOTROPH: Releases PROLACTIN
- Organized in families according to Structural and Functional Homology:
a) ACTH Family
b) TSH, FSH, and LH Family
c) Growth Hormone and Prolactin Family
Summary of Control of the Anterior Pituitary
1) TRH —–> Thyrotrophs (10%)—–> TSH
2) CRH —-> Corticotrophs (10-25%)—-> ACTH
3) GnRH —–> Gonadotrophs (10-25%)————>(LH, FSH
4) GHRH, Somatostatin —–> Somatotrophs (50%) —–> GH
5) PIF (Dopamine), TRH (Elevated) ——> Lactotrophs (10-15%)——> Prolactin
The ACTH Family
Proopiomelanocortin (POMC)**
- ACTH has MELANOCYTE-Stimulating Hormone Activity
- ** INCREASE in Blood Levels of MSH contains fragments can cause Skin Pigmentation
CLINICAL RELEVANCE:
- In ADDISON Disease ACTH levels INCREASE, Skin Pigmentation is a Symptom of this disorder
The HPA Axis
- Corticotrophs in Anterior Pituitary produce ACTH
- ACTH is under the Stimulatory control of the Hypothalamus (CRH)
- ACTH Stimulated Two Zones of the Adrenal Gland:
1) Medulla
2) Cortex - Stress is a Regulator of the HPA Axis
a) Source of Stess - *** Neurogenic (Ex: Fear)
- *** Systemic (Ex: Infection, Surgery)
b) HYPOTHALAMUS HAS THE ABILITY TO RESET THE SET POINT IN RESPONSE TO STRESS!!!!!!!!!!!!!!!!!!!
The HPT Axis
1) TSH is released by THYROTROPHS in the Anterior Pituitary
- TSH is a Glycoprotein Hormone
2) TSH is under the Stimulatory Control of the Hypothalamus
- Stimulated by the Release of TRH from PARAVICELLULAR Hypothalamic Neurons
3) TSH Stimulates the Thyroid Gland
4) STRESS (Ex: Physical Stress, Starvation, Infection) INHIBITS TRH SECRETION!!!!!!!!!
The HPG Axis
1) FSH and LH are released by Gonadotrophs in the Anterior Pituitary
- Secreted into different Secretory Granules allowing Independent Secretion by Gonadotrophs
2) FSH and LH are under the Stimulatory Control of the HYPOTHALAMUS
- GnRH
3) FSH and LH regulate the Function of Gonads in Males and Females, stimulates the Thyroid Gland
Regulation of Growth Hormone Secretion
**SOMATOMEDINS (IGF), from Target Tissues, inhibits the release of Growth Hormone from the Anterior Pituitary and also the release of GHRH and Somatostatin from the Hypothalamus
Pulsatile Secretion of Growth Hormone
- Growth Hormone is secreted in a PULSATILE PATTERN, with Burst of Secretion Occurring about every 2 Hours!!!
