1. HYPOTHALAMUS AND ITS HORMONES
HORMONES OF THE PITUITARY
Jana Jurcovicova

2. hypothalamo-pituitary complex.
ANATOMICAL NOTES
Pituitary has a coordinating role in regulation of peripheral endocrine glands. It is connected with with part of diencephalon - hypothalamus to form
hypothalamo-pituitary complex.
Hypothalamus acts as a regulating and connecting center which enables the control of endocrine functions by central nervous system.
Hypothalamus is located on the base of third ventricle and extends between
- mammilary bodies (caudally)
- optic chiasm (frontally)
- optic tract (laterally)
- thalamus (dorsally)
On its base is median eminence, an important structure where converge regulatory pathways form hypothalamus into peripheral blood.

3. BASAL VIEW OF THE HYPOTHALAMUS

5. HYPOTHALAMO-HYPOPHYSEAL CONNECTION
Central part of neuroendocrine regulation is hypothalamo-hypophyseal complex. Structural components of this complex are neurosecretory cells grouped into secretory nuclei located around the third ventricle. These secrete neuropeptides into portal blood connecting hypothalamus with adenopituitary. The other cell groups secrete neuropeptides to systemic circulation through posterior lobe via long axons of magnocellular hypothalamic neurons.
Pituitary is located in sella turcica and is composed from 2 distinct structures - adenopituitary and posterior pituitary
arcuate nucleus and other nuclei
supraoptic and paraventricular nuclei
adenopituitar hormones
posterior pituitary hormones

6. ENDOCRINE HYPOTHALAMUS
Hypothalamic secretory nuclei synthesize neuropeptides regulating adenopituitary secretion. These either exert either stimulatory or inhibitory effects.
There are 4 stimulatory - releasing hormones
and 2 inhibitory - statins
releasing hormones:
reproduction function activates gonadotropin releasing hormone - GnRH
growth hormone activates growth hormone releasing hormone - GHRH
thyroid function activates thyrotropin releasing hormone – TRH,
adrenocortical function activates corticotropin releasing hormone – CRH.
inhibiting hormones (statins)
growth hormone inhibits somatostatin - SRIF (mild inhibitory activity also on TSH)
prolactin inhibits prolactostatin - dopamine

7. TOPOGRAPHY OF ENDOCRINE HYPOTHALAMUS
The highest endocrine activity resides in medial hypothalamus (tuberal region), then lateral and proptic regions
Medial hypothalamus: arcuate nucleus (ARC) containis GHRH, somatostatin and PIH, paraventricular nucleus (PVN) contains CRH and TRH. Periventricular nucleus contains somatostatin.
Lateral hypotalamus: supraoptic nucleus (SON) contains neurohypophyseal hormons arginin-vasopressin (AVP or ADH) and oxytocin, suprachiasmatic jnucleus (SCN) which is a central pacemaker of daily rhythms
Preoptic region is rich in GnRH.

8. SCHEMATIC DRAWING OF HYPOTHALAMIC NUCLEI
AC: anterior commissure PO: preoptic nucleus SC: suprachiasmatic nucleus OC: optic chiasma TC: tuber cinereum AP: anterior pituitary IN: infundibulum: posterior pituitary ME: median eminence AH: anterior hypothalamic nucleus SO: supraoptic nucleus TH: thalamus PV: paraventricular nucleus (not to be confused with periventricular nucleus, which is not shown) DM: dorsomedial nucleus VM: ventromedial nucleus AR: arcuate nucleus (associated with periventricular nucleus, which is not shown) LT: lateral nucleus PN: posterior nucleus MB: mamillary body

