6 Flashcards
Which hormone is structurally similar to prolactin? What are the differences?
GH
peptide hormones, similar to GH
few differences- number of AAs- 198 a.a. (vs 191 in GH)
Apart from strucutre, how does GH differ from PRL?
the amount of prolactin you find in pituitary is much less, compared to GH
there’s more GH producing cells in the pituitary (50%)
only ~16% of prolactin producing cells-> less prolactin is produced by the pituitary compared to GH
how much PRL is secrted by pituitary?
0.1 mg
What hormones are essential for initiation and maintenance of milk secretion?
Milk produciton?
initiation and maintenance of milk secretion- PRL and cortisol
milk production- Decrease of estrogen and progesterone after parturition is permissive for milk production
What happens to milk after Hypophysectomy and adrenalectomy? WHat does it suggest?
Hypophysectomy leads to immediate cessation of milk production- thus PRL is absolutely essential for milk production
Adrenalectomy leads to a gradual reduction in milk production- thus cortisol is somewhat esential for milk production
What is the PRL locus? GH?
GH has multiple locus
Prolactin locus has one gene – PRL
What kind of hormone is PRL? is it stored?
peptide hormone
stored in granules in lactotrophs
What are the circulatory sizes of PRL?
After prodcution, PRL protein is processed-> Circulates in various sizes – monomeric, dimeric and polymeric
Monomeric, has 1 copy – most bioactive
What is PRL’sgene expression and release regulated by ?
Gene expression and release are regulated by
postivie regulation: PrRP, EGF, FGF, VIP, estrogen, TRH, thyroid hormone,
negative regulation: dopamine, endothelin, TGFb, somatostatin
Is PrRp the releasing factor of PRL? What is the structure of it>
we are not sure
it’s a peptide
What is major pathway of PRL release regulation?
negative pathways are most common, especially via negative regulation by dopmaine
dopamine has an inhibiting effect on prolactin releasing cells- these cells have a dopamine receptors
more dopamine = less prolactin
Does PRL have an effect on dopamin
They both have negative effects on each other
prolactin has negative feedback on dopamine release
prolactin receptors are expressed by dopaminergic neurones in the hypothalamus
What is the half-life of PRL
25-45 min-> short
What is the type of PRL release? When does it occur
episodic release- 4-14 pulses
lowest 10:00-12:00, highest at dark times of the day
PRL levels and age
Levels reduce with age
Where are PRL receptors expressed?
PRL receptors are expressed in breast tissue and in many other tissues including pituitary, liver, adrenal cortex, kidneys, prostate, ovary, testes, intestine, epidermis, pancreatic islets, lung, myocardium, brain, and lymphocytes
Prolactin signaling
PRL is a peptide-> uses a membrance receptor
Uses a tyrosine kinase with an adaptor in the form of JAK
dimerization of PRL receptro sometiemes requires PRL-> PRL dependent dimerization
in some, it doesn’t - indepenedent dimerization (dimerization occurs and only after PRL can interact wiht the receptor)
in any case, dimerization in essential with an adaptor-> needed to initiate kinase cascade
Desribe the mamary gland structure
- Mammary gland has an epithelium layer which are milk-producing cells
These alveolar epithelium cells act as exocrine gland
Myoepithilum cells are contractile and surround the alveolar epithelium- needed to push out the milk produced by the alveolar epithelium
Alveolar epithelium release- they produce milk and milk is released by exocytosis that damages the whole cell- half of the cells is taken out as milk is released- a lot of proliferation occurs there
what is the main target of prolactin?
mammary gland
is PRL necessary for the development of the mammary gland?
no
Which part of the breast tissue is under the control of PRL? WHat is their role?
alveolar epithelium- require PRL amongst other hormones such as estrogen and progestreone , as well as adrenal steroids
Hormonal regulation of production and secretion
milk synthesis and secretion regulation: PRL help epithelial cells to produce and secrete milk which then goest to alveolar cavity
oxytocin act on myoepithelial cells that are contractile and contract under the influence of oxytocin -> contraction of alveoli and ejection of milk
durign lactation both PRL and oxytocin are necessary- > coordinated function
Which hormones are required for Duct system development?
