Transcript Normal pituitary Magnetic resonance scan

Hypothalamic &
Pituitary hormones
Eric Lazartigues, Ph.D.
Department of Pharmacology
[email protected]
(504) 568-3210
Hypothalamus-Pituitary: Anatomy
Hypothalamus: nervous tissue below
thalamus
Pituitary: small outgrowth of the
forebrain, size of half a pea
• Two functional parts
– Adenohypophysis (anterior pituitary)
• Rathke’s pouch – ectoderm above
mouth
– Neurohypophysis (posterior pituitary)
• Hypothalamus
• Move together during development
HypothalamusPituitary:
Blood and nerve
supplies
• Hypothalamus
– Hypothalamic neurons release hormones directly into
capillary plexus
• Anterior pituitary
– Blood supply from median eminence of hypothalamus –
portal system
– Hormones from hypothalamus to pituitary
– Sympathetic/parasympathetic nerves
• Posterior pituitary
– Supraoptic and paraventricular nuclei in hypothalamus
mIU/ml
20
15
Frequency
LH
amplitude
10
ng/ml
Ultradian
6
4
2
Testosterone
0 1 2 3 4 5 6 7 8
Hr
Serum ACTH Levels
5
Awake
Sleep
The pulsatile nature of hormone release from the hypothalamus is critical for
maintained optimal responsiveness of the pituitary cells.
-Pulsatile secretion decreases the extent of down-regulation of pituitary
receptors.
-Continuous release of hypothalamic hormones actually suppresses the secretion
of pituitary hormones.
Functions of the HPA
Pituitary releasing hormones
•
•
•
•
•
•
•
CRH:
Corticotrophin releasing
hormone (ACTH)
TRH:
Thyrotrophin releasing
hormone
GHRH:
GH releasing hormone
Somatostatin: GH inhibition
GnRH:
Gonadotrophin (LH, FSH)
releasing hormone
Dopamine:
Prolactin inhibition
Vasopressin: ACTH release
Pituitary releasing hormones
• Small peptides
• Active at relative high
concentrations
• Rapidly degraded
• Low concentration in
peripheral circulation
• Special circulation allows
high concentrations to
reach targets
Feedback control
Feedback
STRESS, Metabolic status
CNS Control
Stress
HYPOTHALAMUS
XRH XIH
Short loop
Tropic
Hormone
(+)
(-)
Long loop
Target Hormone
(- )
Tropic Hormone
PITUITARY
Long loop
Tropic Hormone
(+ )
Target Gland
Target Hormone
(- )
Anterior pituitary hormones
Anterior
Pituitary
Posterior
Pituitary
Adrenal
Cortex
Milk
Production
Thyroid
Corticosteroids
Thyroxine
ovary
Estrogen
Progesterone
Testosterone
Bone Growth
Muscle Mass
Fat mobilization
Thyrotrophin (TSH)
• Stimulates: thyroxine synthesis
thyroid growth
• Regulation:
– TRH: stimulates release
– Inhibited by thyroid hormones (T3, T4) –
feedback inhibition
• Acts via cAMP
Thyroid Stimulating Hormone: TSH
• Thyrotrophs:
Thyroid Stimulating Hormone
(TSH)
• Hypothalamic Control
Thyrotropin Releasing
Hormone (TRH)
• Target Tissue
Follicular cells of the Thyroid
gland
•
Hormone effects:
controls the production
of T3 and T4
Endocrine activity of
the Thyroid Gland
• Follicular cells:
T3 and T4
• Target Tissue;
Almost all body tissues
• Hormone effects:
Increases body
metabolism
Increases gluconeogenesis
Increases glycolysis
Increases lipolysis
Increased basal metabolic
rate (BMR)
Increases heart rate and
force of contraction
Hypothyroidism
• Hypothyroidism (3% of population)
endemic goiter: (due to I2 deficiency)
Classification: I, II or III
Treatment: Thyroxine (T4) daily
(levothyroxine) or combination T3+T4
• Congenital hypothyroidism (Cretinism):
1:4000 newborns Physical and mental
growth and development are greatly
retarded
Treatment: Thyroxine daily
(levothyroxine)
Hyperthyroidism
Grave’s Disease with
exophthalmos
• Temporary treatment:
– Thyrostatics:
• Methymazole: inhibit formation of T4
• Propylthiouracil: prevent conversion T4 to T3
– Beta blockers:
• Metoprolol: Management of symptoms only
• Permanent treatment:
– Surgery: remove whole or part of thyroid
– 131Iodine orally: destroy hyperactive cells
Toxic multinodular goiter
Toxic thyroid adenoma
Corticotrophin (ACTH) secretion
Proopiomelanocortin (POMC)