9. SCHEMATIC CROSS SECTION OF HYPOTHALAMUS
suprachiasmatic
Ganong and Hall, 2006
Guyton and Hall, 2006

10. CROSS-SECTION OF THE ROSTRO - MEDIAL PART OF THE BRAIN

11. CROSS- SECTION OF THE MIDDLE PART OF THE BRAIN

12. HISTOCHEMICAL STAINING OF HYPOTHALAMIC NUCLEI

13. HYPOTHALAMIC HORMONES
SECRETED HORMONE
abbr
PRODUCED BY
EFFECT
Thyrotrophic-releasing hormone (Prolactin-releasing hormone)
TRH, PRH
Parvocellular neurosecretory neurons
Stimulate thyroid-stimulating hormone (TSH) release from anterior pituitary (primarily) Stimulate prolactin release from anterior pituitary
Dopamine (Prolactin-inhibiting hormone)
DA or PIH
Dopamine neurons of the arcuate nucleus
Inhibit prolactin release from anterior pituitary
Growth hormone-releasing hormone
GHRH
Neuroendocrine neurons of the Arcuate nucleus
Stimulate Growth hormone (GH) release from anterior pituitary
Somatostatin (growth hormone-inhibiting hormone)
SS, GHIH, or SRIF
Neuroendocrine cells of the Periventricular nucleus
Inhibit Growth hormone (GH) release from anterior pituitary Inhibit thyroid-stimulating hormone (TSH) release from anterior pituitary
Gonadotropin-releasing hormone
GnRH or LHRH
Neuroendocrine cells of the Preoptic area
Stimulate follicle-stimulating hormone (FSH) release from anterior pituitary Stimulate luteinizing hormone (LH) release from anterior pituitary
Corticotropin-releasing hormone
CRH
Stimulate adrenocorticotropic hormone (ACTH) release from anterior pituitary
Oxytocin
Magnocellular neurosecretory cells
Uterine contraction Lactation (letdown reflex)
Vasopressin (antidiuretic hormone)
ADH or AVP
Magnocellular neurosecretory neurons
Increase in the permeability to water of the cells of distal tubule and collecting duct in the kidney and thus allows water reabsorption and excretion of concentrated urine

14. HYPOTHALAMO – PITUITARY CONNECTION
Neurons of medial and preoptic hypothalamus end in the external layer of median eminence. Here they secrete neurohormones into primary plexus of portal vein system which converges along the pituitary stalk into the long veins. The neurohormones are then transported to adenopituitary secretory cells by veins of secondary blood plexus.
The existence of releasing / inhibiting hormone dates back to early 70-ties of the last century, when in was first proved that adenipotuitary is regulated by humoral factors coming from the hypothalamus.
Many neurohormones are produced also in GIT and are released into circulation. Therefore the concentration of releasing hormones in portal blood must be higher than in peripheral blood system.

15. HYPOTHALAMO – PITUITARY CONNECTION

16. HYPOTHALAMO-PITUITARY REGULATION

17. DEVELOPMENT AND STRUCTURE OF PITUITARY
posterior
anterior
diencephalon
Rathke’s pouch
of pharynx
neural tissue
ectoderm
pars tuberalis
pars distalis
pars intermedia
pars nervosa

18. HYPOTHALAMO - PITUITARY SYSTEM
Primary capilary
plexus
Neural lobe
Adenopituitary
Anterior lobe
Oxytocin
Vasopresin
ACTH, GH,
TSH, LH, FSH, Prolactin
Secretory
cells
Chiasma
opticum
Nc. supraopticus
Nc. paraventricularis
Portal vein *
magnocellular
parvocellular
Hypothalamic neurons
secreting releasing, inhibiting
hormones (nuclei:nARC, mPOA NPE)

19. INNERVATION OF ANTERIOR AND POSTERIOR PITUITARY BY NEURONES OF PARAVENTRICULAR AND SUPRAOPTIC NUCLEI

20. STRUCTURES OF ARGININE VASOPRESSIN AND OXYTOCIN

21. LIST OF PITUITARY HORMONES

22. STRUCTURE OF PROOPIOMELANOCORTIN
PC1 – PROHORMONE CONVERTASE1
PC2 – PROHORMONE CONVERTASE2

23. REGULALION OF ENDOCRINE HYPOTHALAMUS
Feedback regulations
Neural inputs mainly from higher CNS centers
Inputs from peripheral blood - leptin, ghrelin, insulin, cytokines , adenopituitary hormones, plasma levels of glucose, osmolality, steroid hormones (gonadal steroids and corticosteroids)
Light - photoperiod for the synchronization of circadian rhythms
Stress – various stress stimuli depending on the character of stressor

