Clinical Hypothalami

Chemistry 2 c
Lecture | Mr. Dave A. Tangcalagan & Pituitary
Function
forming nonfunctioning, benign,
INTRODUCTION cystic enlargements of the pituitary.
Pituitary derived from both Latin and Greek that
means to “spit mucus”. 3. Posterior Pituitary (neurohypophysis)
 Reflecting the primitive notion of pituitary - Arises from the diencephalon
function. - Responsible for the storage and
 Ancient physiologists were correct in release of oxytocin and arginine
believing that the brain was responsible vasopressin (AVP) previously called
for signaling the pituitary to secrete as the antidiuretic hormone (ADH).
mucus; however instead of mucus, it was
later discovered that the brain directs the  Other Critical Events of the Hypothalamic
pituitary to secrete hormones that regulate Hypophyseal Unit:
other endocrine glands. - Creation of the median eminence
 Pituitary gland is considered to be the - Creation of the inferior portion of the
“master gland”. hypothalamus
 Without the pituitary gland there will be; - Creation of the pituitary stalk
a. Cessation of Growth  Pituitary functions can be detected between
b. Profound Alterations in Intermediary the seventh to ninth weeks of gestation
Metabolism  The ultimate determination of anterior
c. Failure of Gonadal, Thyroidal and pituitary cell types is dependent in the
Adrenal Function. formation of lactotrophs (prolactin-secreting
 Pituitary is also referred to as the cells), somatotrophs (growth hormone [GH]
hypophysis, from Greek meaning – secreting cells), thyrotrophs (thyroid
“undergrowth,” attesting to its unique stimulating hormone [TSH] – secreting
position under the hypothalamus. cells), corticotrophs (adrenocorticotropin
hormone [ACTH] – secreting cells) and
The concept of pituitary function and role of gonadotrophs (luteinizing hormone [LH]
being the mater gland has changed, it is more and follicle-stimulating hormone [FSH] –
appropriately recognized as a transponder that secreting cells.
translates neutral input into hormonal products.  The pituitary resides in a pocket of the
sphenoid (the sella turcica meaning “Turkish
Features that distinguish the function of the saddle” and is surrounded by dura mater.
pituitary includes:
FUNCTIONAL ASPECTS
1. Feedback Loops Hypothalamic – Hypophyseal Unit
2. Pulsatile Secretions  Afferent pathways (inputs) to the
3. Diurnal Variation hypothalamus are integrated in various
4. Environmental/External Modification of the specialized nuclei, processed, and then
Gland’s Performance resolved into specific patterned responses.
 Because the hypothalamus has many
These characteristics of pituitary operation can efferent neural connections (outputs) to
distort the clinical evaluation of suspected higher brain centers (the limbic system, the
endocrine disease or, alternatively, ;end incredible autonomic nervous system, and the
insight into subtle defects in endocrinologic pituitary), these responses are similar for
function. each specific pituitary hormone and
characterized by negative feedback
EMBRYOLOGY & ANATOMY mechanisms, pulsatility, and diurnal
Pituitary Gland variation.
 A simple example of an endocrine feedback
 The three distinct parts of the pituitary are loop is the hypothalamic– pituitary–
the: thyroidal axis. The hypothalamus produces
1. Anterior Pituitary (adenohypophysis) the hypophysiotropic hormone, thyrotropin-
- Largest portion of the gland releasing hormone (TRH), and releases it
- Originates from the Rathke pouch into the portal system where it directs the
An evagination of buccal ectoderm that progressively extends
upward and is eventually enveloped by the sphenoid bone. thyrotrophs (or TSH-producing cells) in the
2. Intermediate Lobe anterior pituitary to secrete TSH.
- Poorly developed in humans  TSH circulates to the thyroid and stimulates
- Little functional capacity other than several steps in the thyroid that are critical in
to confuse health care providers by the production and release of thyroid
hormone (thyroxine).
