ERS12 Physiology Of Pituitary Hormones Flashcards
Hypothalamus
Many small nuclei
- Paraventricular nucleus (PVN) (Parvocellular + Magnocellular neuron)
- Supraoptic nucleus (SON) (Magnocellular neuron)
- Arcuate nucleus
—> Synthesise + Secrete neurohormone
—> Act as conduit between Nervous / Endocrine system via pituitary gland
2 connections between Hypothalamus / Pituitary
Anterior pituitary:
- Portal blood system (Hypothalamo-Hypophyseal portal system)
- Short portal vein
- Blood borne molecules from Hypothalamus act on Anterior pituitary before diluted by blood in larger vessels
Posterior pituitary:
- Neurons (Hypothalamo-Hypophyseal tract)
- Neurosecretory neurons’ axons in PVN / SON extend directly to posterior pituitary
- Hormones stored inside axonal terminal —> Released directly into capillary when needed
Hormones from Hypothalamus and Pituitary
Hypothalamic-pituitary axis:
Releasing / Inhibiting hormone —> Tropic hormone —> Hormone from target endocrine cell
Anterior Pituitary:
- Arcuate nucleus:
- GH-releasing hormone (GHRH) / Somatostatin (inhibit) —> GH (Somatotroph) —> All kinds of tissues
- (Prolactin —(inhibit)—>) GnRH —> FSH, LH (Gonadotroph) —> Gonads
- Dopamine —> ***inhibit Prolactin (Lactotroph) —> Mammary glands - PVN:
- Corticotropin releasing factor (CRH) —> ACTH (Corticotroph) —> Adrenal cortex
- Thyrotropin-releasing hormone (TRH) —> TSH (Thyrotroph) —> Thyroid gland
Posterior Pituitary:
- Magnocellular neurons in PVN, SON:
- ADH (produced by Hypothalamus) —> Kidney
- Oxytocin (produced by Hypothalamus) —> Uterus (contraction) + Mammary glands
(ACTH, TSH, FSH, LH: Tropic hormone)
Growth hormone: Synthesis and Secretion
Stimulated by GHRH (peptide) from ***Arcuate nucleus:
GHRH bind to GHRH-R (GPCR) on Somatotroph
—> Gαs activation
—> ↑ cAMP
—> GH synthesis + secretion (short loop -ve feedback to Arcuate nucleus)
Inhibited by **Somatostatin (SS) from **Periventricular nucleus
Physiological effects of Growth hormone
GH / Somatotropin:
- Peptide hormone (191 a.a. in single polypeptide chain)
Effects mediated by GH-R —> ***Enzyme-linked receptor
Physiological effects:
1. Direct effects
- GH binding to GH-R on target cells (**Adipocytes, Muscle cells)
—> Adipose tissue: **↑ Lipolysis / ↓ Glucose uptake —> Provide energy for tissue growth
—> Muscle: ***↑ Protein synthesis / ↓ Glucose uptake (via ↓ GLUT4 stimulated by insulin) —> Muscle growth
- Antagonise action of insulin —> ***↓ Glucose uptake by different tissues —> ↑ Blood glucose level
- Indirect effects
- GH binding to GH-R induce production of **IGF-1 in **Hepatocytes (Insulin-like growth factor-I)
- IGF-1:
—> Growth stimulating effect on wide variety of tissue —> differentiation, proliferation of myoblasts —> **Muscle growth
—> Stimulatory effect on osteoblasts, chondrocytes —> **Bone growth
IGF-1:
- +ve feedback to Periventricular nucleus (↑ Somatostatin) —> Inhibit Somatotroph —> ↓ GH
- -ve feedback to Somatotroph —> ↓ GH
Disorders related to Growth hormone
- Hypersecretion of GH
- Acromegaly (adult) / Gigantism (children)
- ***tumour of Somatotrophs
- associated with enlargement of other organs (e.g. skull growth), CVS diseases, hypertension, DM (∵ insulin effects antagonised), vision problem (∵ compression on optic chiasm) etc. - GH deficiency (Hyposecretion)
- Dwarfism
- Damage to Hypothalamus / Pituitary OR Gene mutation regulating synthesis + secretion
- Growth retardation evident within first 2 years of life
- associated with Hypoglycaemia, ↓ energy, ↓ muscle strength, ↓ bone density, delayed puberty
- Treatment: GH administration - Hyporesponsiveness (Irresponsiveness to GH)
- Laron syndrome
- Autosomal recessive