Growth Hormone has Multiple Metabolic Functions
- Actions result from either DIRECT or INDIRECT EFFECTS
a) DIRECT: Effect on Target Tissues (Ex: Skeletal Muscle, Liver, Adipose Tissue)
b) INDIRECT: Mediated by the production of SOMATOMEDIN in the Liver (IGF-1)
Actions are:
1) DIABETOGENIC EFFECT (INCREASE in Blood Glucose Concentration)
- Causes Insulin Resistance
- DECREASE Glucose uptake and Utilization by Target Tissues
- INCREASE LIPOLYSIS in Adipose Tissue
* RESULTS in INCREASE BLOOD INSULIN Levels*
2) INCREASE PROTEIN SYNTHESIS and ORGAN GROWTH
- INCREASE Uptake of Amino Acids
- Stimulates SYNTHESIS of DNA, RNA, and Protein
- Mediated by SOMATOMEDIN
3) INCREASE LINEAR GROWTH
- Stimulates Synthesis of DNA, RNA, and Protein
- Mediated by SOMATOMEDINS
- INCREASE Metabolism in Cartilage-forming Cells and Chondrocytes PROLIFERATION
Pathophysiology of Growth Hormone
GROWTH HORMONE DEFICIENCY:
1) DECREASE Secretion of GHRH (Due to Hypothalamic Dysfunction)
2) DECREASE Growth Hormone Secretion (Primary Deficiency)
3) Failure to Generate SOMATOMEDIN
4) GH or Somatomedin Resistance (Deficiency of Receptors)
5) GH Deficiency in Children is Treated with HUMAN GRWOTH HORMONE REPLACEMENT
GROWTH HORMONE EXCESS:
1) Causes ACROMEGALY
2) Mostly due to a GRWOTH HORMONE- Secreting PITUITARY ADENOMA
3) Consequences depends on Development Stage:
A) Before Puberty: GIGANTISM
B) After Puberty: Increased Periosteal Bone Growth, Increased Organ Size, Increased Extremities Size, Coarsening of Facial Features, Insulin Resistance, and Glucose Intolerance
C) Conditions with Excess Secretion of GH are treated with Somatostatin Analogues (OCTREOTIDE)
- Inhibits GH Secretion
Prolactin supports the actions of Estrogen and Progesterone
1) BREST DEVELOPMENT (Combined actions with Progesterone and Estrogen)
- At PUBERTY: Stimulate Proliferation and Branching of Mammary Ducts
- During PREGNANCY: Stimulates Growth and Development of the Mammary Alveoli
2) LACTOGENESIS: Induces the Synthesis of Lactose, Casein, and Lipids
- Although PROLACTIN Levels are high during Pregnancy, Lactation doesn’t occur because High Levels of Estrogen and Progesterone DOWN-REGULATE Prolactin Receptors
- At BIRTH, the Inhibition is released when Estrogen and Progesterone levels DROPS PRECIPITOUSLY, when this occurs LACTOGENESIS is Stimulated
3) SUPPRESSION OF OVULATION
- Inhibits Synthesis and Secretion of GnRH
Pathophysiology of Prolactin
1) PROLACTIN DEFICIENCY:
- Results in Inability to LACTATE
- Causes: Destruction of the Entire Lobe of the Pituitary or Selective Destruction of the Cells that Secrete PROLACTIN (LACROTROPHS)
2) PROLACTIN EXCESS
- Results in GALACTORRHEA (Excessive Milk Production) and INFERTILITY (Caused by Inhibition of GnRH Secretion by PRLACTIN)
- Causes:
A) Destruction of the Hypothalamus or Interruption of the HYPOTHALAMIS-HYPOPHYSIAL TRACT; Resulting in Loss of TONIC Inhibition of DA
B) PROLACTINOMAS (Prolactin- Secreting Tumors)