Clinical Hypothalami
Chemistry 2 c
Lecture | Mr. Dave A. Tangcalagan & Pituitary
Function
 Thyroxine is released in the blood and  The term zeitgeber (“time giver”) refers to
circulates to the hypothalamus and pituitary the process of entraining or synchronizing
to suppress further TRH and TSH these external cues into the function of
production. This axis can be partially internal biologic clocks.
inhibited by adrenal steroids  As a result, many pituitary hormones are
(glucocorticoids) and by cytokines; as a secreted in different amounts, depending on
result, thyroid hormone production may the time of day. These circadian, or diurnal,
decline during periods of severe physiologic rhythms are typified by ACTH, or TSH
stress. secretion.
 The feedback of thyroxine at the level of the  With ACTH, the nadir of secretion is
pituitary is called a short feedback loop, and between 11:00 PM and 3:00 AM, and the
feedback at the level of the hypothalamus is peak occurs on awakening or around 6:00
called a long feedback loop. to 9:00 AM.
 Feedback between the pituitary and  The circadian rhythm of ACTH is a result of
hypothalamus when present is called an variations in pulse amplitude and not
ultrashort feedback loop. alterations in pulse frequency. The nocturnal
levels of TSH are approximately twice the
daytime levels; the nocturnal rise in TSH is
a result of increased pulse amplitude.

KINDS OF PITUITARY HORMONES

 Examples:
> LH: Gonad
 Feedback: Sex steroids
> FSH: Gonad
 Feedback: Inhibin
> TSH: Thyroid
 Feedback: T3/T4
> ACTH: Adrenal
 Feedback: Cortisol
2. Direct Hormones
 All anterior pituitary hormones are secreted  Acts directly on different peripheral
in a pulsatile fashion. The pulse frequency tissues and has no specific target organ.
of secretion is generally regulated by neural  Examples:
modulation and is specific for each > GH: Multiple target gland
hypothalamic–pituitary–end-organ unit.  Feedback: IGF-1
 Best example of pituitary pulsatility is the > Prolactin: Breast
secretion of the hormones that regulate  Feedback: Unknown
gonadal function (LH and FSH).
 In normal male subjects, the median HORMONES UNDER ANTERIOR
interpulse interval for LH is 55 minutes, and PITUITARY GLAND
the average LH peak duration is 40 minutes. Growth Hormone
 The pulse frequency of the regulatory  Somatotrophs:
hypothalamic hormone, gonadotropin- o the pituitary cells that
releasing hormone (GnRH), has profound produce GH it comprise
effects on LH secretion profiles— increasing over 1/3 of normal pituitary
the frequency of GnRH pulses reduces the weight)
gonadotrope secretory response, and
 Somatostatin:
decreasing the GnRH pulse frequency
increases the amplitude of the subsequent o inhibits the secretion of
LH pulse Somatotropin
 Hypothalamic–pituitary unit is the cyclic o it has an average interpulse
nature of hormone secretion. The nervous interval of 2-3 hours, with
system usually regulates this function its peak levels occurring at
through external signals, such as light–dark the onset of sleep
changes or the ratio of daylight to darkness. o considered an Amphibolic
Clinical Hypothalami
Chemistry 2 c
Lecture | Mr. Dave A. Tangcalagan & Pituitary
Function
hormone because it directly anterior pituitary hormones
influences both Anabolic & (Hypopituitarism)
Catabolic processes  familial or it may be due to tumors, such
 The anabolic effects of GH are as Craniopharyngiomas which means it
reflected by enhanced protein is the recessive mutation in the GHrH
synthesis in skeletal muscle & other gene that causes failure of GH secretion.