24. FEEDBACK REGULATIONS

25. REGULATION OF HYPOTHALAMIC HORMONES BY SHORT LOOP AND ULTRASHORT LOOP FEEDBACK

26. REGULATION OF HYPOTHALAMIC HORMONES BY COMPLEX FEEDBACK
SDDDDDDDDDDD

27. NEURAL STIMULI OF THE HYPOTHALAMUS

28. NEURON synaptic buttons myelin Ranvier cleft axon dendrites
oligodendroglia
nucleus
mitochondrion
vesicles with mediator
exocytosis
synapse
postsynaptci
receptots

29. NEUROTRANSMITTER SYSTEMS REGULATING HYPOTHALAMIC SECRETION
DOPAMINE
SEROTONIN
NORADRENALINE
nigrostriatal pathway
mesocortical pathway
tuberoinfundibular pathway v

30. NEUROTRANSMITTES REGULATING INDIVIDUAL RELEASING HORMONES
Although many findings come from animal studies and cannot be applied to human physiology absolutely, the principal regulatory mechanisms are equal.
It is generally accepted that central noradrenaline plays a pivotal role in stimulation of GHRH, CRH, AVP a TRH.
The effect of noradrenaline on GnRH is unequivocal.
Central serotonin stimulates the secretion of GHRH and also pituitary prolactin via its not yet known releasing hormone.
Central dopamine participates in the inhibition of GnRH and in stimulation of CRH. CRH is also stimulated by acetylcholine.

31. BLOOD BORNE STIMULI OF THE HYPOTHALAMUS

32. BLOOD BRAIN BARRIER (BBB)
Neurotransmitters and other molecules affecting neurosecretory activity of the hypothalamus (toxins, inflammatory agents) are found also in the circulation.
Hypothalamus is protected from these influences by blood brain barrier (BBB).
BBB is a complex mechanism regulating exchange of mediators between blood and CNS. It functions as protection from harmful stimuli (toxins) and also as transport system (for example glucose) into brain.
BBB represented by tight junctions between endothelial capillary cells which are 100 times tighter than junctions in peripheral veins. These junctions are formed by ineractions of transmembrane proteins (claudins, occludins), adhesion molecules and cytoplasmic proteins (zona ocludens) bound to cytoskeletal actin filaments.
BBB undergoes dynamic change during maturation, aging, under the influence of toxins or stress.
For neuroendocrine secretion it is important that not all areas in brain are protected by BBB. These are: pineal gland, posterior pituitary, median eminence, and region around the third ventricle: area postrema, subcommissural organ, subfornical organ and organom vasculosum laminae terminalis

33. BRAIN ENDOTHELIAL CELL – CELL TIGHT JUNCTIONS
transmembrane molecules
adhesion molecules
linked to actin skeleton
Engelhardt and Sorokin, 2009

34. AREAS WITHOUT BLOOD BRAIN BARRIER
OVLT - organum vasculosum laminae terminalis; SFO – subfornical organ; ME – median eminence; SCO – subcomissural organ; PG – pineal gland; PL – posterior lobe; AP - area postrema;

35. MODULATION OF ADENOPITUITARY RESPONSIVENESS TO HYPOTHALAMIC REGULATION

36. HYPOTHALAMIC REGULATION OF FOOD INTAKE

37. PHYSIOLOGY OF GROWTH HORMONE - GH
INCREASES PROTEIN SYNTHESES
DECREASES UTILIZATION OF CARBOHYDRATES IN MUSCLE
STIMULATES OSTEOBLAST GROWTH AND IGF-I
HIGH LEVELS ARE DIABETOGENIC
STIMULATES IMMUNE SYSTEM