1 gene,
multiple
hormones
Oligosaccharides
ACTH biosynthetic intermediate b-LPH
16K Fragment
ACTH
g-LPH
-MSH sequences
b-Endorphin
ACTH
• Corticotrophs
Adrenocorticotropic hormone
(ACTH)
• Hypothalamic Control
Corticotropin releasing hormone
(CRH)
• Target Tissue
Adrenal cortex, Zona
Fasciculata
• Hormone affects:
control production of
glucocorticoids such as
cortisol
Endocrine activity of
the Adrenal Cortex
• Zona glomerulosa
Mineralocorticoids such as
Aldosterone
• Hormonal control
renin-angiotensin pathway
permissive effect of ACTH
• Target tissue:
Principle cells of the DCT and
collecting duct
• Hormone affects:
increases reabsorption
of Na+ and water
Endocrine activity of the Adrenal
Cortex
• Hyper-secretion:
Aldosteronism:
Hypokalemia, increase
in extracellular fluid and
blood volume,and
hypertension, may also
have period of muscular
paralysis
• Hypo-secretion:
Addison’s disease
Mineralocorticoids
deficiency, death occurs
in four days to two
weeks if untreated
Endocrine activity of
the Adrenal Cortex
• Zona Fasciculata
Glucocorticoids such as
cortisol and cortisone
• Hormone control:
ACTH
• Target tissue:
Liver and general body cells
• Hormone affects:
Stimulates
gluconeogenesis by the
liver
Decreased glucose
utilization by cells
Endocrine activity of
the Adrenal Cortex
• Hormone effects:
Elevated blood glucose
levels
Reduction of protein stores
in all body cells except the
liver
increased plasma protein
levels
promote lipolysis and beta
oxidation of fat
Helps body recover from
stress
Prevention of inflammation
Endocrine activity of the Adrenal
Cortex
• Hypo-secretion
Addison’s disease - glucocorticoid
deficiency
person becomes highly susceptible to
disease and deteriorating effects of
stress
ACTH stimulation test (tetracosactide)
• Hyper-secretion:
Cushing’s Syndrome
mobilization of fat from lower body to
the thoracic and upper abdominal
regions giving raise to “Buffalo
Torso”
Stress overcomes negative feedback regulation
STRESS
Hypoglycemia
- Infection
- Trauma
- Surgery
- Pain, Cold
Plasma ACTH (pg/ml)
250
200
150
100
Sleep/wake
50
0
CRH
Short
Loop
ACTH
HYPOTHALAMUS
8
1
am 2
Cortisol
Figure 4
CRH
Long
Loop
ACTH
Cortisol
-MSH
Corticotroph
Long
Loop
Cortisol
4
8 12
pm pm am
4
8
am am
Anterior Pituitary Hormones: Stimulation Testing
ACTH (ATHAR, COSYNTROPIN)
- Not used clinically to treat adrenal insufficiency due to expense
- Used for stimulation testing. ACTH (IV ACTH should result in  in peak
plasma levels of glucocorticoids in 3-60 min
- Tx myasthenia gravis
Adverse Effects (Prolonged use): Suppression of hypothalamic pituitary-adrenal
axis, immunosupression, hypertension
Drug Interactions:  natriuretic and diuretic effects of diuretics. Use with K+depleting diuretics can produce severe hypokalemia.
Contraindications: Surgery, 1o adrenal insufficiency, heart failure
TRH/TSH (Thyrotropin; recombinant human TSH (THYROGEN)
Not commonly used to treat thyroid disorders but are used to distinguish
between hypothalamic-pituitary-thyroid gland dysfunction.
Endocrine activity of
the Adrenal Cortex
• Zona reticularis
Produces small amounts
of androgens, mostly
dehydroepiandrosterone
(DHEA), DHEA may be
converted into estrogens
• Hormone Control:
Believed to be ACTH
• Target tissue:
General body cells
Endocrine activity of
the Adrenal Cortex
• Hyper-secretion:
Adrenogenital Syndrome
Congenital Adrenal hyperplasia:
11b-hydroxylase deficiency (90-95%)
– Salt wasting crises in infancy
– virilization of female infants
– Sex assignment issues and
controversies
Gonadotropic hormones
GnRH: pulsatile secretion
Cyclical secretion LH, FSH
Females: ovary
• LH: ovulation, corpus luteum
•FSH: dvpt follicle, oestradiol and
progesterone
Males: testes
• LH: Leydig cells: testosterone
•FSH: Sertoli cells: spermatogenesis
FSH: inhibin: negative feedback
GnRH and analogs
• Decapeptide half-life of 2-4 min.
