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
Hypothalamus-Pituitary:
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
Ultradian
0 1 2 3 4 5 6 7 8
amplitude
Frequency
LH
Testosterone
2
4
6
ng/m
lm
IU/m
l
5
10
15
20
Awake SleepS
erum
AC
TH
Lev
els
HrThe 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
XRH
HYPOTHALAMUS
PITUITARY
Tropic Hormone
Short loopLong loop
XIH
Target Gland
Tropic Hormone(+ )
Target Hormone(- )
(-)(+)
Tropic Hormone
Stress
STRESS, Metabolic status
Target Hormone(- )
Feedback
CNS Control
Long loop
Anterior pituitary hormones
AdrenalCortex
Corticosteroids
Thyroid
Thyroxine
Testosterone
EstrogenProgesterone
ovary
Bone GrowthMuscle MassFat mobilization
MilkProduction
Anterior Pituitary Posterior
Pituitary
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 ControlThyrotropin Releasing Hormone (TRH)
• Target TissueFollicular 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 metabolismIncreases gluconeogenesisIncreases glycolysisIncreases lipolysisIncreased 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
16K Fragment ACTH -LPH -Endorphin
-MSH sequences
Proopiomelanocortin (POMC)
Oligosaccharides
-LPHACTH biosynthetic intermediate
1 gene, multiple
hormones
ACTH
• CorticotrophsAdrenocorticotropic hormone (ACTH)
• Hypothalamic ControlCorticotropin releasing hormone (CRH)
• Target TissueAdrenal cortex, Zona Fasciculata
• Hormone affects:control production of glucocorticoids such as cortisol
Endocrine activity of the Adrenal Cortex
• Zona glomerulosaMineralocorticoids such as Aldosterone
• Hormonal controlrenin-angiotensin pathwaypermissive 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 FasciculataGlucocorticoids such as cortisol and cortisone
• Hormone control:ACTH
• Target tissue:Liver and general body cells
• Hormone affects:Stimulates gluconeogenesis by the liverDecreased glucose utilization by cells
Endocrine activity of the Adrenal Cortex
• Hormone effects:Elevated blood glucose levelsReduction of protein stores in all body cells except the liverincreased plasma protein levelspromote lipolysis and beta oxidation of fatHelps body recover from stressPrevention 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”
Long Loop
Long Loop
Cortisol
Cortisol
Corticotroph
ACTH
CRHHYPOTHALAMUS
CRH Cortisol
Short Loop
STRESS - Infection - Trauma - Surgery
Sleep/wake
ACTH
Hypoglycemia
-MSH
0
50
100
150
200
250
8 am
12
4 pm
8 pm
12 am
4 am
8 am
Pla
sma
AC
TH
(pg
/ml)
Figure 4
Stress overcomes negative feedback regulation
- Pain, Cold
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:11-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/LHDiagnostic 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 (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• 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 phenothiazine-type 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
Glucose Uptake
Increased
Protein Synthesis
Glucose Uptake
Fat deposition
Protein SynthesisGluconeogenesis
Increased Organ and
Tissue growth
Physiological Effects of GH
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
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
Clinical Uses of Recombinant Human Growth Hormone
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 ACTIONSsermorelin 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 mutationMecasermin: 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.
Treatment of GH insufficiency (all SC or IM) :
Growth hormone release
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Normal
Acromegaly
•Periosteal Bone growth
•Excess soft tissue
•Enlarged organs.
•Cardiomyopathy
•Often diabetic
•Infertile? GH ~ PRL
Growth Hormone Excess
Don Fermin y Urieta (1870-1913)
“The Giant of Aragon”
229 cm tall
• Hyper-secretion:During childhood causesGigantism (up to 8 – 9 ft.)
During Adulthood causesAcromegaly:Enlargement of the small bones of the hand and feetEnlargement of the cranium, nose, and lower jawTongue, liver, and kidneys become enlarged
Drug Type Dosing
Octreotide Short-acting Subcutaneous 3 times/day; dose range of 50-500 g
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
SOMATOSTATIN (SS) ANALOGS
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
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)
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 AVPCarbamazepine 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, hypo-
osmolality• 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 ductsLithium: 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.
Stretch
Oxytocin
Uterus Contractions
Breast: milk ejection
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
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.
Clinical Use of OXYTOCIN
-positive feedback
- participates in parturition but not required
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
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.
-adrenergic agonists Ritodrine
L-type Ca2+ channel blockers; Nifedipine
Preterm (premature) labor begins before the 37th week of pregnancy.
Tocolysis: The delaying or inhibition of labor during the birth process.