C) BROMOCRIPTINE (DA receptor Agonist) can be used for treatment of Prolactin EXCESS
Hypopituitarism
- PANHYPOPITUITARISM is a Condition of inadequate or Absent production of the ANTERIOR PITUITARY HORMONES
- Causes: Problems that affect the Pituitary Gland and either REDUCE or DESTROY its Function or Interfere with HYPOTHALAMIC SECRETION of the varying PITUITARY-RELEASING HORMONES
Hypopituitarism Causes
1) BRAIN DAMAGE
- Ex: Traumatic Brian Injury, Subarachnoid Hemorrhage, Irradiation, Stroke
2) PITUITARY TUMORS
- Ex: Adenomas
3) NON-PITUITARY TUMORS
- Ex: Craniopharyngioma: MOST COMMON TUMOR affecting the HP Axis in Children
4) INFECTIONS
- Ex: Meningitis, Encephalitis, Hypophysitis
5) INFACRTION
- Ex: SHEEHAN SYNDROME: The Pituitary in Pregnancy is ENLARGED and MORE VULNERABLE to INFARCTION
6) AUTOIMMUNE DISORDERS
7) PITUITARY HYPOPLASIA OR APLASIA
8) GENETIC CAUSES
9) IDIOPATHIC CAUSES
Pituitary Adenoma
- Most Pituitary Tumors are PITUITARY ADENOMAS
- Most Pituitary Adenomas occur SPONTANEOUSLY
Classified according to:
1) SIZE:
- Microadenoma (1 cm )
2) Aggressiveness
- Nearly all Pituitary Adenomas are benign and Slow-Growing
3) HORMONE SECRETION:
- Functional Tumors: Adenomas that release an Active Hormone, usually an Excessive Amount
- Clinically Non-Functioning Adenomas: DO NOT Release an Active Hormone
Pituitary Adenomas Cont
- Hormone Producing Pituitary Adenomas release an Active Hormone in EXCESSIVE Amounts into the Blood Stream
a) The patients usually Experience Symptoms related to the Hormone ACTION on the Body
Examples Include:
1) PROLACTINOMA (60%), a Tumor that OVERPRODUCES PROLACTIN
- Associated with HYPOGANODISM and GALACTORRHEA
2) ACROMEGALY (Adults) GIGANTISM (Child), caused by an Excess Growth Hormone (20%)
3) CUSHING’S DISEASE, caused by a Pituitary Tumor stimulating an OVERPRODUCTION of Cortisol (10%)
- Pituitary Adenomas develop in 25% of patients with MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 (MEN 1)
Posterior Lobe Hormones
1) Neuropeptides:
- ADH and Oxytocin
2) Secreting Neurons:
- ADH Neurona have Cell Bodies PRIMARILY in the SUPRAOPTIC NUCLEI of the Hypothalamus
- OXYTOCIN Neurons have cell bodies PRIMARILY in the PARAVENTRICULAR NUCLEI of the Hypothalamus
3) PRECURSOR PEPTIDES:
- ADH: Preprossophysin
- Oxytocin: Prepro-Oxyphysin
ADH
- ADH is the Major Hormone concerned with REGULATION of BODY FLUID
- Released from the POSTERIOR LOBE of the Pituitary and acts on Target Tissues of the Kidneys and Blood Vessels
Triggers of ADH Secretion
1) DECREASE Blood Pressure
- Cardiac and Aortic Baroreceptors
2) DECREASE Arterial Stretch due to LOW BLOOD VOLUME
- Atrial Stretch Receptors
3) INCREASE Osmolarity (> 280 mOsM)
- Hypothalamic Osmoreceptors
***All of these cause ADH to be released from POSTERIOR PITUITARY
Actions of ADH
*** Secretion of ADH is MOST SENSITIVE to PLASMA OSMOLARITY Changes! An INCREASE of only 1% in the Osmolarity will INCREASE ADH SECRETION!!!!
Secretion Triggers:
