Hypothalamic and Pituitary Hormones Flashcards
Protein Hormones of the Anterior Pituitary
Placental in brackets
Somatotropic:
GH
Prolactin
(Placental Lactogen)
Glycoprotein: Luteinising Hormone Follicle Stimulating Hormone Thyroid Stimulating Hormone (Human Chorionic Gonadotropin)
POMC- Derived Hormones
Adrenocorticotropic Hormone
Alpha Melanocyte Stimulating Hormone
Regulations of GH
GH secretion increased by:
GHRH (hypothalamus)
Ghrelin (released from stomach and pancreas)
GH secretion decreased by:
Somatostatin
IGF (negative Feedback)
Major Effect of GH: Direct and Indirect
Direct:
Promote bone and muscle growth
Glycolysis
Indirect through IGF:
Increased lipolysis and gluconeogenesis
GH Mechanism of Action
GH–>GH-R–> JAK/STAT Pathway (incease gene express)
–> Increase IGF-1
JAK P STAT–> STAT dimerisation–> translocated to nucleus–> bind DNA–> alters expression
GH Deficiency:
Causes
Symptoms
Diagnosis
Causes: Mainly hypothalamic (decrease GHRH)
Rarely pituitary injury ex irradiation
Symptoms: Pituitary Dwarfism (growth deficit in kids)
Decrease of muscle mass and increase in fat mass adults
Diagnosis: Provocative Test (insulin induced hyperglycaemia increases se GH levels)
GH Deficiency Treatment
Th Options
Preparation
Formulation(s)
Th Options:
GH Analogue
GHRH Analogue- withdrawn
IGF-1- only th in Laron Dwarf or 1 deficiency in IFG-1
Preparation:
Produced in E. Coli by DNA recombinant somatotropin
Formulations:
Short Acting Injectable Solutions, daily. SC
Withdrawn: Long Acting Depot Injections (not reliable)
GH Deficiency Treatment
Pharmacokinetics
Indications
Side Effects
Pharmacokinetics:
Elimination: Degradation into AA (renally)
T1/2: 30 min BUT duration of action of SC dose:
12-48hrs (due to IGF induction by drug)
Indications:
GH Deficient Kiddies and Adults
Chronic Renal Disease leading to growth
retardation in kiddies
AIDS associated cachexia
Side Effects: Kids
Idiopathic Intracranial Hypertension; typ early SE
Scoliosis and other skeletal problems accelerated
Unknown Mech: Type 2 DM
Unknown Mech: Leukemia
Side Effects: Adults
Peripheral and Periorbital Oedema
Myalgia, Neuropathy (carpal tunnel syndrome)
How to measure therapy
Initial response measured by se IGF1 levels
GH Analogues
Somatropin and Somatrem
GHRH Analogues
Sermorelin- Withdrawn
GH Excess:
Causes
Symptoms
Diagnosis
Causes:
Micro or Macroadenoma of Pituitary
Symptoms:
Gigantism (Kiddies) and Acromegaly (Adults)
Diagnosis:
High se GH or IGF-1 Levels (glucose fails to suppress)
GH Excess Treatment Options
Somatostatin Analogues
Dopamine Receptor Agonist
GH Antagonist
Non Pharmacological Option: Removal via surgery or
irradiationSomatostatin Analogues:
Structure
Mechanism
Effect
Structure:
Octa- or hexapeptides (longer action and more stable
than somatostatin)
Mechanism of Action:
Activate SST-R–>Gi–>decrease AC–>decrease cAMP–>
decrease hormone secretion
In Addition: via SST-R activation: K+ channels open–>
hyperpolarisation
Effects (due to hyperpolarisation and decrease cAMP and
Ca)
Inhibition of GHRH and GH release
Inhibition of secretion of TSH, insulin, VIP, carcinoid
Due to wide inhibition—> many indications for SST analogue usage
Somatostatin Analogues:
Preparations
Indications
Side Effects
Preparations (using octreotide as example)
Short Acting SC Injections- T1/2: 90 min, DoA: 12hrs
Long Acting IM Injections
Slow releasing octreotide: 1x/month
Slow releasing lanreotide: 1x/2 weeks
Indications: decrease hormones or cytokines in:
Pituitary Adenoma
Thyrotrope Adenoma (overprod. TSH)
GI Tumors prod. VIP of 5HT
Th of imflammatory diseases ex IBD/RH
Side Effects:
GI Symptoms
