Trans by : nahaeminrmt

Introduction: Chapter 20 (Pituitary Hormones)  Short feedback loop - pituitary (TSH) to the thymus
(Thyroxine)
 Pituitary (Latin and Greek) - “spit mucus”  Long feedback loop - hypothalamus to thymus
 Brain is responsible for the signaling the pituitary to  Ultrashort feedback loop - feedback loop between
secrete hormones that regulate other endocrine glands. pituitary and hypothalamus
 Pituitary is also known as “master gland” or “hypophysis”
as it underneath the hypothalamus
 Functions of Pituitary Gland: feedback loops, pulsatile
secretions, diurnal rhythms, and environmental or
external modification of its performance
 Pituitary function can be detected between seventh and
ninth weeks of gestation
Anatomy of Pituitary Gland
 The pituitary resides in the pocket of sella turcica
 Three distinct parts of pituitary gland:
 Anterior pituitary (adenohyophysis)  Pulsatile Secretions
 Intermediate lobe (pars intermedialis) - poorly  e.g. Gonadotropin-Releasing Hormone
developed in humans and has little functional  ↑ frequency of GnRH pulses = ↓ in the
capacity. gonadotrope secretory response
 Posterior pituitary (neurophypophysis)  ↓GnRH pulse frequency = ↑ LH pulse
 Anterior Pituitary  Cyclic Rhythms
 Largest portion  Diurnal rhythms
 Originates from the Rathke’s pouch  Zeitgeber (“time giver”) - the process of entraining
 Enveloped by the sphenoid bone or synchronizing these external cues into the
 It receives 80%-90% of its blood supply and many function of internal biologic clocks.
hypothalmic factors via the hypothalmic-  e.g ACTH lowest secretion during 11PM to 3AM
hypophyseal portal system but at peak during 6AM-9AM; TSH more of a
 Hormones produced: prolactin, GH, TSH, cortisol, nocturnal hormone than diurnal.
LH, FSH Hypothalmic Hormones
 Posterior Pituitary
 Arises from the diencephalon  These hypophysiotrophic hormones are found
 It is responsible for the storage and release of throughout the CNS and various other tissues (gut,
oxytocin and vasopressin pancreas, and other endocrine glands)
 It is connected to the supraoptic and Hormone Structure Action
paraventricular hypothalmic nuclei TRH 3 Amino Acids Releases TSH
 Paraventricular hypothalmic nuclei - where and prolactin
vasopressin and oxytocin are produced) GnRH 10 Amino Acids Releases LH and
FSH
Functio of Hypothalmic-Hypophyseal Unit CRH(corticotropin- 41 amino acids Releases ACTH
releasing hormone)
 Open-loop Negative Feedback Mechanisms
 Open means they are subjected to external Vasopressin (pituitary gland) Releases ACTH
modulation and generally influenced or modified GHRH 44 amino acids Releases GH
by higher neural input or other hormones Somatostatin 14 and 28 amino Inhibits GH and
 e.g. hypothalmic-pituitary-thyroidal axis acids TSH release
 It can be inhibited by adrenal steroids Dopamine 1 amino acid Inhibits
(glucocorticoids) and cytokines which are (prolactin prolactin
released during physiological stress inhibitory factor) release

hypothalamus will release TRH → thyrotrophs (TSH-producing Pituitary Tumors

cells) in the anterior pituitary will respond and release TSH → TSH
will stimulate thyroid to release thyroxine → thyroxine will be
released in the blood → signals the hypothalamus and pituitary
to suppress their action
 20% of people harbor clinically silent pituitary
adenomas and findings are consistent with pituitary
tumors observed in 10%-30% normal individuals
undergoing MRI examinations.
