Hypothalamus and
adenohypophysis
HypothalamusVentrolateral medulla
(heart, stomach)
Amygdala
(associative regions of neocortex,
olfactory bulb, hippocampal
formation, subcortical structures
including brain stem)
Hippocampus
(associative regions of neocortex,
thalamus, reticular formation
nuclei, etc.)
Nucleus solitarius
(viscerosensory information–
heart, lungs, GIT, blood vessels –
baro-/chemoreceptors) Locus coeruleus
(prefrontal cortex, N.
paragigantocellularis –
integration of external and
autonomic stimuli – stress,
panic)
Orbitofrontal cortex
(sensory perception, reaction to
reward/punishment)
Body temperature
regulation
Neuroendocrine
regulation
Appetitive behavior
(hunger, thirst, sexual
behavior)
Defensive reactions
Autonomic nervous
system (modulation)
Biorhythms and their
regulation
Lamina terminalis
(blood, blood
composition)
Behavior
Circumventricular organs
CC – corpus calosum
OC – chiasma opticum
ac – commisura anterior
pc – commisura posterior
AP – area postrema
CP – choroid plexus
ME – eminentia mediana
NH – neurohypophysis
OVLT – organum vasculosum
laminae terminalis
PI – pineal gland/epiphysis
SCO – subcommissural organ
SFO – subfornical organ
Eminentia mediana
- Afferent sensoric organ
- Functional connection of
hypothalamus and hypophysis
- Point of entry of some hormones from
circulation (fenestration) – leptin
- CONVERSION - HUMORAL FACTORS –
HYPOTHALAMIC REGULATION
NEURONS
OVLT
- Regulation of autonomous
processes
- Febrile regulation
- Blood osmolality
- Regulation of secretion of GnRH
stimulated by estrogens
Subfornical organ
- Body fluid homeostasis
- Blood pressure regulation (R for ANP and ATII)
- Oxytocin secretion regulation
Area postrema
- Afference (n. vagus, n.
glossopharyn-geus)
- R for GLP-1 and amylin
- Chemosensoric neurons with osmoR
- „detection“ of toxins
- coordinated regulation of blood
pressure (R for ATII, ADH, ANP)
Subcommissural organ
- Mainly unknown function
- R for neuropeptides and
neurotransmitters
- ? Production of somatostatin
- „catching“ of monoamines from CSF
Anatomical and functional connection of hypothalamus and
hypophysis, neuroendocrine secretion
Hypothalamic hormones
Hypothalamic hormones are secreted in eminentia
mediana region and enter portal circulation via
fenestrations
Axons of oxytocin and ADH synthesizing neurons go
through eminentia mediana region. Hormones are
secreted in neurohypophysis
PIH (prolactin-inhibiting hormone) = dopamine
Environmental factors
Neural stimuli
Hormonal stimuli
Synthesis and secretion
of hypothalamic
hormones
Signal integration to regulate endocrine functions and to maintain hoemeostasis
Adenohypophyseal hormones
Nerveendings–eminentiamediana
neurohormones
+/- Receptor(Gprot.)
Suprachiasmatic nucleus Circulating hormones Feedback system
Circadian
rhythms
Sleep
(dwaves
Sleep–TSH
(st.1st,2ndNREM)
Physiologicaleffect–homeostasismaintainance
Adenohypophysis
HORMONE PRODUCTION UNDER DIRECT HYPOTHALAMIC CONTROL
- ACTH – adrenocorticotropic hormone
- TSH – thyroid-stimulating hormone
- GH – growth (somatotropic) hormone
- PRL – prolactin
- LH – luteinizing hormone
- FSH – follicle-stimulating hormone
Adenohypophyseal
cells
Represent
ation
Hypothalamic
hormone(s)
Adenohypophyseal
hormones
Localization
Lactotropic Up to 25 % Dopamine prolactin whole AH
Corticotropic Ca 20 % CRH POMC – ACTH, bLPH,
a-MSH, b-end.