estrogen, GH, adrenal steroids
Hormones required for alveolar growth
estrogen, progesterone, adrenal steroids, PRL
suckling effect on milk ejection and secretion
sucking stimulation is important
mechanic receptors bring these signals to the brain, and they are integrated in the hypothalamus which stimulate release PRL from anterior pituitary. oxytocin release from posterior pituitary is also stimulated
PEL form anterior pituitary acts to synthesis ans secrete milk
Oxytocin from posterior acts on myoepithelial cells around each alveolus-> lead to milk ejection
reproductive function and PRL
Involved in regulation of the reproductive systems
negative regulation in humans, in some species, the regulaiton is positive
Effects of high levels of PRL on the repdocutive system
hyperprolactinemic conditions associated with hypogonadism in males and females
high levels of PRL inhibits reproductive function, especially gonadotropins
high levels of PRL inhibit those
true for both males and females
PRL and amenorrhea
high levels of PRL associated with breast feeding associated with lactational amenorrhea
vcommon birth control method in many cultures
the longer the breast feeding - the longer is reproduction cessation
do gonadotrophs have PRL receptors?
yes
PRL and immunomodulation
- PRLR on both B and T cells and macrophages
- PRL acts as a mitogen (proliferation) and promotes survival, especially for resident macrophages
- PRL receptors found in most tissues
- exact role is no known, but it seems to act synergistically with many other hormones
- deleted PRLR-> compromised function
What is Adrenocorticotrophin?
Adrenocorticotrophin (ACTH) is the anterior pituitary mediator of the hypothalamic–pituitary–adrenal axis that regulates responses to a variety of stressors, including hypoglycemia, psychological stressors such as fear, and physical stressors
What is ACTH derived from? How?
- ACTH is derived by proteolytic cleavage of a large precursor molecule pro-opiomelanocortin (POMC)
- POMC is cleaved by prohormone convertases PC1 and PC2
- In ACTH producign cells, ACTH portion is kept, the rest is digested
Molecular pathway of tanning
- UV DNA damage – Local production of MSH by keratinocyte- this msh is not exogenous, it is localy produced by keratinocytes
- Stimulate melanocyte to produce melanin
- Melanin transported back to keratinocyte to reduce UV damage
- significance of MSH/endorphin, which is thus not localy produced, but produced in the pituitary, production by human pituitary unclear
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What is the target organ of ACTH?
Use of MSH/endorphins produced by POMC neurons?
MSH/endorphins produced by POMC neurons and used as neurotransmitters in brain->reduction of pain sensation
Mechanism of action of ACTH
- Binds to receptors in the adrenal gland
- Activate Gsα-protein-> stimulates AC-> cyclic AMP
- Enhanced mobilization of cholesterol into mitochondria as adrenal cortex makes steroid hormones
- Increased conversion of cholesterol to pregnenolone, which is the precursor for steroids
Control of ACTH secretion
- Circadian rhythm
- Controlled by the hypothalamic hormone CRH, corticotropin releasing hormone from the hypothalamus
- CRH induced by stress (pain, fear, fever, hypoglycemia)- these signals are analyzed by hypothalamus
- Lowest around midnight, morning peak and then declines
- CRH action is potentiated by other hormones (vasopressin) vSubject to feedback control by cortisol- negative feedback both on hypothalamus and pituitary
Which hormones act in pain reduction
MSH/endorphins produced by POMC neurons in the hypothalamus ONLY- local produciton
Feedback control of cortisol on the hypothalamus and pituitary
Thyrotropin (TSH)- thyroid stimulating hormone strucurre
- Secreted by the thyrotrophs
- Two protein chains (⍺ and β) Glycosylated.
- Unique β-chain; Common ⍺-chain with FSH/LH
Thyrotropin (TSH)- receptor type
- Receptor signaling via G-proteins (cAMP).