 These tumors account for 91% of the lesions removed Effector)
from carefully selected patients who have undergone
transphenoidal surgery. Growth Hormone
 Pituitary tumors:
1. Prolactin-secreting pituitary tumors - most common  Also called as “somatotropin”
2. Non-functioning or null cell tumors  Kapag walang GH, pero present yung ibang hormones
3. Tumors that secrete GH, gonadotropins, ACTH, or TSH (T4, adrenal steroids, and gonadal steroids) wala pa ring
 Atypical Pituitary Tumors growth unless nag-administer ng GH. Kung may GH pero
 Most of these tumors are macroadenomas (>1 cm wala naman yung ibang hormones, wala pa ring growth.
in diameter) and show invasion into surrounding In short, kailangan maayos talaga yung pituitary gland.
structures like the cavernous sinuses  DIRECT EFFECTOR (Multiple)
 MIB-1 is a monoclonal antibody that is used to  It is structurally related to prolcatin and human
detect the Ki-67 antigen, a marker of cell placental lactogen
proliferation  A single peptide with two intramolecular disulfide
 A high “proliferation index” suggests higher bridges
degree of atypia  It takes complete functioning of the pituitary to
 Tumors that have an MIB-1 proliferative index establish conditions ripe for the growth of the individual
greater that 3%, excessive p53 immunoreactivity,  Adequate nutrition, normal levels of insulin, and
and increased mitotic activity overall good health
 Physiologic Enlargement of Pituitary Gland  Somatotrophs - pituitary cells that produce GH;
 Pregnancy - It is due to lactotroph hyperplasia composed the 1/3 of the normal weight of pituitary
 Puberty  Pulse secretion
 Long-standing primary thyroidal failure -  Average interpulse interval - 2 to 3 hrs
thyrotroph and lactotroph hyperplasia  Peak secretion happen on the onset of sleep
 Long-standing primary gonadal failure -  Ghrelin - An enteric hormone that plays important roles
gonadotrph hyperplasia in nutrient sensing, appetite and in glucose regulation; a
potent stimulator of GH
Anterior Pituitary Hormones
 More complex Hypothalmic GHRH → Pituitary Gland will release GH →
 Either tropic or direct effector Secretion of GH will be inhibited by somatostatin
 Tropic - the effect is specific for another endocrine
gland  Actions of GH
 TSH - regulate thyroid function (it is directed  Amphibolic Hormone - directly influences anabolic
to the thyroid gland) and catabolic process
 LH - directs testosterone (Leydig Cells) and  CATABOLIC - Breakdown
ovulation  ANABOLIC - Build
 FSH - folliculogenesis and spermatogenesis  GH allows an individual to effectively transition
 ACTH - regulates adrenal steroidogenesis from a fed state to a fasting state without
 Direct Effector - act directly on peripheral tissue experiencing a shortage of substrates required for
 Growth Hormone - it affects numerous normal intracellular oxidation.
tissues and also stimulates the liver to  GH antagonizes the effect of insulin on glucose
produce growth factors metabolism, promotes hepatic gluconeogenesis,
 Prolactin - direct effector of breasts and stimulates lipolysis
Enhanced lipolysis (Catabolic) → oxidative substrate for peripheral tissue
Pituitary Target Structure Feedback (skeletal muscle)
Hormon Gland Hormone Hepatic gluconeogenesis (Anabolic) → conserves glucose for the CNS
e
LH Gonad Dimeric Sex steroids *GH deficiency in children may be accompanied with
(Tropic) glycoprotein (Estradiol/Testost hypoglycemia
erone) *Adult hypoglycemia may occur if both GH and ACTH are
FSH Gonad Dimeric Inhibin deficient
(Tropic) glycoprotein  Other anabolic effects of GH
TSH Thyroid Dimeric Thyroid  Protein synthesis in skeletal muscle and other
(Tropic) glycoprotein Hormones (T4/T3) tissues → positive nitrogen balance and
ACTH Adrenal Single peptide Cortisol phosphate retention
(Tropic) derived from  Indirect effects of GH
POMC  Mediated by factors that were initially called,
GH Multiple Single Peptide IGF-I somatomedins now called Insulin-like Growth