Anteromedial
region
Thyreotropic Ca 5 % TRH TSH Anteromedial
region
Gonadotropic Up to 15 % GnRH LH/FSH Posterolateral
region
Somatotropic Ca 40 % GHRH/GHIH GH Posterolateral
region
Axis GHRH/GHIH-GH-IGF-1
Somatoliberin, (GHIH, growth hormone-releasing hormone)
Characteristics
- Two types present in hypothalamus
- GHRH receptor (cAMP)
- R – homology with R secretin, GLP-1, glucagon, calcitonin, PTH,
PTHrP
Hypothalamo-hypophyseal axis
- Fast GH secretion
- + estrogens, glucocorticoids and starvation
- - Somatostatin, age and obesity
Clinical significance
- Nowadays without clinical significance
- GHRP
Regulation of secretion
- stimulation
- Ghrelin
- Leptin
- Galanin
- GABA
− a2-adrenergic and dopaminergic
input
- inhibition
- CRH
− b2-adrenergic input
Somatostatin (GHIH, growth hormone–inhibiting hormone )
Characteristics
- Neurotransmitter – neuromodulator
Hypothalamo-hypophyseal axis
- GH secretion regulation
- TSH inhibition
- PRL and ACTH secretion inhibition
Clinical significance
- Somatostatin analogues (octreotide, lanreotide, vapreotide,
seglitide, pasireotide)
- Therapy of acromegaly, TSH producing or neuroendocrine
tumors
- ! Negative GIT side effects
- Imaging methods (111In-somatostatin)
- Potential use in tumor treatment
Main effects of somatostatin
Inhibition of hormone secretion GIT inhibition Other
Adenohypophysis – TSH, GH, ACTH, PRL Stomach and duodenal secretion
including HCl
Inhibition of activated immune cells
GIT – gastrin, secretin, motilin, GLP-1,
GIP, VIP
Stomach emptying Inhibition of tumor growth
(proliferation)
Endocrine pancreas – insulin, glucagon,
(somatostatin)
Pancreatic enzymes and bicarbonates
secretion
Kidneys - renin Bile secretion
Decrease of GIT blood flow
Stimulation of intestinal water and
electrolytes absorption
Growth hormone (GH)
Characteristics
-hGH genome – 5 products including human chorionic
somatomammotropin
-hGH-N – somatotrophs – 20/22 kDA
-hGH-V – placenta – feedback regulation
-Circulating GH:
- 20 (25 %) and 22 kDA (75 %) monomers
- Acetylated 22 kDA form
- Deaminated forms
Regulation of secretion
-GHRH, somatostatin, ghrelin, IGF-1, thyroid hormones,
glucocorticoids
-Relatively complicated system of regulation based on:
- Neuropeptides
- Neurotransmitters
- Endogenic opioids
Growth hormone (GH) – regulation of secretion
- GHRH (continual), somatostatin (pulsatile secretion)
- Desensitization of R for GHRH
- IGF-1 - somatostatin
- Ghrelin
- GHS receptors – stimulation of GHRH secretion
- Synthesis – stomach and CNS, regulation of
food intake
- Diurnal rhythm with maximum during sleep (first
episode of slow-wave sleep)
- Very low basal secretion, decrease with age (peak
in puberty, then decrease)
Stimulation of GH secretion - overview
Physiological factors Hormones and neurotransmitters Pathological factors
Exercise Arginin, lysin Acromegaly
Stress (various causes) Neuropeptides (ghrelin, GHRH,
galanin, opioids – m receptors,
melatonin)
TRH, GnRH
Sleep Neurotransmitters (agonists a2-AR,
antagonists b-AR, M1 agonists, 5-HTD1
agonists, H1 agonists)
Glu, Arg
Decrease in postprandial glycemia GABA IL-1, 2, 6
Starvation Dopamine (D2R) Protein depletion
Insulin-induced hypoglycemia Estrogens Starvation, anorexia nervosa
Testosterone Kidney failure
Glucocorticoids (acute, not chronic) Liver cirrhosis
DM 1st type
Inhibition of GH secretion
Physiological factors Hormones and neurotransmitters Pathological factors
Postprandial hyperglycemia, glucose
infusion
Somatostatin Acromegaly