tissues. LABORATORY DIAGNOSIS:
 it directly antagonizes the effect of Specimen:
Insulin on glucose metabolism,  fasting serum (complete rest for 30
promotes Hepatic gluconeogenesis minutes before collecting blood)
& stimulates Lipolysis
I. GH DEFICIENCY TEST:
 In children, GH deficiency may be
accompanied by Hypoglycemia. In • INSULIN TOLERANCE TEST
adults, Hypoglycemia may occur if • gold standard test
both GH & ACTH are deficient • confirmatory test
 Somatomedin: are factors that • ARGININE STIMULATORY TEST
mediates indirect effects of GH. • 2nd confirmatory test
* INSULIN-LIKE GROWTH FACTOR • failure of GH to rise >5 ng/mL (adults)
 has structural homology to Proinsulin and >10 ng/mL is considered abnormal
 but they have their own specific II. SCREENING TEST FOR
own receptor that are distinct from ACROMEGALY:
Insulin  Somatomedin C or Insulin-like Growth
 IGF-I / Somatomedin C: Factor-I:
o the major growth factor  IGF-I is ↑ in patients with Acromegaly
 IGF-II:  IGF-I is ↓ in GH deficiency
o can bleed over the insulin III. CONFIRMATORY TEST FOR
receptor & cause ACROMEGALY:
Hypoglycemia, &  GLUCOSE SUPRESSION TEST /
Hyperinsulinemia can OGTT
partially activate IGF-I
 requires fasting sample
receptors
 GH stimulates the production of IGF-  75g of glucose load
I from the liver & as a result, IGF-I  blood is collected every 30mins for 2hrs
becomes a biologic amplifier of GH  if GH fails to decline <1 ng/mL, it is
levels. Acromegaly
 A normal response for this test is a
Clinical Disorders: suppression of GH <1 ngmL
a. PITUITARY DWARFISM
 retain normal body proportions & show HORMONES UNDER ANTERIOR
no intellectual abnormalities PITUITARY GLAND
b. PITUITARY GIGANTISM Prolactin
 is due to the overproduction of GH (> 50 “a pituitary stress and lactogenic hormone”
ng/mL)  Estrogen also directly stimulates lactotrophs
 IGF are complexed to specific serum to produce Prolactin.
binding proteins that have been shown to  It is needed during Parturition; in the
affect the actions of IGF in multifaceted initiation & maintenance during Lactation
ways  Also acts in conjuction with Estrogen &
 IGF-binding protein III (IGFBP-III): Progesterone to promote breast
the carrier protein development.
c. ACROMEGALY  It is elevated during Seizure & Exercise.
 pathologic or autonomous GH excess,  Highest lvl: 4 AM-8AM & 8PM-10PM
pituitary tumor (ectopic production of  Dopamine inhibits the secretion of
GHrH) Prolactin
 insulin antagonist, glucose intolerance  Stimulation of breasts, as in nursing, causes
or diabetes can occur, including the release of Prolactin releasing hormones
muscle weakness from the hypothalamus through a spinal
 headache & visual complaints or reflex act.
symptoms related to the loss of other
Clinical Hypothalami
Chemistry 2 c
Lecture | Mr. Dave A. Tangcalagan & Pituitary
Function
▪ Clinical Disorders: Gonadotrophin
a. HYPERPROLACTINEMIA  Important markers in diagnosing Fertility
 ↑ levels of Prolactin is also seen in & Menstrual cycle disorder
infertility, menstrual irregularity, PCOS,  Present in the blood of both male &
renal failure, Amenorrhea, Galactorrhea, female at all ages types of gonadotropins:
& Hypothyroidism. a. Follicle Stimulating Hormone (FSH)
 May be due to the disruption of Pituitary  In females = Folliculogenesis
stalk such as trauma, inflammation, or  In males = Spermatogenesis
tumor.  Elevation of FSH is a clue in the
 may be due to medications such as: diagnosis of Premature
o Phenothiazines Menopause
o Butyrophenones  Increased levels of FSH & LH
o Metoclopramide after menopause is due to lack of
o Reserpine Estrogen.
o Aldomet b. Luteinizing Hormone (LH)
o Tricyclic antidepressant &  In females = Ovulation / Final
antidepressants follicular growth
o Hypogonadism is the  In males = helps Leydig cells to
consequence of Prolactin excess, produce Testosterone
either by:  acts on Thecal cells to cause the
 Suppression of gonadotropin synthesis of Androgens,
secretion from the Pituitary gland Testosterone, Estrogens &
 Inhibition of gonadotropin action at the Progesterone
gonad
c. Thyroid Stimulating Hormone (TSH)
b. PANHYPOPITUITARISM  Its Alpha subunit has the same
 commonly results from a pituitary tumor Aminod Acid sequences of LH,
(Adenoma) or from a pituitary blockage FSH, & HCG
(Ischemia)  Its Beta subunit carries the
 complete loss of its function specific information to the
binding receptors for expression
c. PITUITARY ISCHEMIA of hormonal activities
 Sheehan’s Syndrome: hemorrhage or  It acts to increase the number &
shock in a pregnant female at the time of size of follicular cells
delivery which can lead to the mother’s  It stimulates Thyroid hormone
death. synthesis
 Main stimulus for the update of
Iodide by the Thyroid gland.