(Direct Factor (IGF) due to its homology to proinsulin
Effector)  IGF-I: Major growth factor induced by GH; it
Prolactin Breast Single Peptide Unknown has distinct cell surface receptors that are
(Direct distinct from insulin
  Produced in the liver when stimulated  GH-producing tumors occurs before
by GH epiphyseal closure
 IGF-I receptors can be activated by  Growth in impressive height
hyperinsulinemia  Classical symptoms include:
 IGF-II: supraphysiologic levels could cause  Insidious, features of bony and soft tissue
hypoglycemia overgrowth
 IGF Binding Protein 3 (IGFBP-3) - it could  Progressive enlargment of the hands and feet
inhibit neoplastic proliferation  Growth of facial bones (mandible and skull)
 Significant teeth gaps (severe cases)
P53 tumor supressor gene → upregulate active IGFBP-3 secretion  Diffuse (puberty) overgrowth of the ends of
→ inhibits IGF-I signaled mutagenesis → inhibition of neoplastic
the long bones
cell proliferation
 Spine can produce debilitating form of
Other Modifiers of Growth Hormone arthritis
Stimulate Growth Hormone Inhibit Growth Hormone  Glucose intolerance or overt diabetes can
Secretion Secretion occur
Sleep Glucose loading  Hypertension
Exercise β-antagonists (e.g.,  Accelerated atherosclerosis
epinephrine)  Proximal muscle weakness due to acquired
Physiologic Stress α-Blockers (e.g., myopathy (may be seen late in illness)
phentolamine)  Sleep apnea
Amino Acids (e.g., arginine) Emotional/Psychogenic  Organomegaly esp. Thyromegaly
Stress (hyperthyroidism is exceedingly rare unless
Hypoglycemia Nutritional deficiencies the tumor cosecretes TSH)
Sex Steroids Insulin deficiency  Hypermetabolic condition → excessive
α-Agonists (e.g., Thyroxine deficieny sweating or heat intolerance
norepinephrine)  Symptoms of acromegaly manifest GRADUALLY
β-Blockers (e.g., propanolol)  Patients may complain about local effects of
the tumor (headache or visual complaints) or
symptoms related to hypopituitarism
 Testing of GH
 Acromegaly if left untreated will lead to
 Rarely diagnostic
 Shortened life-span
Possible Laboratory Results
 Increase risk for heart disease (combination
Disease Associated Characteristics
of hypertension, coronary artery disease, and
Hepatoma associated with ↑ of IGF-I
diabetes/insulin resistance
Patients with active has ↑ level of IGGBP-3  Development of cancer
acromegaly  Cosecretion of prolactin can be seen up to 40% of
Inadequate production of GH ↓ IGF-I patients with acromegaly; few cases TSH-GH
Poorly controlled diabetes ↓ IGF levels secreting tumors have also been reported
 Oral Glucose Testing (100g glucose load)  Laboratory Diagnosis of GH
 GH levels are undetectable in normal  ↑ levels of GH do not suppress normally with
individuals glucose loading (definitive test)
 Patients with acromegaly - ↑GH  Some patients have normal level of GH
 Insulin-induced hypoglycemia - once a gold  Elevated levels of IGF-I are helpful
standard for testing patients with GH deficiency  Treatment of Acromegaly
 Combination infusion of GHRH and amino acid l-  Goal: tumor ablation with continued function
arginine or infusion of l-arginine coupled with oral of the remainder pituitary
l-DOPA  Transphenoidal adenomectomy - procedure
 GH level up to 3-5 ng/mL - unlikely that the of choice
patient is GH deficient  External beam or Focused irradiation - for
*provocative GH levels is not necessary for px with low IGF-1 patients with extremely large tumors and may
levels, or with panhypotuitarism invade local structures
 GH decline may take several years
 Acromegaly  Temporary suppression of GH:
 It results from pathologic or autonomous GH  SS analogs - octreotide, pasireotide, and
excess or in majority, pituitary tumor lanreotide
 Pituitary tumor due to ectopic production of  Dopaminergic agonists - cabergoline
GHRH or GH (rare) and bromocriptine
 Familial Acromegaly - mutations in the aryl-  GH Receptor Antagonists - pegvisomant
hydrocarbon-interacting protein gene (AIP)