38. REGULATION OF GROWTH HORMONE (GH ) SECRETION

39. GROWTH HORMONE CHANGES DURING THE DAY
Guytom and Hall, 2006

40. NORMAL FUNCTIONS OF GH PRODUCED BY THE BODY
Main pathways in regulation of growth and etabolism
Effects of growth hormone on the tissues is anabolic.
Increased height during childhood is the most widely known effect of GH. Height is stimulated by at least two mechanisms:
Through receptor mechanism GH directly stimulates division and multiplication of chondrocytes and osteoblasts.
GH also stimulates the production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin The liver is a major target organ of GH for this process and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. IGF-1 is generated within target tissues, thus it is an endocrine and paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth.
GH Increases calcium retention, and strengthens the mineralization of bone
GH increases muscle mass through sarcomere hyperplasia
GH promotes lipolysis, release of FFA from fat tissue and enhanced production of acetyl-CoA
GH inncreases protein synthesis by increased transport of aminoacids into cells
GH decreases glucose uptake in skeletal muscle and fat – hyperglycemic effect
GH increases glucose production by the liver
GH (in excess) promotes insulin resistance
GH stimulates the immune system

41. INSULIN-LIKE GROWTH F-1 (IGF-1) AND GROWTH
[U/ml] 10 6 4 2 1
gigantism / acromegaly
treatment - somatostatin
normal GH-deficit
(treatment – GH administration)

42. PHYSIOLOGY OF PROLACTIN - PRL
STIMULATES LACTATION (MILK PROTEIN CASEIN)
STIMULATES IMMUNE SYSTEM (DIRECT EFFECT ON IMMUNE CELL PROLIFERATION)
ANTIGONADAL ACTION (PROGESTERONE)

43. HORMONE LEVELS DURING PREGNANCY AND
LACTATION
A- HCG
B-ESTROGENS
C-PRL
D-PROGESTERONE

44. EFFECT OF BREST FEEDING ON PRL RELEASE

45. PRL levels in women after brest feeding on days
2, 4 ,6, post partum
A- good lactation
B- medium lactation
C- poor lactation
F - before feeding
G - after feeding

46. THE PINEAL GLAND Known over 2000 years
Producing hormone of the night –MELATONIN
It aggregates pigment granules containing melanin, and thus makes
the skin lighter.
Pineal gland EPIPHYSIS has a shape of a pine cone

47. HISTOLOGY OF PINEAL GLAND
The pineal is consists of connective tissue , blood vessels, glial cells, and pinealocytes (which secrete melatonin).
Pinealocytes have larger, lighter staining nuclei
glial cells have small darker staining nuclei.
With age, calcified formations appear in the pineal gland (brain sand or corpora aranacea ).

48. CIRCADIAN REGULATION OF MELATONIN PRODUCTION
HINDBRAIN
LIGH
EYE
EYE
SPINAL CORD
Superior cervicale ganglion
ß-adrenergic receptors
Synthesis of
N-acetyl
transferases
dark period
α -adrenergic receptors

49. 24-HOUR SECRETION OF MELATONIN IN HEALTHY AND ARTHRITIC RATS** ** ** + ** +

50. CIRCADIAN SYNCHRONIZATION
CIRCADIAN OSCILATOR - SCN
Principle of the circadian rhythmicity of the SCN are feedback
mechanisms of clock genes
SYNCHRONIZATION of the internal environment is the light/dark cycle
Synhesis and release of melatonin is regulated from SCN, but
synchronized by light/dark cycle.
RHYTHM of melatonin secretion is indicator of CIRCADIAN
PACEMAKER
EFFECTS OF MELATONIN:
improves quality of sleep
activates immune system
antioxidant (prevents oxidative stress)