Increased FAA in plasma Calcitonin L-DOPA
Increased GH concentration in plasma Neuropeptide Y D2R agonists
Increased IGF-1 concentration in plasma CRH Phentolamin
REM sleep Neurotransmitters (a1,2-AR
antagonists, b-AR agonists, H1
antagonists, serotonin receptor
antagonists, nicotine cholinergic
receptor agonists)
Galanin
Aging Glucocorticoids (chronic) Obesity
Hypothyroidismus
Hyperthyroidismus
GH and interaction with other hormonal axes
ACTH – Glucocorticoids
- Acute (+) – effect after ca 3 hours
- Chronic (-)
TRH – TSH – thyroid hormones
- Necessary for GH secretion
- Hypothyroidismus (-)
GnRH – FSH a LH – sex hormones
- Testosterone (+)
- Estrogens (+) – only p.o. – decreased inhibition of
IGF-1 + feedback
- aromatization of androgens affects GH synthesis
and secretion (paracrine effect of estrogens in CNS)
GH and its effects
METABOLIC
-Energetic metabolism
-Together with insulin (metabolism of sugars, fats, proteins)
-Lipolysis and FA oxidation(+) (hormone-sensitive lipase, + LDL)
-Glucose – direct or indirect effect,
- (+) uptake of Glu
- (-) Glu oxidation
- (+) gluconeogenesis
-Proteins
- (+) anabolism, (-) urea
- (+) AA transport
- (+) incorporation of AA to proteins
- (-) protein oxidation
GROWTH
-Mediated by IGF-1 (auto-/paracrine)
GH – clinical aspects
GH deficiency – gained or congenital – often tumors or inflammation
- nonspecific symptoms (i.e. loss of energy, social isolation, loss of focus)
- myocardium changes (left ventricle)
GHR – mutation
Significance of markers (IGF-1, IGFBP3)
Substitution therapy – wide array of side-effects, contraindication – cancer
Experimental indications:
- catabolic states (i.e. extensive burns)
- osteoporosis
- HIV/AIDS
- sport medicine, aging
Axis PIH-prolactin
PIH, prolactin-inhibiting hormone
Characteristics
- dopamine
Hypothalamo-hypophyseal axis
- Inhibition of PRL (D2R) secretion – lactotropic cells
- ! Lactotrophs with continual high PRL production
- Paracrine and autocrine regulation of PRL secretion
Other functions and places of synthesis
- Blood vessels – vasodilatation (physiological concentrations)
- Kidneys – sodium secretion
- Endocrine pancreas – decrease in insulin secretion
- GIT – lower motility
- Effect of dompamine on immune system
Clinical significance
- Effect of medication on dopamine and PRL secretion
- Neurodegenerative diseases (Parkinson)
- Antipsychotics (antag.)
- Important feedback mechanism (short
loop) of PRL secretion regulation
- Circadian rhythm (maximum in the
morning)
- Nipple stimulation (1-3 min, peak
10 – 20 min)
PROLACTIN-RELEASING FACTORS (PRF)
- TRH, oxytocin, VIP
- under specific conditions ADH, ATII,
NPY, galanin, substance P, GRP,
neurotensin
- prolactin-releasing peptide (PrRP) –
stress, satiety (other parts of CNS)
Prolactin - PRL
Characteristics
- Lactotropic cells (only PRL)
- Mammosomatotropic cells (PRL and GH)
- Hyperplasia – pregnancy and lactation
- Expression regulated by estrogens, dopamine, TRH, thyroid hormones
- PRLR – mammary gl., adenohypophysis, adrenal gl., liver, prostate,
ovaries, testicles, small intestine, lungs, myocardium, SNS, lymphocytes
Regulation of secretion
- Pulsatile secretion – 4 – 14 pulses/day
- Highest levels during sleep (REM, nonREM)
- Lowest between 10:00 and 12:00
- Lower secretion with aging
- TIDA cells – dopamine Paracrine – endothelin-1, TGF-b1, calcitonin,
histamine (-)
- FGF, EGF (+)
- TRH, estrogens, VIP, serotonin, GHRH in higher concentrations (+)
- Cholecystokinin - ?