Gall Bladder Stones
Hypothyroidism (inhib TSH secretion)
Dopamine Receptor Agonists
D R Agonists decrease GH secretion in some acromegaly patients
GH Antagonist
Chemistry
Action
Indication
Elimination
Dose
Side EffectsChemistry:
Recombinant human GH with covalent addition of PEG
chains (–> bind to R and displace GH)
Action:
Binds to R but doesn’t activate it
Indication:
Acromegaly patients not resp to SST analogues
Elimination:
Slow due to pegylation (T1/2: 6 days)
Dose:
Loading + Maintenance
Side Effects:
Antibody Formation (uncertain relevance, may not
inhibit effect)
Somatostatin Analogues
Drug List
Octreotide
Lanreotide
Dopamine Receptor Agonists
Cabergoline
GH Antagonist
Pagvisomant
Regulation of Prolactin Secretion:
Secreted From…:
Inhibitory Reg.
Stimulators
Secreted From…:
Lactotrope Cells in Ant. Pituitary
Decidual Cells of Endometrium (Luteal and pregnancy)
Inhibitory Regulation: Dopamine
Mechanism: D2 R on Lactotropes: Gi
Stimulators:
Physiological: Breast suckling or manipulation
Non Physiological: elevated TRH
Major Effects of Prolactin
Mechanism of Prolactin Action
Th Use of Prolactin
Major Effects of Prolactin:
Breast: prep for lactation (growth and diff of mamma tis)
Other sites: Liver, Kidney, Testes, Ovaries
Mechanism of Prolactin Action:
Prolactin Receptors work like GH Receptors
JAK/STAT Pathway–> increase transcription
Th Use of Prolactin:
None
Hyperprolactinemia
Causes
Symptoms
Th Effects
Causes:
Prolactinoma (Micro or Macroadenoma Pituitary)
1 Hyperthyroidism (inc TRH), renal failure (dec TRH sec)
Drugs: cent. acting D-R Antag. and D depletors
Antipsychotics, Prokinetics, a methydopa, reserpine
Symptoms:
Gynecomastia, galactorrhea, loss of libido
Female spec: amenorrhea, anovulation
Male spec: Impotence
Th Effect:
normalisation of se prolactin levels
decrease tumor size (not curative)
normalisation: ovulation, restoration of fertility
Safe to use in pregnancy
Hyperprolactinemia
Side Effects
Other Uses
Side Effects: due to D2 R activation or 5HT R
Nausea/Vomiting (D2 and 5HT–>CTZ activation; delay
of gastric emptying)
Postural Hypotension (D2)
Digital Vasospasm (5HT2 R), Raynaud Like
CNS: psychosis, hallucinations, nightmares via 5HT2 R
Fibrosis post long term use: cor, pulmo
Other Uses:
Acromegaly: High dose D also decreases GH secretion
Parkinsons: High Dose
D2 Receptor Agonists
Mechanism of Action
Medical USe
Mechanism of Action: D2 R (inhibitory) (decrease AC, cAMP, PKA) 5HT2 agonists too: not all
Medical Use:
Prolactinoma induced Hyperprolactinemia
Acromegaly: High dose D also decreases GH secretion
Parkinsons: High Dose
D2 Receptor Agonists: Ergot Derivatives
Drug List
Bromocriptine
T1/2: 5 hours, Bioavailability only 5%
Pergolide
T1/2: 27 hours
Cabergoline
T1/2: 65 hrs, greater D2 selectivity–> less nausea
D2 Receptor Agonists: Non Ergot Derivatives
Drug List
Quinagolide
Pure D2 Agonist–> no vasospasm, fibrosis
T1/2: 25 hrs
Gonadotropin Releasing Hormone and Gonadotropins
Regulation of Gonadotropin Secretion
GnRH: released intermittently under control of arcuate;
cont admin–> desensitisation and down-regulation
GnRH controls: FSH and LH secretion
acts on GnRH-R on gonadotropes
Gq–>PLC increase–>IP3 increase–>Ca increase
Sex Steroids: Feedback Inhibiton
Inhibit prod of GnRH and Gonadotropins
Inhibins (prod. in ovary and testes)
Inhibit FSH (not LH)
Gonadotropins
Action and Mechanism of Action
Action:
LH (and hCG) act on LH-R
FSH acts of FSH-R
Mechanism of Action
Normal: Gs–>AC increase–>cAMP
High level: Gq->PLC increase->IP3 increase->Ca increase
Effect of Gonadotropins
Men:
LH: act on testicular Leydig Cells–> testosterone prod.