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TRH and TSH control of release
Hypothalamus produced TRH which stimulates TSH release from pituitary
Short feedback loop: there seems to be a short feedback loop between the pituitary and the hypothalamus where TSH inhibits hypothalamic release of TRH
Direct feedback loop: thyroid hormones inhibit TSH release by pituitary
Indirect feedback loop: thyroid hormones inhibit hypothalmic release fo TRH
Gonadotropins: LH and FSH structure
Secreted by the gonadotrophs
Same basic structure as TSH- share the same alpha-chain, but different beta-chains which are expressed by specific genes
Action of FSH
Act via G-coupled receptors
Females: Development of ovarian follicles and estradiol secretion
Males: Spermatogenesis, production of sex-hormone binding globulin, which is necessary for transport of testosterone
Both sexes: Secretion of inhibin (negative feedback on FSH)
Actions of LH in both sexes
- Females: Steroidogenesis in follicles, induction of ovulation (main function), maintenance of steroidogenesis by the corpus luteum (corpus luteum is a major source of progesterone )
- Males: Stimulation of testosterone production in the Leydig cells
Leydig cells, FHS and LH connection
make testosterone and express LH receptor
FSH is necessary as it allow testosterone to be transported
Describe LH and FSH secretion
- LH and FSH secretion is pulsatile:
- vabout every 60 min in response to GnRH pulses
- each pulse of GnRH is followed by a pulse of LH
- FSH seems to be more independent
The hypothalamo-pituitary-gonadal axis in males
- GnRh from hypothalamus stimulates anterior pituitary to release LH and FSH which act on testes
- in testes, LH receptors are expressed on leydig cells, which produce testosterone
- FSH receptors are expressed on sertoli cells . Sertoli cells support sperm differentiation
- together, testosterone and sertoli cells produce binding protein that brings both gonadotropins, regulation male response to testosterone
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Describe inhibin in males + it’s negative fedback
vs
testosterone
inhibin- peptide hormone; produced by sertoli cells
has -ve feedback on pituitary to inhibit ONLY FSH production (no effect on LH)
testosterone has effect on BOTH hypothalamus and pituitary to regulate BOTH gonadotropins
BOTH inhibin and testosterone act through negative regulation
The hypothalamo-pituitary-gonadal axis in females
GnRH form hypothalamus acts on pituitary-> FSH and LH production
FSH stimulates follicular cells-> estrogen production
LH stimulates luteal cells-> secretes progesterone and estrogen.
These 2 steroids mainly have negative effect at pituitary and hypothalamic levels
Inhibin impact in LH and FSH
- Inhibin is produced in the ovary; Has negative impact on FSH, but no effect on LH
- main action of inhibin is at pituitary level
Hypothalamic-Pituitary target organ axes summary
for each anterior pituitary hormone there’s a target organ
a hormone produced by that organ has manly negative feedback
What are Disorders of the anterior pituitary most commonly caused by? Are they easy to diagnose
Most commonly due to benign tumors of the pituitary (adenomas)-> arise from adenomaphysis
have very slow growth rate-> hard to diagnose
Types of adenomas in terms of size
Microadenomas < 10mm
Macroadenomas > 10mm
2 types of pituitary adenomas
- Functional tumors more common at younger age-> hyperpituitary
- Non-functional tumors are more typical in older patients-> hypopituitary
- as these cells are already poorly functioning in old people
- tumor occurs-> further reduction of function
Stages of development of adenomas
Normal-> hyperplasia-> adenoma
hyperplasia result in non-uniform strucutre-> adenoma
Prevalence of pituitary adenomas
- Prolactin cell adenoma - most common (30%)
- Nonfunctioning adenoma 2nd most common (25%)
- unclassified (2%)
- Also - GH cell adenoma, ACTH, Gonadotroph, TSH
Pituitary adenomas – signs and symptoms
- Usually due to hypofunction, hyperfunction, or mass effect
- as pituitary are close to optic chiasma-> eyes are usually affected first
- Lateral extension to cavernous sinuses – diplopia (double vision), ptosis (drooping eyelids), altered facial sensation
Hypopituitarism- 4 types- name
GH, Gonadotropin, ACTH and TSH deficiencies
Describe Hypopituitarism- GH deficiency
decreased muscle strength and exercise tolerance, diminished libido, increased body fat
Describe Hypopituitarism- Gonadotropin deficiency
oligo/amenorrhea, diminished libido, infertility, hot flashes, impotence (clinically like primary hypothyroidism)
Describe Hypopituitarism- ACTH deficiency
malaise, fatigue, anorexia, hypoglycemia
Describe Hypopituitarism- TSH deficiency
malaise, leg cramps, fatigue, dry skin, cold intolerance
low thyrid hormone levels
Name hormones of anterior pituitary
Adrenocorticotrophic hormone (ACTH)
Thyroid-stimulating hormone (TSH)
Luteinising hormone (LH)
Follicle-stimulating hormone (FSH)
Prolactin (PRL)
Growth hormone (GH)
Melanocyte-stimulating hormone (MSH)
Why may tumors arise>
Tumors may arise de novo (cells either become more active or increase in number) or because of the lack of feed-back control
Give an example of over-secretion of hormones of the anterior pituitary due to the absence of negative feedback
Cushing disease → primary defect in negative feedback control of CRH and ACTH secretion by cortisol → ACTH-producing cells are continuously stimulated by CRH → tumor formation
What are the most common tumors that result in the over-production of hormones? rare?