Prolactin - functions
Production of breast milk during pregnancy and lactation =
function necessary for survival
Other functions – metabolic, melatonin synthesis, maternal
behavior
Development of mammary gland and lactation
- Puberty – development of mammary gland due to GH
and IGF-1
- Effect of estrogens and progesterone
- At age 8 – 13
- During pregnancy proliferation of alveoli and
production of breast milk proteins and colostrum
- During third trimester – colostrum production (PRL,
estrogens, progesterone, GH, IGF-1, placental
hormones)
- Lactation – increase of PRL after birth, without breastfeeding
decrease after ca 7 days
- Accumulation of breast milk stops further production
- Role of OT
Reproductive function of PRL
- Lactation = amenorrhea and secondary infertility
- Inhibition of GnRH secretion
- Role of kisspeptin neurons (PRLR)
- Possible role of metabolic factors
Immune function of PRL
- Antiinflammatory effect ?
Clinical significance
- hyperprolactinemia – drugs including some
antihypertensives, chronic kidney failure
- Macroprolactinemia
- Galactorrhea – role of GH (acromegaly)
- PRL deficiency
Axis GnRH-LH/FSH-gonads
GnRH, Gonadotropin-Releasing Hormone, GnIH
Characteristics
- Specific origin of GnRH neurons outside of CNS
- Downregulation – malnutrition, lactation, seasonal effects, aging,
continual GnRH
- Upregulation – effect of GnRH on gonadotrophs (menstrual cycle)
Hypothalamo-hypophyseal axis
- FSH, LH
- Importance of GnRH pulses frequency (glycosylation)
- Menstrual cycle, puberty and its onset
Clinical significance
- Continually distributed
analogues of GnRH –
treatment of
estrogen/steroid-dependent
tumors of reproductive
system
- Premature puberty
treatment (leuprorelin –
agonist!)
Regulation of secretion
- Inputs from various CNS regions (brain
stem, limbic system)
- Inhibitory effect of sex-hormones with
exception of estradiol (negative/positive
feedback)
- Importance of kisspeptin for females
- Inhibitory effect of PRL
- Effect of circulating substrates (FA, Glu)
- Leptin (NPY, kisspeptin)
- Stress (various causes)
- Acute – disruption of MC without
effect on fertility
- Chronic – disruption of fertility,
lowering of circulating sex-hormones
levels
GnIH, Gonadostatin
Characteristics
- Discovered in 2000
- Dorsomedial nucleus of the hypothalamus
- Projection to the eminentia mediana
- Binding to GnIH receptor (hypothalamus,
adenohypophysis, ovary)
- Differential secretion during the ovarian cycle
Functions
- Regulation of the reproduction axis, including the onset
of puberty
- Regulation of the reproduction behaviour
- Regulation of some CNS functions (neurotransmitter
synthesis)
Glycoproteins – FSH a LH
Characteristics
- Heterodimer, different expression of subunits, glycosylation
- Structurally close to hCG (placenta)
Regulation of secretion
- sex hormones, local factors – paracrine (activins, inhibins,
follistatin)
- (+) – glutamate, noradrenaline, leptin
- (-) – GABA, opioids
- Key role of kisspeptins, neurokinin B and substance P in
GnRH secretion – FSH/LH
- Estrogens, progesterone, androgens – direct effect on
gonadotrophs, indirect through GnRH
- Estrogens (-) – inhibition of transcription (a)
- Kisspeptin – stimulation of LH/FSH, GnRH
- Estrogens (+) shift
- Progesterone (-) – influences pulsatile secretion of
GnRH
- Testosterone, estradiol (-) – males, kisspeptin neurons
and AR
- GnRHR – Ca2+ mobilization
- Different half-life for circulating LH and FSH
FSH and LH functions
FEMALES
- FSH
- Growth and development of follicular cell (maturation)
- Biosynthesis of estradiol
- Regulation of inhibin synthesis during follicular phase
- Upregulation of LH receptors (preovulatory follicles)