and therefore 2ary sexual characteristics
FSH: act on testicular Sertoli Cells–> spermiogenesis
Females:
LH: Induce ovulation (rupture of follicle)
Increase progesterone synth by corpus luteum
Increase androstenedion synth in theca cells
FSH: Induce follicle development
Increase estrogen formation in granulose cells
REM: hCG has LH-like effects
Synthetic GnRH
Name
Usage
Characteristics
Gonadorelin
Usage: diagnostic purpose as so unstable T1/2: 3min
used to determine cause of hypogonadism
whether hypothalamic or pituitary
GnRH Analogues: Agonists
Name
Indications
Mech of Action
Side EffectsBuserelin, Goserelin
Mechanism of Action:
repeat admin–> desensitisation and down reg GnRH-R
decrease LH and FSH secretion
decrease gonadal steroid secretion-> pharma. castrat.
Indications:
Gonadotropin dep. precocious puberty
Sex steroid dep. tumors
Other sex steroid resp conditions ex endometriosis
Side Effects:
Transrient stimulation of tumor growth
Signs of estorgen def: flush, vaginal atrophy, bone
density decrease
GnRH Analogues: Antagonists
Name
Indications
Mech of Action
Side EffectsCetrorelix, Ganirelix
Indications:
Sex steroid dep. tumor
Suppression of LH secretion and therefore premie
ovulation in FSH treated women (IVF)
Mechanism of Action:
Antagonist of GnRH-R–> direct pharma. castration
Side Effects:
HSR
Signs of estrogen deficiency: flush, vaginal atrophy,
bone density decrease
Use of Gonadotropins
Diagnostic Uses
Diagnosis of Pregnancy: measure hCH in urine or plasma
Timing of ovulation: detect LH increase in urine
Diag of reproductive diseases such as:
Hypogonadotropic Hypogonadism (low FSH and LH)
Reduced female fertility: High FSH (sign of low estrog.)
Use of Gonadotropins
Therapeutic Use: Indications
Treatment of female infertility with FSH and hCG
- in vivo fertilisation to induce dev of single follicle - in vitro: to induce dev of multiple follicles
Treatment of male infertility: th of gonadotropin def.
Admin androgen+gonadotropin (2nd when fertility
desired)
Treatment of cryptorchidism: induction of testicular desc.
Using hCG (due to LH like effect)
Gonadotropin Preparations
Urinary Gonadotropins: Largely replaced by recombinant
Menotropin: from urine of postmeno. females: IM
Urofollitropin: highly purified FSH–> SC
Recombinant Gonadotropins:
Follitropin: recomb FSH
Lutropin: recom LH
Ovarian Hyperstimulation Syndrome
Side Effect of Th Use of Gonatotropins
FSH–> increase vascular permeability, secretion of VEGF
–> decrease claudin 5 (imp. protein in tight junctions)
Severe cases: not only ovaries but also ex peritoneum, thorax
Th: Induce ovulation via GnRH (shorter T1/2)