• Pulsatile secretion, arcuate nucleus
• Continuous secretion: downregulation (clinical use)
• Diagnostic use: synthetic GnRH, Gonadorelin (FACTREL)
stimulation testing: pituitary can secret LH/FSH?
• Therapeutic uses:
• Management of infertilty: promote physiological cycle
• Suppression of gonadotropin secretion: non-pulsatile
• GnRH-dependent precocious puberty: before 8-9 year-old
• Endometriosis, Uterine leiomyomata (fibroids) estrogen-sensitive
fibrous growths
• Pharmacological castration (paraphilia): triptorelin (TRELSTAR)
GnRH and analogs (continued)
Side Effects (chronic non-pulsatile administration)
Females: Typical symptoms of menopause: hot flashes, sweats,
headaches and  bone density. Depression,  libido, generalized
pain, vaginal dryness, and breast atrophy may also occur.
Men: Testicular atophy, sweats, edema, gynecomastia,  libido,
hematocrit,  bone density,
Both: dizziness, vertigo, insomnia,, and headache
Drug-drug Interactions:
Androgen therapy: DECREASE Efficacy
Discontinue nasal decongestants
Contraindications: Pregnancy, breast-feeding, osteoporosis,
undiagnosed abnormal vaginal bleeding
GnRH antagonists
Ganirelix (ANTAGON) and cetrorelix (CETROTIDE)
• Mechanism of Action: Inhibit the secretion of LH>>FSH in a dose
dependent manner. Administer subcutaneously
• Use: Inhibit premature (LH) surges in women undergoing controlled
ovarian hyperstimulation with FSH and hCG, followed by subsequent
assisted insemination or reproductive technology (ART) procedures
• Adverse effects: nausea and headaches.
• Contraindications: primary ovarian failure, pregnancy, breast feeding
Abarelix (PLENAXIS)
• Indication: Prostate cancer to prevent adverse consequences of
tumor growth. Distribution limited (hypersensitivity reactions).
Clinical use of FSH/LH
Diagnostic uses:
a. Pregnancy: hCG detection in urine or plasma
b. Timing of ovulation: occurs 36 hours after the onset of LH surge
c. Diseases of Male and Female Reproductive Systems
Low LH and FSH: hypogonadotrpoic hypogonadism : hypothalamic or pituitary disease
High LH and FSH: primary gonadal diseases
Therapeutic Uses of Gonadotropins:
• Purified
from the urine of pregnant women or postmenopausal women
hCG (PREGNYL, NOVAREL, PROFASI…) mimics action of LH
Menotropins (PERGONAL, REPRONEX): equal amount LH and FSH
• Recombinant FSH: rFSH: follitropin  (GONAL-F) and follitropin b (PUREGON, FOLLISTIM)
Female infertility in combo with ART: Anovulation, Polycystic Ovary disease
Adverse effects: multiple pregnancies and ovarian hyperstimulation syndrome (OSS)
Male Infertility Secondary to gonadotropin deficiency, cryptorchidism
Most common side effect is gynecomastia
Prolactin
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•
•
•
•
•
Secreted by lactotrophs
Lactation
Inhibits reproductive hormone secretion
Release inhibited by dopamine
Animals: osmoregulation, growth
Stalk transection   prolactin
• No therapeutic use
• Hyperprolactinemia:
• Women: galactorrhea, amenorrhea, infertility
• Men: loss of libido, impotence, infertility
• Rx: surgery, radiation, D2 agonists
Pharmacological Treatment of
Prolactin excess: DA agonists
Bromocriptine interacts with D2R on lactotrophs
- Note only 7% reaches circulation do first-pass metabolism by the liver.
Longer acting version (PARLODEL-LAR) –
Pergolide (PERMAX) off label treatment
Cabergoline (DOSTINEX) ergoline-derived dopamine agonist .More potent and
longest half-life
Mechansism of Action: Shrink pituitary PRL-secreting tumors, lower circulating
PRL levels, and restore ovulation in approximately 70% of women with
microadenomas and 30% of women with macroadenoma
Side Effects: Nausea, headaches, orthostatic hypotension
Drug-drug Interactions: May effects of anti-hypertensives, and  effectiveness
of dopamine antagonists such as the antipsychotics and the phenothiazinetype antiemetics
Growth hormone
• Promotes growth: skeleton,
muscles, viscera
• Effects mediated by
somatomedins (e.g. IGF1, 2...)