- **Mutant GH-R —> Insensitivity to GH
- Treatment: **IGF-1 administration (bypass GH-R)
Gonadotropins: Synthesis and Secretion
Stimulated by GnRH from **Arcuate nucleus:
—> released in **pulsatile manner after puberty
—> frequency of pulses control LH / FSH synthesis + secretion from Gonadotrophs
—> Low frequency GnRH (1 pulse per 3 hr): FSH
—> High frequency GnRH (1 pulse per hr): LH
記: 低頻FSH, 高頻LH
Physiological effects of Gonadotropins
FSH / LH
- Peptide hormone
Effects mediated by Gonadotropin-R (***GPCR)
LH:
- Steroidogenesis: Sex steroid synthesis + secretion from gonads
Male:
- Testosterone production in ***Leydig cells of testis (for spermatogenesis / secondary sexual characteristics) (-ve feedback to Hypothalamus, Anterior pituitary)
Female:
- Testosterone production in **Theca cells of ovary (converted to Estrogen by **Granulosa cells) (-ve feedback to Hypothalamus, Anterior pituitary)
- Complete 1st meiosis —> formation of Secondary oocyte
- Causes ***Ovulation + Corpus luteum formation
FSH:
- Spermatogenesis, Oogenesis
Male:
- Induce Spermatogenesis in ***Sertoli cells
- Stimulate testosterone-binding protein in ***Sertoli cells (able to respond to Testosterone)
- Inhibin production (-ve feedback on ***FSH only)
Female:
- Stimulate maturation of ovarian follicles
- Induce LH receptor expression on ***Granulosa cells (Follicle able to respond to LH)
- Inhibin production (-ve feedback on ***FSH only)
Disorders related to Gonadotropins
- Hypergonadism (↑↑ FSH / LH)
- Pituitary tumour
- Ectopic hormone-productions tumours of lung, liver cell lines
- Elevated GnRH - Gonadotropin deficiency (↓↓ FSH / LH)
- ***Hyperprolactinaemia —> inhibit GnRH
- Genetic problems
—> mutation leading to developmental problem of GnRH neurons
—> mutation in GnRH-R
—> mutation in β-subunit of gonadotropin gene (FSH, LH share same α subunit) (造唔到FSH/LH)
- Associated with Hypogonadism (diminished functional activity of gonads)
E.g. Kallmann syndrome (both sexes)
- X-linked recessive / Autosomal recessive
- GnRH-secreting neurons absent congenitally in Hypothalamus
- Affected individual does not go through puberty
- Infertile
- Reduced smell sensation (GnRH neurons originate from olfactory placode, developmental problems with olfactory nerve fibres —> Kallmann syndrome)
Prolactin: Synthesis and Secretion
Predominantly under **Inhibitory control by Hypothalamus (Dopaminergic input into Anterior pituitary)
—> Dorsal medial of **Arcuate nucleus + ***Periventricular nucleus
—> D2 receptor (Gαi)
—> inhibit Adenyl cyclase
—> inhibit cAMP
—> excitation voltage-gated K channels
—> inhibition of voltage-gated Ca channel
—> inhibition of Prolactin release
Prolactin:
- by Lactotroph
- single chain peptide
- Breast-feeding (Neurogenic via ANS):
—> Reduction of tonic inhibitory effect (Dopamine) of Hypothalamus
—> freeing Lactotrophs to express inherent capacity
—> secrete Prolactin at very high rate
2. Pregnancy (Physiologic) —> Estrogen —> Directly act on Lactotroph (uncouple D2 receptor with Gαi) —> Lactotroph less sensitive to Dopamine —> secrete Prolactin
Physiological effects of Prolactin
Prolactin
- Peptide hormone
Effects mediated by Prolactin-R —> Enzyme-linked receptor (JAK/STAT signalling pathway)
Prolactin binding to Prolactin-R
—> Receptor dimerisation
—> Activation of JAK
—> STAT5 phosphorylation
—> Transcription of genes
—> 1. **Growth and development of mammary gland (Alveolar epithelial cells) for lactation (Alveolar multilobular branching morphogenesis —> Lobes + Ducts)
—> 2. **Milk production by alveolar epithelial cells in mammary gland
Homeostasis:
Prolactin receptors also expressed in GnRH afferent neurons of Hypothalamic GnRH neurons (2 different neurons)