 Sporadic (irregular) cases - due to polymorphisms  GH Deficiency
in the SS receptor type 5 gene  Children - genetic or may be due to tumors
 Gigantism (craniopharyngiomas)
  Adults - structural or functional abnormalities of
the pituitary
 Decline of GH is an inevitable consequence of
aging
 Children GH Deficiency
 Several genetic defects identified in the GH
axis
 Recessive mutation in the GHRH gene
causing a failure of GH secretion - most
common
 Lose of GH gene itself - rare
 Mutation result to GH insensitivity have
also been reported - involve GH receptor,
IGF-I biosynthesis, IGF-I receptors,
defects in GH signal transduction
 Patients do not respond normally
to exogenously administered GH
 Structural lesions of the pituitary or
hypothalamus
 May be associated with other anterior
pituitary hormone deficiencies
 Adult GH Deficiency
 Complete or even partial failure of the
anterior pituitary
 Symptoms are vague and include: social
withdrawal, fatigues, loss of motivation, and
diminished feeling of well being
 Osteoporosis and alterations in body
composition
 Therapy
 It has become relatively simple with the
advent of recombinant human GH
 GH has been employed by athletes as a performance
enhancing substance and as an aid in injury recover
Prolactin
 It is structurally related to GH and human placental
lactogen
 Produced by the lactotrophs in the pituitary
 It is considered as a stress hormone
 It has a vital relationship to reproduction
 DIRECT EFFECTOR - it has diffuse target tissue and lacks
a single endocrine end organ
 Major hypothalmic regulation is tonic inhibition rather
than intermittent stimulation
 Ibig sabihin, di nagsstimulate si hypothalamus,
pinapatigil niya yung secretion ni pituitary
 Prolactin Inhibitory Factor (PIF) was once
considered a polypeptide hormone capable of
inhibiting prolactin secretion
 Dopamine - ONLY neuroendocrine signal that
INHIBITS prolactin and is now considered to the
elusive PIF
 Medications that cause hyperprolactinemia
 Phenothiazines
 Butyrophenones
 Metoclopramide
 Reserpine
 Tricyclic anti-depressants
 α-methyldopa
 Antipsychotics that antagonize the dopamine D2
receptor
 Disruption of the pituitary stalk (e.g., tumors,
trauma, or inflammation) interrupted flow of
dopamine from the hypothalamus to the
lactotrophs
 TRH directly stimulates prolactin secretion
 ↑ in TRH (primary hypothyroidism) = ↑
prolactin levels
Stimulation of Prolactin
Pathologic Physiologic
Neural suckling reflex (due to Exercise
chest wall injuries)
Renal failure Seizures
PCOS
Primary hypothyroidism
 Prolactin is not only regulated by dopamine but
also by: GnRH, TRH, and vasoactive intestinal
polypeptide
 Stimulation of breasts in nursing causes the
release of prolactin-secreting hormones from the
hypothalamus through a spinal reflex arc
 Physiologic effect of prolactin: lactation
 Usual consequence of prolcatin excess: hypogonadism
 Suppression of gonadotropin secretion from the
pituitary
 Inhibition of gonadotropin action at the gonad
 Suppression of ovulation is seen in lactating
postpartum women
 Prolactinoma
 It is a pituitary tumor that directly secretes
prolactin
 Most common type of functional pituitary tumor
 Symptoms vary in age and sex
 Premenopausal woman - menstrual
irregularity/amenorrhea, infertility, or
galactorrhea
 Postmenopausal women - symptoms of
pituitary mass (headaches or visual
complaints)
 Men - same with postmenopausal women
and may be presented with erectile
dysfunction and reduced libido
 Prolactin induced hypoginadism maybe
presented with osteoporosis
 Other causes of Hyperprolactinemia
 It may be of physiologic, pharmacologic, and
pathologic causes
 Prolactinoma is indicated if the prolactin level
is >150 ng/mL with correlation to the tumor size
 Moderate elevations in prolactin (25-100ng/mL) is
caused by the following
 Pituitary stalk interruption
 Use of dopaminergic antagonist medications
 Primary thyroidal failure
 Renal failure
 PCOS
 Breast or genital stimulation