LABORATORY DIAGNOSIS:
 Specimen: blood should be collected d. Adrenocorticotrophic Hormone
3-4hrs after the patient has awakened (ACTH)
(requires fasting)  for the secretion of
Cortisol—regulator
 If Pituitary tumor is suspected, a
of Adrenal Androgen
careful assessment of other pituitary
synthesis
function is performed:
 produce in response
o LH, FSH, Basal cortisol, &
to low serum cortisol
gender-specific gonadal
 Highest lvl: 6 AM-9
steroid—either Estradiol or
AM; lowest lvl: 11
Testosterone
PM & 3 AM
o high resolution MRI should
 Clinical Disorders:
be obtained Treatment:  Increased levels of ACTH is
 Obtain TSH & free T4 (Total Thyroxine seen in Addison’s disease,
& T3 resin) to eliminate Hypothyroidism
Ectopic tumors, & after protein-
as a cause of the elevated Prolactin.
rich meals
HORMONES UNDER ANTERIOR  ACTH deficiency can lead to
PITUITARY GLAND Atrophy of the Zona
Clinical Hypothalami
Chemistry 2 c
Lecture | Mr. Dave A. Tangcalagan & Pituitary
Function
Glomerulosa & Zona  results in severe Polyuria (>3L of
Reticularis of Adrenal gland urine/day)
 Laboratory Diagnosis:  Clinical features:
• Normoglycemia
 Specimen for ACTH testing
• Polyuria w/ low Specific Gravity
should not be allowed to have
• Polydypsia
contact with glass
• Polyphalgia
 Instead, blood should be
Types of Diabetes Insipidus:
collected into Pre-chilled
a. NEUROGENIC DIABETES
Polystyrene Plastic tube
INSIPIDUS
 also called as “Hypothalamic /
HORMONES UNDER ANTERIOR
Neurogenic / Cranial / Central
PITUITARY GLAND
Diabetes Insipidus”
Oxytocin
 failure of the Pituitary gland to
 stimulates contraction of the gravid
secrete ADH
uterus at term called “Fergussin
 there is Polyuria (3-20 L/day)
reflex”
b. NEPHROGENIC DIABETES
 released in response to neural INSIPIDUS
stimulation of receptors in the birth  has normal ADH, but has abnormal
canal, uterus, & of touch receptors in ADH receptors
the breast  renal resistance to ADH action
 stimulates muscle contraction during  failure of the kidneys to responds to
birth delivery & lactation normal or elevated ADH level
 synthetic preparation of oxytocin are c. SYNDROME OF
used to increase weak uterine INAPPROPRIATE
contractions during labor & to aid in ANTIDIURETIC HORMONE
lactation. SECRETION (SIADH)
 refers to sustained production of
HORMONES UNDER ANTERIOR ADH in the absence of known
PITUITARY GLAND stimuli
Antidiuretic Hormone/ Arginine Vasopressin Laboratory Tests:
 non-peptide that acts on the water a. OVERNIGHT H20 DEPRIVATION
reabsorption of the kidney TEST
 it increases blood pressure  for Diabetes Insipidus
 it’s a potent pressor agent & afects  after 8-12 hrs without fluid intake,
blood clotting by promoting Factor urine osmolality does not rise above
VII & release of VWF 300 mOsm/kg.
 increased levels of ADH is seen
during Physical & Emotional stress
 Emectic stimuli (anything that can
induce vomiting): potent physiologic
stimuli to release of ADH
 Ethanol, Cortisol, & Lithium:
Inhibits release of ADH
 ↑ Plasma Osmolality: principal
regulator of ADH secretion
 ADH secretion is maximally
stimulated at a serum osmolality of
>295 mOsm/kg & suppressed when
the osmolality falls below 284
mOsm/kg
Clinical Disorders:
a) DIABETES INSIPIDUS
 result of ADH deficiency