Hypothalamic & Pituitary hormones

Eric Lazartigues, Ph.D.Department of Pharmacology

elazar@lsuhsc.edu(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

06:00 06:0024:0018:0012:00

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.