 Significant hyperprolactinemia in pregnancy
 In most circumstances, prolactin is a 23-kD
 Macroprolactinemia (150-kD) - patients are
asymptomatic
  It can be excluded by precipitating serum  Idiopathic Galactorrhea
samples with polyethylene glycol prior to  A condition in which lactation occuring in
measuring prolactin women with normal prolactin levels
 Clinical Evaluation of Hyperprolactinemia  It can be seen with women who became
 Careful history and physical examination is pregnant several times and has no pathologic
enough to exclude non-endocrine causes of implication
hyperprolactinemia
Hypopituitarism
 Examination of TSH and free T4 - to eliminate
primary hypothyroidism  Definitions/Characteristics
 Evaluation of other anterior pituitary function  It is a condition where there is a failure of either
 Evaluation of sellar anatomy with a high- the pituitary or the hypothalamus results in the
resolution MRI should be obtained loss of anterior pituitary function
 Management of Prolactinoma  Panhypopituitarism - It is the complete loss of
 Goal of the therapy: reduction of tumor mass, function of the pituitary gland
restoration of normal gonadal function and  Monotropic hormone deficiency - a loss of only a
fertility, prevention of osteoporosis, and single pituitary hormone
preservation of normal anterior and posterior  A loss of a tropic hormone = malfunctioning
function of the end endocrine gland
 Possible therapeutic options: simple  A loss of direct effectors = may not be readily
observation, surgery, radiotherapy, or apparent
medical managements with dopamine  Primary and Secondary Hypo___
agonists.  Kapag PRIMARY, yung organ mismo yung may
 Management of prolactinoma also depend on problema. Kunyare, Priamary Hypothyroidism,
the tumor size (macroadenoma or increased ang TSH pero low ang kanyang T4.
microadenoma)  Kapag SECONDARY, si pituitary ang may problema.
 Dopamine Agonists Secondary Hypothyroidism, low ang TSH kaya low
 Most commonly used therapy for din ang iyong T4
microprolactinomas  Etiology of Hypopituitarism/Causes
 Tumor shrinkage is noted in more than  Pituitary tumors
90% of patients treated with either  It can cause panhypopituitarism, by
bromocriptine mesylate (Parlodel) or compressing or replacing normal tissue or
cabergoline (Dostinex) dopamine interrupting the flow of hypothalmic
receptor agonists hormones by destroying the pituitary stalk
 The said drugs also shrink prolactin-  Large, nonsecreting tumors (e.g.,
secreting macroadenomas chromophobe adenomas or null cell tumors)
 Resumption of menses and restoration or macroprolactinomas
of fertility  Parasellar tumors (e.g., menangiomas and
 Adverse effects of bromocriptine: gliomas)
 Orthostatic hypotension  Metastatic tumors (e.g., breast and lungs)
 Dizzines  Hypothalmic tumors (e.g.,
 Nausea craniopharyngiomas or dysgerminomas)
 GI adverse effects  Hemorrhage in pituitary tumor is rare but
 Cabergoline has fewer adverse affects may lead to complete pituitary failure
 It has the ability to interact with 5-  Postpartum ischemic necrosis
hydroxytryptamine (5-HT)  Occur after a complicated delivery (Sheehan’s
serotonergic receptor leading to Syndrome)
development of valcular heart  Failure to lactate in the puerperium
disease  Infiltrative Diseases
 Neurosurgery  Hemochromatosis
 It is only considered when:  Sarcidosis
 Pituitary tumor apoplexy  Histiocytosis
(hemorrhage)  Fungal infections, tuberculsosis, and syphilis - can
 Acute visual loss due to involve hypothalamus or pituitary
macoradenoma  Lymphocytic hypophysitis
 Cystic prolactinoma  Autoimmune disease of the pituitary, may
 Intolerance to medical therapy only affect a single cell type in the pituitary
 Tumor resistance to dopaminergic  It could lead to monotropic hormone
agonists deficiency or can involve all cell types,
 Cure rates are INVERSELY yielding total loss of function
proportional to the tumor size  Ipilimumab
 Radiotherapy  A monoclonal antibody that blocks cytotoxic