—> activation of GnRH afferent neurons
—> inhibit Hypothalamic GnRH neurons
—> ↓ GnRH secretion
—> ↓ FSH / LH
—> prevents fertility to protect lactating women from premature pregnancy (Lactational amenorrhea)
Disorders related to Prolactin
- Hyperprolactinaemia
Causes:
- Prolactinomas (tumour of anterior pituitary)
- Hypophysitis (inflammation of pituitary)
- Ectopic prolactin secretion from other tumours
- Hypothalamic / Pituitary stalk disorders (e.g. compressive macroadenoma) to deplete Dopamine
- ***Dopamine antagonists (e.g. antipsychotics)
- ***Vit B6 deficiency (Vit B6: Co-factor for DOPA decarboxylase —> transformation of DOPA into Dopamine)
Signs/Symptoms:
- **Galactorrhea
- **Hypogonadism / Infertility (∵ GnRH secretion inhibited)
—> Female: lack of ovulation (Anovulation), lack of mensturation (Amenorrhea)
—> Male: lack of sex desire, erectile dysfunction (∵ low Testosterone level), enlarged breast tissue
- Headaches / visual problems (if related to tumour)
Treatment:
- ***Dopamine agonists
- Prolactin receptor antagonists
- Hypoprolactinaemia
Causes:
- General pituitary hormones deficiency (Hypopituitarism)
E.g. ***Sheehan syndrome
- Postpartum pituitary necrosis due to blood loss, hypovolemic shock during / after childbirth
—> damage to Lactotrophs (+ other pituitary cells)
—> inability to breast-feed
ACTH: Synthesis and Secretion
- Peptide hormone
- synthesised as a large prohormone: ***Proopiomelanocortin (POMC)
—> can be cleaved into ACTH, MSH (melanocyte-stimulating hormone), Endorphin (opioid) etc.
CRH from ***Parvocellular neurons in PVN
—> activation of CRH-R (GPCR) on Corticotroph
—> ↑ POMC production
—> ACTH secretion
Physiological effects of ACTH
ACTH receptor:
- belong to subfamily of melanocortin receptors (5 total: MC1R-5R)
- only MC2R bind with ACTH at high affinity
- **MC2R found in Adrenal **cortex
Physiological effects:
Binding of ACTH to MC2R (GPCR —> ↑ cAMP):
1. Activates transcription of gene involved in **Cholesterol uptake by adrenal cortical cells
—> **Adrenal cortex expansion
- Activates transcription of several key steroidogenic enzymes
—> ***Steroidogenesis (including Cortisol, Androgens)
End-result: Cortisol production in Adrenal cortex (Zona fasciculata)
Homeostasis:
Cortisol (+ other hormones from Adrenal cortex)
- Long -ve feedback loop
—> ↓ CRH (Hypothalamus)
—> ↓ POMC production + ↓ ACTH release (Anterior pituitary)
Extremely high ACTH (due to ↑ ACTH production / ↑ POMC expression / ↓ Cortisol)
- bind to MC1R in melanocytes of skin / hair follicles
—> hyperpigmentation (brown/black melanin pigment production)
—> ***skin darkening
Disorders related to ACTH
- ACTH deficiency (Secondary adrenal insufficiency)
- failure of Hypothalamus / Anterior pituitary
—> ↓ CRH / ↓ ACTH production
- symptoms
—> same as primary adrenal insufficiency e.g. Addison’s disease / mutation in MC2R gene
Primary adrenal insufficiency (Adrenal gland problem: 造唔到Cortisol):
- ↑ CRH, ↑ ACTH, ***↓ Cortisol
Secondary adrenal insufficiency:
- Hypothalamus failure (造唔到CRH): ***↓ CRH, ↓ ACTH, ↓ Cortisol
- Anterior pituitary failure (造唔到ACTH): ↑ CRH, ***↓ ACTH, ↓ Cortisol
- Overproduction of ACTH
- Pituitary adenoma
- Ectopic CRH / ACTH production in fast-growing tumours (oat cell carcinoma of lung)
E.g. Cushing’s disease
Cushing’s disease vs Cushing’s syndrome
Cushing’s disease:
- excessive secretion of ***ACTH from Anterior pituitary
- one of causes of Cushing’s syndrome
- ***Secondary disorder (Hypothalamus / Anterior pituitary)
Cushing’s syndrome:
- simply describing symptoms due to ***↑↑ Cortisol (i.e. adrenal disorder)
- usually describe ***Primary disorder
TSH: Synthesis and Secretion
