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Pharma 3 > Hypothalamic and Pituitary Hormones > Flashcards

Hypothalamic and Pituitary Hormones Flashcards

1
Q

Protein Hormones of the Anterior Pituitary

Placental in brackets

A

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

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2
Q

Regulations of GH

A

GH secretion increased by:
GHRH (hypothalamus)
Ghrelin (released from stomach and pancreas)

GH secretion decreased by:
Somatostatin
IGF (negative Feedback)

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3
Q

Major Effect of GH: Direct and Indirect

A

Direct:
Promote bone and muscle growth
Glycolysis

Indirect through IGF:
Increased lipolysis and gluconeogenesis

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4
Q

GH Mechanism of Action

A

GH–>GH-R–> JAK/STAT Pathway (incease gene express)
–> Increase IGF-1

JAK P STAT–> STAT dimerisation–> translocated to nucleus–> bind DNA–> alters expression

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5
Q

GH Deficiency:
Causes
Symptoms
Diagnosis

A

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)

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6
Q

GH Deficiency Treatment
Th Options
Preparation
Formulation(s)

A

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GHRH Analogue- withdrawn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Withdrawn: Long Acting Depot Injections (not reliable)

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7
Q

GH Deficiency Treatment
Pharmacokinetics
Indications
Side Effects

A

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)

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8
Q

How to measure therapy

A

Initial response measured by se IGF1 levels

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9
Q

GH Analogues

A

Somatropin and Somatrem

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10
Q

GHRH Analogues

A

Sermorelin- Withdrawn

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11
Q

GH Excess:
Causes
Symptoms
Diagnosis

A

Causes:
Micro or Macroadenoma of Pituitary

Symptoms:
Gigantism (Kiddies) and Acromegaly (Adults)

Diagnosis:
High se GH or IGF-1 Levels (glucose fails to suppress)

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12
Q

GH Excess Treatment Options

A 
Somatostatin Analogues
Dopamine Receptor Agonist
GH Antagonist
Non Pharmacological Option: Removal via surgery or 
    irradiation
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13
Q

Somatostatin Analogues:
Structure
Mechanism
Effect

A

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

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14
Q

Somatostatin Analogues:
Preparations
Indications
Side Effects

A

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)

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15
Q

Dopamine Receptor Agonists

A

D R Agonists decrease GH secretion in some acromegaly patients

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16
Q 
GH Antagonist
    Chemistry
    Action
    Indication
    Elimination
    Dose
    Side Effects
A

Chemistry:
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)

17
Q

Somatostatin Analogues

Drug List

A

Octreotide

Lanreotide

18
Q

Dopamine Receptor Agonists

A

Cabergoline

19
Q

GH Antagonist

A

Pagvisomant

20
Q

Regulation of Prolactin Secretion:
Secreted From…:
Inhibitory Reg.
Stimulators

A

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

21
Q

Major Effects of Prolactin

Mechanism of Prolactin Action

Th Use of Prolactin

A

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

22
Q

Hyperprolactinemia
Causes
Symptoms
Th Effects

A

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

23
Q

Hyperprolactinemia
Side Effects
Other Uses

A

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

24
Q

D2 Receptor Agonists
Mechanism of Action
Medical USe

A 
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

25
Q

D2 Receptor Agonists: Ergot Derivatives

Drug List

A

Bromocriptine
T1/2: 5 hours, Bioavailability only 5%

Pergolide
T1/2: 27 hours

Cabergoline
T1/2: 65 hrs, greater D2 selectivity–> less nausea

26
Q

D2 Receptor Agonists: Non Ergot Derivatives

Drug List

A

Quinagolide
Pure D2 Agonist–> no vasospasm, fibrosis
T1/2: 25 hrs

27
Q

Gonadotropin Releasing Hormone and Gonadotropins

Regulation of Gonadotropin Secretion
A

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)
28
Q

Gonadotropins

Action and Mechanism of Action

A

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

29
Q

Effect of Gonadotropins

A

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

30
Q

Synthetic GnRH
Name
Usage
Characteristics

A

Gonadorelin

Usage: diagnostic purpose as so unstable T1/2: 3min
used to determine cause of hypogonadism
whether hypothalamic or pituitary

31
Q 
GnRH Analogues: Agonists
    Name
    Indications 
    Mech of Action
    Side Effects
A

Buserelin, 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

32
Q 
GnRH Analogues: Antagonists
    Name
    Indications 
    Mech of Action
    Side Effects
A

Cetrorelix, 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

33
Q

Use of Gonadotropins

Diagnostic Uses

A

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.)

34
Q

Use of Gonadotropins

Therapeutic Use: Indications

A

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)
35
Q

Gonadotropin Preparations

A

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

36
Q

Ovarian Hyperstimulation Syndrome

A

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)

Pharma 3 (14 decks)

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