Tumors secreting PRL, GH or ACTH are most common.
Tumors affecting the release of thyroid stimulating hormone (TSH) and the gonadotropins release (LH and FSH) are rare.
What is the most common cure for tumors that result in Over-secretion of hormones of the anterior pituitary
Most common cure is surgery through the nose
Describe Prolactinoma
- excess of PRL-> negative effect on reproduction
- oligo/amenorrhea (less cycles, incomplete or absence ), galactorrhea (production of milk/secretion at the wrong time), infertility, *decreased libido, *headaches, *visual field defects
- often the presentation in men and post- menopausal women
Effects of GH over-secreting tumors
best way of treating?
- Gigantism (high levels of GH during the growth phase e.g. in adolescents ) and acromegaly (GH levels increased in adults after they stopped growing-> large bones, jaws)
- GH produced at a high level without pulsatility.
- IGFs elevated as a consequence (positive effect on most tissues in terms of growth)
- Treated with long-acting somatostatin analogues
- Best is surgical removal
Effect of GH therapy
Administration of GH allows growth to catch up, but there are a lot of side-effects
Diagnosis of adenomas
- Usually delayed due to non-specific nature of many symptoms
- MRI is imaging is the best way to confirm
- Tests can reveal whether adenoma is hypo- or
- hyperfunctional
- Visual field defects (first symptom) often require resection of pituitary gland
Diagnosis of deficiency for gh, gonadotropins, ACTH, TSH
hormone levels can be measures
either the hormone itself, or associated hormones
- GH: insulin tolerance test, GHRH/arginine test, IGF-1 levels
- Gonadotropins: sexual history, menstrual history, FSH/LH/estradiol/prolactin/testosterone levels (directly on indirectly- e.g. by measuring LH or FSH or target hormones such es estradiol)
- ACTH: AM cortisol, cosyntropin test (ACTH), insulin tolerance test
- TSH: T4 and TSH levels
Describe cosyntropin test
The ACTH stimulation test measures how well the adrenal glands respond to adrenocorticotropic hormone (ACTH).
An increase in cortisol after stimulation by ACTH is normal.
No increase in cortisol-> problems
Diagnosis of excess- prolactinoma, acromegaly, TSH
directly from blood or MRI
- Prolactinoma: prolactin level, drug history, clinical setting (e.g. pregnancy, breast stimulation, stress, hypoglycemia)
- PRL < 200ng/ml w/ large adenoma suggests stalk compression as etiology
- Acromegaly: IGF-1 level, oral glucose tolerance test
- TSH overproduction: free T4, T3, TSH levels
Treatment of overpdouction of hormones
- Typically requires surgical resection of adenoma
- Exception: prolactinoma in which 1st line treatment is dopamine agonist therapy- as prolactin’s regulation is primarily through negative regulation by dopamine
- Treatment with bromocriptine: Binds and activates dopamine receptors → inhibition of PRL secretion
- Somatostatin analogs (inhibit GH secretion) are used for acromegaly
- Deficiency states require replacement of the indicated hormone
Estogen and progesterone
Impacts on LH, FSH and GnRH
estrogen inhibits both GnRH and FSH release
progesterone inhibits both LH and GnRH release.
Name POMC derived hormones
- b- lipotropin
- ACTH
- MSH
- PRL
- Endorphin
testtosterone and inhibin interaction
testosterone promotes inhibin production