- Selection of dominant follicle
- Recruitment of follicles for next cycle
- LH
- Stimulation of estrogen synthesis (theca)
- Oocyte maturation (preovulatory follicle)
- Rupture of ovulatory follicle, ovulation
- Conversion of follicle wall to corpus luteum
Clinical significance
- Possible deficiency of gonadotropins
- Hypogonadotropic hypogonadism
- Kallmann syndrome
- Syndrome Prader-Willi
- Reproductive dysfunction
MALES
- LH
- Intratesticular synthesis of testosterone (Leydig cells)
- FSH
- Spermatogenesis (Sertoli cells)
Activins and inhibins
Inhibins – dimeric peptides (a + 1 or two bA or bB)
– inhibin A – dominant follicle, corpus luteum
– inhibin B – testes, luteal and early follicular phase of MC
- FSH inhibition
Activins
– dimeric peptides – dimers of b subunits
– FSH stimulation
– autocrine/paracrine factors
– other tissues – growth and differentiation
Folllistatin
– monomeric polypeptide
– FSH inhibition
- „supplementary “ regulation of FSH and LH secretion
Hormones of hypothalamus secreted
by neurohypophysis
Neurohypophysis
Synthesis - magnocellular neurons (SON, PVN)
Termination (neurohypophysis, eminentia mediana)
Precursor protein (signal peptide, hormone,
neurophysin 2, glycopeptide copeptin)
Posttranslational modification – ADH/OT +
neurophysins + copeptin
Secretion – voltage-gated Ca2+ channels
Circulation – free, elimination – kidneys, liver
Neurophysins – importance – ADH transport and
secretion
Oxytocin
Characteristics
- Mechanoreceptors/tactile receptors
- endogenous opioids, NO, GABA (-)
- Prolactin, relaxin (-), Estrogens (+)
- Works together with prolactin and sex hormones
Functions
- Lactation (under 1 min)
- Childbirth
- rhythmical contractions of smooth muscles (gapjunction,
stimulation of prostaglandin synthesis –
extracellular matrix)
- postpartum bleeding, uterus involution
- Ejaculation (males)
- Behavior
Other functions and places of synthesis
- CNS
- Stimulation of ACTH secretion through CRH
- Stimulation of ADH/induced vasoconstriction
- Stimulation of prolactin secretion
- Memory traces recollection inhibition
- Maternal behavior
Clinical significance
- Oxytocin analogues
Antidiuretic hormone (ADH, vasopresin, AVP)
Characteristics
- receptors (G protein)
- V1R - V1a (Gq/11) – liver, smooth muscles, CNS, adrenal glands –
only ligand ADH
- V2R (Gs) – kidneys
- V3R - V1b (Gq/11) – corticotropic cells (CNS), kidneys, thymus,
heart, lungs, pancreas, uterus
Function
- Water reabsorption (distal tubule, collecting tubule) –
tubular system with different water permeability in different
parts
- AQP1 – proximal tubule, HL descending limb HK – 90 % of
water reabsorption
- AQP2 – collecting tubule (only ADH; acute X chronic effect)
- AQP3, AQP4
- Vasoconstriction (hemorrhagic shock, sepsis)
Other functions and places of synthesis
- CNS – increased recollection of memory traces
- Periphery – stimulation production of factor VIII and von
Willebrand factor
phosphorylation
ADH - regulation of secretion
- Osmotic regulation
- Regulation volume-pressure
- Predominantly inhibitory effect of R on
magnocellular N
ADH is the main hormone regulating water
homeostasis and osmolality, RAAS is the main
regulatory system of blood volume and pressure.
ADH – clinical aspects
Diabetes insipidus (DI)
- Primary polydipsia
- Decreased ADH synthesis/secretion (ADH gene)
(neurogenic)
- Decreased kidney sensitivity (nephrogenic)
SIADH – Syndrome of Inappropriate Antidiuretic
Hormone Secretion
- Increased ADH synthesis/secretion
- Absence of physiological ADH secretion stimuli
Absence of thirst after osmotic stimulation
Ethanol lowers ADH secretion
Unregulated ADH secretion
Increased basal
ADH secretion
Reset of osmostat
Decreased ADH
secretion