- INCREASE Plasma Osmolarity
- DECREASE Blood Pressure
- DECREASE Blood Volume
- INCREASE Angiotensin II
- Sympathetic Stimulation
- Dehydration
**UREA can pass with Water, but Electrolytes CANNOT!!!
V1 Receptors: Blood Vessels (Vasoconstriction)
V2 Receptors: Kidney (Increase Reabsorption of Water)
**ADH causes AQUAPORIN-2 Channels to be made in the Renal Collecting Duct so that Water can be Reabsorbed (Adenyl Cyclase —-> cAMP —> PKA)
Hyperosmolarity (Dehydration)
- Hypothalamus detects TOO LITTLE WATER
- Pituitary Gland RELEASES ADH
- Kidneys remove LESS WATER from the Blood so less Water is LOST in URINE. (The Urine is MORE CONCENTRATED)
Hypoosmolarity/ Hypervolemia
- Hypothalamus detects TOO MUCH water in Blood
- Pituitary Gland releases LESS ADH
- Kidneys remove MORE WATER from Blood so MORE WATER is LOST in URINE (The Urine becomes MORE DILUTE)
Control of ADH Secretion by Osmolarity and Extracellular Fluid Volume
270 mOsm/L Plasma Osmolarity:
- Volume CONTRACTION
280 mOsm/L Plasma Osmolarity:
- Normal
288 mOsm/L Plasma Osmolarity:
- Volume EXPANSION
Pathophysiology Changes in ADH Secretion
DIABETES INSUPIDUS (DI) - Lack of an effect of ADH on the Renal Collecting Duct
- Causes FREQUENT URINATION
- The Large Volume of Urine is Diluted
Central Diabetes Insupidus
- LACK of ADH (Decrease Plasma ADH)
Results from:
- Damage to the Pituitary
- Destruction of the hypothalamus
Treatment:
- DESMOPRESSIN (Drug that prevents Water Excretion)
Nephrogenic Diabetes Insipidus
- KIDNEYS UBANLE to RESPOND to ADH (INCREASE Plasma ADH)
Causes:
- Drugs like LITHIUM
- Chronic Disorders (Ex: POLYCYSTIC KIDNEY DISEASE, SICKLE CELL ANEMIA)
***DESMOPRESSIN Treatment DOES NOT WORK
Water Deprivation Test for DI
1) Allow fluids overnight before Test and give Breakfast with no Fluids
2) WEIGH PATIENT
3) Allow no Fluid for 8 Hours
- Every 1 to 2 Hr: Weight patient (Stop test if Weight Drops by > 5% initial Body Weigth)
Patient Empties Bladder:
- Measure Urine Volume and Osmolarity
- Measure Plasma Osmolarity (Stop test is Osm > 300 mOsM)
4) If results suggest DI, allow patient to Drink (No more than TWICE Urine Volume of Period of Fluid Deprivation) and Administer DESMOPRESSIN
5) Measure Plasma and Urine Osmolarity, Urine Volume
Differential Diagnosis following Water Deprivation Test Procedure
NORMAL:
1) Plasma Osm:
- 297
2) Urine Osm:
- 814
3) Plasma ADH:
- INCREASE
4) Urine Osm post Desmopressin
- 815
CENTRAL:
1) Plasma Osm:
- 342
2) Urine Osm:
- 102
3) Plasma ADH:
- DECREASE
4) Urine Osm post Desmopressin
- 622
NEPHROGENIC:
1) Plasma Osm:
- 327
2) Urine Osm:
- 106
3) Plasma ADH:
- INCREASE
4) Urine Osm post Desmopressin
- 118
Pathophysiological Changes in ADH Secretion
SYNDROME OF INAPPROPRIATE ADH SECRETION (SIADH)
- Excessive SECRETION of ADH
- Excessive WATER RETENTION
- Hypoosmolatiy FAILS to INHIBIT ADH Release
SIADH Treatment:
1) Fluid Retention
2) IV Hypertonic Saline (3%)
3) V2 Receptor Antagonist
4) DEMECLOCYCLINE
Regulation of Oxytocin Secretion
1) Prepro- Oxyphysin
- —>
2) Pro-Oxyphosin
- —>
3) Oxytocin in Posterior Lobe of Pituitary
- —>
4) Oxytocin to Target Tissues in BREAST
Highlights about Clinical Consequences of Pituitary Failure
GH:
- Children short stature
- Adults: No effect
FSH/LH:
- Infertility
- Male Hypogonadism, Reduced Sperm Count
- Female Hypogonadism, Menstrual Irregularity
TSH:
- Hypothyroidism
ACTH:
- Loss of Pigmentation
- Hypoadrenalism
ADH:
- Diabetes Insipidus
Hyponataemia
1) HYPOVOLEMIA:
- Total Body Water DECREASES
- Total Body Sodium GREATLY DECREASES
2) EUVOLEMIA:
- Total Body Water INCREASE
- Normal Total Body Sodium
3) HYPERVOLAEMIA
- Total Body Water GREATLY INCREASES
- Total Body Sodium INCREASES
***SIADH characterized by EUVOLEMIA but HYPONATREMIA!!!!!!!!!