 Only for high surgical risk with T-lymphocyte-associated antigen 4 (CTLA-4)
intolerance of dopamine agonists
  It is proven to increase survival in melanoma  Function: regulate renal free water excretion for water
patients balance
 Associated with lymphocytic hypophysitis  Vasopressin receptors (V2) in the kidney are
 Severe Head Trauma concentrated in the renal collecting tubulus and
 It may shear the pituitary stalk or may the ascending limb of the loop of Henle
interrupt the portal circulation
V2 → bind to adenylate cyclase → activated! → induce
 Radiotherapy induced panhypopituitarism insertion of aquaporin-2 (water channel protein) in the
 Familial panhypopituitarism tubular luminal membrane
 Idiopathic hypopituitarism
Hypopituitarism Etiology  It is a potent pressor agent and effects blood
1. Pituitary tumors clotting
2. Parapituitary/Hypothalmic tumors  Vasopressin promotes Factor VII release from
3. Trauma hepatocytes and von Willebrand factor
4. Radiation therapy/Surgery release from endothelium
5. Infarction  V1a and V1b are coupled to phospholipase C
6. Infection  Hypothalmic osmoreceptors and Vascular
7. Infiltrative disease baroreceptors - It regulate the release of vasopressin
8. Immunologic from the posterior pituitary
9. Familial  Osmoreceptors
 These are extremely sensitive to even small
10. Idiopathic
changes in plasma osmolality
 ↑Plasma osmolality = ↑ vasopressin
 Treatment of Panhypotuitarism
baroreceptors causing reduction in renal free
 Replacement therapy
water clearance, lowering plasma osmolality
 Pulsatile GH infusions - induced puberty and
 Vascular Baroreceptors
restored fertility in patients with Kallman’s
 It is located in the left atrium, aortic arch, and
syndrome
carotid arteries
 Gonadotropin preparation - restored ovulation/
 Vasopressin is released in response to a fall in
spermatogenesis
blood volume or blood pressure
Posterior Pituitary Hormones  A 5%-10% fall in arterial blood pressure in
normal humans will trigger vasopressin
 An extension of the forebrain and represents the
release
storage region for vasopressin and oxytocin
 Diabetes Insipidus
 These peptide hormone are synthesized in the
 Polyuria and polydipsia is a consequence of
supraoptic and paraventricular nuclei of the
vasopressin deficency
hypothalamus and transported to the neurohypophysis
 Causes of Hypothalmic DI include:
via their axons in the hypothalamoneurohypophyseal
 Apparent autoimmunity to vasopressin-
tract
secreting neurons
 The synthesis of these hormones is tightly linked to the
 Trauma
production of neurohypophysin (larger protein)
 Diseases affecting pituitary stalk function
 Neurohypophysis - storage area for hypothalmic
 Various CNS or pituitary tumors
hormones
 Low vasopressin levels and elevated plasma
 The said hormones have an autocrine and paracrine
osmolality is a reasonable secure diagnosis of DI
function
 Therapeutic trial of vasopressin or a synthetic
 Autocrine - the cell signal signals itself
analog such as desmopressin (dDAVP) and assess
 Paracrine - the cell signals the nearby cell
patient’s response
Oxytocin  Amelioration of both polyuria and polydipsia
would be considered a positive response and
presumptive diagnosis of DI is mafe
 It is a cyclic nonapeptide, with a disulfide bridge
 Vasopressin excess leads to pathologic retention of
connecting amino acid residues 1 and 6
water
 C terminus is amidated
 Conivaptan and Tolvaptan (V2 receptor antagonists) -
 Function: lactation, labor and parturition
for management of euvolemic hyponatremia due to
 Positive Feedback Loop
vasopressin excess
 Instead na patigilin ng oxytocin yung contraction,
mas magrerelease ng oxytocin to contract
 Pitocin - a synthetic oxytocin to induce labor
 Oxytocin has been shown to have effects on pituitary,
renal, cardiac, metabolic, and immune function
Vasopressin
 Cyclic nonapeptide with an identical disulfide bridge; it
differs from oxytocin by only two amino acids