- 1 of 3 pituitary ***glycoprotein hormone (other 2 FSH, LH)
—> α + β subunit
—> α subunit common to all 3 hormones, β subunit confers specificity
TRH (smallest peptide hormone: 3 a.a.) from ***Parvocellular neurons in PVN
—> TSH released from Thyrotrophs
Physiological effects of TSH
TSH receptor:
- on Thyroid follicular cells
Binding of TSH to TSH-R
—> modulation of Thyroidal gene expression
—> Thyroid hormone production + Growth of Thyroid cells
Functions:
- Stimulate thyroid cell growth, differentiation
- Stimulate thyroid gland to produce T3, T4
Homeostasis:
Thyroid hormone:
1. -ve feedback to Anterior pituitary —> ↓ TSH β subunit synthesis —> ↓ TSH secretion
2. -ve feedback to Hypothalamus —> ↓ TRH secretion
Disorders related to TSH
- Thyrotropin deficiency
- ~ primary hypothyroidism - Excess Thyrotropin
- ~ hyperthyroidism
- Pituitary adenomas —> **TSH overproduction
- Pituitary **resistance to -ve feedback by Thyroid hormones
- weight loss
E.g. Graves’ disease
- Abnormal Ab (TSI) that mimic TSH function —> TSH-R continuously activated
Vasopressin and Oxytocin: Synthesis and Secretion
Vasopressin (ADH) / Oxytocin:
- 9 a.a. peptide hormone
- similar in structure (differ by 2 a.a.)
Synthesis:
(Different) **Magnocellular neurons in PVN + SON
—> Transported along axons of Neurosecretory neurons (Hypothalamo-hypophyseal tract) to Posterior pituitary
—> stored in **Herring bodies (secretory granules)
Secretion:
Stimulus detected at cell body of PVN, SON
—> Depolarisation of neurons
—> Action potential along axons
—> Influx of Ca through voltage-gated Ca channel
—> ↑ intracellular Ca in axonal terminal
—> Exocytosis of Vasopressin/Oxytocin-containing vesicles
—> released from Posterior pituitary into fenestrated capillary
Physiological effects of Vasopressin
Vasopressin receptor: GPCR
V1aR:
- Gαq —> ↑ IP3/PKC —> ↑ Ca
- Vascular smooth muscle
- ***Vasoconstriction —> ↑ BP
V2R:
- Gαs —> ↑ cAMP
- Renal collecting tubules
- **Trafficking of AQP2 to apical membrane —> **Water reabsorption in renal collecting ducts (Anti-diuretic effect)
Physiological effects of Oxytocin
Oxytocin has only 1 receptor (GPCR)
- Gαq —> ↑ IP3/PKC —> ↑ Ca
Physiological effects:
1. Uterus: stimulates ***contraction of Myometrium by ↑ intracellular Ca
—> Labour (+ve feedback)
- Mammary glands: stimulates contraction of **Myoepithelial cells surrounding alveoli by ↑ intracellular Ca
—> **Squeezing of milk into nipple for nursing infant (Milk let-down)
Disorders related to Vasopressin
- Vasopressin deficiency (**Diabetes insipidus)
—> kidney **unable to reabsorb water / concentrate urine adequately
—> large amount of diluted urine
Causes:
- ***Central diabetes insipidus (CDI)
—> Hypothalamus / Pituitary problem
—> defect of vasopressin production / release
- ***Nephrogenic diabetes insipidus (NDI)
—> mutation in V2R (X-linked) / genetic defect in AQP2 gene (Autosomal)
—> impaired trafficking of AQP2
—> kidney unable to respond to vasopressin
- Excess vasopressin (SIADH: syndrome of inappropriate secretion of ADH)
- kidney ***conserving too much water
Causes:
- Type A: certain cancer (small cell lung carcinoma) —> erratic fluctuations (unregulated ectopic release of ADH) unrelated to plasma osmolality
- Type B: heart failure —> aberrant input from baroreceptor (reduced sensitivity due to reduced CO) —> activated to conserve water at lower plasma osmolality (low salt / high water) (downward resetting of anti-osmoregulatory system)
- Type C: diseased hypothalamus —> slow constant leakage of ADH
Signs/Symptoms:
- **Water retention + **Dilutional hyponatraemia
—> headache, muscle weakness
—> **cerebral edema: confusion, hallucination
—> **seizure, coma