• Released at night during growth
• Variety of metabolic effects
– Anabolic, positive nitrogen balance
– Anti-insulin
• Stimulated by GHRH, stress,
exercise
• Inhibited by somatostatin
Physiological Effects of GH
Increased
Organ
and
Tissue
growth
Protein Synthesis
Gluconeogenesis
Increased
Glucose Uptake
Fat deposition
Glucose Uptake
Protein Synthesis
Growth Hormone Deficiency
Children: Dwarfism. Most common is isolated
idiopathic
• Insulin-stimulated hypoglycemia induced GH
< 10 µg/L
• Exclude nutritional deficiencies
• Height ≥ 2–2.5 SD below normal, delayed
bone age.
Adults > 90% have overt pituitary hypofunction
due to disease, pituitary adenoma or iatrogenic
• Insulin-stimulated hypoglycemia induced GH
< 3 µg/L
9 year old Peruvian girl (80 cm)
with GH receptor defect
Clinical Uses of Recombinant Human Growth Hormone
Primary Therapeutic Objective
Clinical Condition
Growth
Growth failure in pediatric patients :
Growth hormone deficiency
Prader-Willi syndrome
Turner syndrome
Small for age with failure to catch up by age 2
Idiopathic short stature in pediatric patients
Improved metabolic state, 
Growth hormone deficiency in adults
lean body mass, sense of well-being
 lean body mass, weight,
AIDS-related muscle wasting
and physical endurance
Improved GI function
Short bowel syndrome in patients
receiving specialized nutritional support
Treatment of GH insufficiency (all SC or IM) :
GH SUPPLEMENTATION
Somatropins GH preparations whose sequence matches native hGH.
Somatrem: GH derivative with an additional methionine at the amino terminus.
Side effects: hyperglycemia (may be contraindicated in diabetes) and increased
intracranial pressure.
Additional approved uses of GH therapy: “Social use” short stature within “normal”
ranges, bodybuilding, athletes, ageing.
GHRH LIKE ACTIONS
sermorelin peptide that corresponds to the first 29 amino acids of GHRH.
- Used diagnostically to Decrease serum GH levels
- Tx Children with 3o (hypothalamic deficiency)
Side effect: angina, flushing
IGF-1 THERAPY For Pts with GH Receptor mutation
Mecasermin: complex of recombinant human IGF-1 (rhIGF-1) and recombinant
human insulin-like growth factor-binding protein-3 (rhIGFBP-3).
Clinical response is monitored Serum IGF-1 levels.
Growth hormone release
Acromegaly
Normal
06:00
12:00
18:00
24:00
06:00
Growth Hormone Excess
•
•Periosteal Bone
growth
•Excess soft tissue
Don Fermin y Urieta (1870-1913)
“The Giant of Aragon”
229 cm tall
•Enlarged organs.
•Cardiomyopathy
•Often diabetic
•Infertile? GH ~ PRL
Hyper-secretion:
During childhood causes
Gigantism (up to 8 – 9 ft.)
During Adulthood causes
Acromegaly:
Enlargement of the small
bones of the hand and feet
Enlargement of the
cranium, nose, and lower
jaw
Tongue, liver, and kidneys
become enlarged
SOMATOSTATIN (SS) ANALOGS
Drug
Type
Dosing
Octreotide
Short-acting
Subcutaneous 3 times/day; dose range of 50-500 mg
Octreotide LAR
Long-acting
Intramuscular every 28 days; dose range of 10-40 mg
Lanreotide depot
Long-acting
Intramuscular every 7-14 days
Lanreotide autogel
Long-acting
Deep subcutaneous every 28 days
Octreotide (SANDOSTATIN) 8 amino acid derivative of somatostatin that
preferentially binds to SS receptors on GH-secreting tumors.
Lanreotide (SOMATULINE-LA) slow release, long-acting octapeptide causes
prolonged GH suppression. Most effective for patients with non-pituitary tumours
Side effects: Inhibits gastrointestinal and pancreatic function
Long-term use causes digestive problems such as loose stools, nausea, and gas ~
25% of patients develop gallstones
Arrhythmias, sinus bradycardia, and conduction disturbances
Drug Interactions: Cyclosporine bioavailability
DOPAMINE-RECEPTOR AGONISTS (see Prolactine section)
- Bromocriptine (Parlodel)
- Cabergoline. (DOSTINEX) Long-acting oral agonist
Paradoxically reduce GH secretion from pituitary tumors
Side effects: nausea and hypotension
Contraindications: Patients with hypertensive
disorders of pregnancy (preeclampsia, eclampsia)
GROWTH HORMONE ANTAGONISTS:
Pegvisomant (SOMAVERT) GH analog binds
receptor but does not induce receptor dimerization or Jak/Stat signaling.
Adverse Effects: No negative feedback at the pituitary or hypothalamus: May
endogenous GH levels. May also see excessive tumor growth.
Contraindications: IV therapy, breast feeding
Posterior pituitary hormones (1)
• Vasopressin/Antidiuretic hormone
(ADH)
– Produced by SON and PVN
magnocellular neurons
– Conserves water - concentrates urine
– Water reabsorption by collecting
tubule
– Deficiency: diabetes insipidus
• Extreme thirst and polyuria
•  plasma sodium and osmolality
– Excess: inappropriate ADH “water
intoxication” (SIADH)
Vasopressin Receptors: Location & Functions
Diseases Affecting the Vasopressin System
AVP hyposecretion:
• Diabetes insipidus: large volume of diluted urine
• Central DI: insufficient secretion (trauma HP axis, idiopathic)
Rx: Desmopressin: increase urine osmolality (test vs. NDI)
Chlorpropamide (oral sulfonylurea): potentiates low AVP
Carbamazepine and clofibrate (rarely): reduce polyuria
• Nephrogenic DI: insufficient response (congenital or acquired)
• Many forms are drud-related: lithium
• X-linked NDI: mutation V2 receptor gene
• Autosomal recessive and dominant NDI: mutation aquaporin 2
Rx: Amiloride: blocks uptake of Lithium
Thiazide: non-lithium related DI: reduce polyuria
Indomethacin: (?) decrease PG and enhance AVP effects
Diseases Affecting the Vasopressin System
AVP hypersecretion:
• SIADH: impaired H2O excretion, hyponatremia, hypoosmolality
• Causes: malignancies, lung/CNS diseases
• Psychotropic , sulfonylureas, vinca alkaloids: Drug-induced SIADH
• Rx: water restriction, hypertonic saline, loop diuretics
Demeclocycline: inhibit AVP action in collecting ducts
Lithium: mild efficacy, irreversible damages (chronic), low TI
Other water retaining states:
• Congestive HF, cirrhosis, nephrotic syndrome: hypovolemia
• hypovolemia→AVP release→hyponatremia
• Need for orally active V2 receptor antagonists
Posterior pituitary hormones (2)
• Oxytocin
– In the periphery:
• Milk let-down
• Uterine contraction
• Sexual intercourse (orgasm ?)
– In the brain:
• Sexual arousal
• Bonding
• various behaviors, including social
recognition,
bonding, anxiety, trust, and maternal
behaviors.
Clinical Use of OXYTOCIN
a.
Induction of labor –oxytocin (PITOCIN,)
is treatment of choice to induce labor.
Due to short half-life it is given as IV drip
-(start at 2-10 mU/min then increase up
to 2 mIU/min at 20-min intervals. If
doses of 40 mIU/min fail, higher rates of
infusion are unlikely to be successful.
b.
Continuous monitoring of fetal and
maternal HR, BP and strength of
uterine contraction is required. Due to
structural similarity to AVP, high doses
may have pressor and anti-diuretic
activity
-positive feedback
- participates in parturition but
not required
Oxytocin
Stretch
Uterus
Contractions
Breast: milk
ejection
c. 3rd stage labor and Puerperium: Oxytocin
is given following delivery of fetus to
help maintain uterine contractions- this
greatly reduces the incidence and extent
of hemorrhage.
Oxytocin (PITOCIN)
Mechanism of Action : Acts on G-protein coupled receptors in the myometrium
Increase intracellular Ca2+
Increase prostaglandins
Increase gap junctions
Net effect: Increased rate and force of myometrial smooth muscle contraction
Side Effects: Hypersensitive uterine reaction: Increased, hypertonic uterine contractions,
resulting in cervical laceration, postpartum hemorrhage, pelvic hematoma, and uterine
rupture
Drug Interactions: Cannot be used with vasopressors
Effectiveness is  general anesthetics
Contraindications: Immature fetal lungs, Evidence of fetal stress (oxytocin challenge test),
abnormal fetal position.
Use of oxytocin during pregnancy can precipitate uterine contractions and abortion
Suppression of Preterm Labor
Preterm (premature) labor begins before the 37th week of pregnancy.
Tocolysis: The delaying or inhibition of labor during the birth process.
b-adrenergic agonists Ritodrine
L-type Ca2+ channel blockers; Nifedipine
Oxytocin-Receptor Antagonists (atosiban)
Peptide analogs that competitively inhibit the oxytocin receptor.
Decreases frequency of uterine contractions and increased the number of
women who remained undelivered,
Comparable efficacy to adrenergic agonists but with a lower incidence of
side effects.