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1

The key to understanding the endocrine system is the concept of homeostasis.

a. There is continuing feedback and feed forward interaction between the various endocrine glands both by circulating levels of hormones as well as products of intermediary metabolism.

b. Multiple points of regulation allow subtle as well as large-scale manipulation of various endocrine functions but they also provide multiple points of dysfunction.

2

Hypothalamus

Large Summary

a. The hypothalamus forms the interphase between the brain and the endocrine system.

b. The connection between the anterior pituitary and the hypothalamus consists of a very specialized structure known as the hypothalamo-hypophyseal portal system.

c. Blood enters the median eminence through the superior hypophyseal arteries, which forms a capillary plexus.
i. Nerve terminals of appropriate hypothalamic neurons terminate here, (the capilllary plexus) and their neurohormones are released into this capillary bed and then are transported via the portal system vasculature to a second capillary plexus in the anterior lobe.

d. The ability of the plexus to have an easy access to the released hypothalamic hormones is because it lies outside the blood brain barrier.

e. Another consequence of this specialized structure is that hormones secreted by the involved hypothalamic neurons reach the anterior lobe relatively undiluted and thus at higher concentrations than would be achieved if they had been released into the general circulation.

f. Further, hypothalamic hormones act on a local rather than distant target.
i. If the portal system is severed or the anterior pituitary is transplanted elsewhere (where it may even become vascularized), secretion of anterior pituitary hormones will no longer be subject to normal hypothalamic control.

3

Hypothalamo-hypophyseal portal system

a. The connection between the anterior pituitary and the hypothalamus consists of a very specialized structure known as the hypothalamo-hypophyseal portal system.

b. Blood enters the median eminence through the superior hypophyseal arteries, which forms a capillary plexus.

c. Nerve terminals of appropriate hypothalamic neurons terminate at the capilllary plexus and their neurohormones are released into this capillary bed and then are transported via the portal system vasculature to a second capillary plexus in the anterior lobe.

d. Hypothalamic hormones are released into the capillary plexus in the median eminence and travel a relatively short distance, for a hormone, to the anterior pituitary.
i. Here, they regulate the secretion of hormones by the anterior pituitary into the general circulation.

4

Hypothalamo-hypophyseal portal system

Why its circulation is separate from the rest of the body

a. These two capillary plexus (the hypothalamic and anterior pituitary) are separate circulation from the rest of the body

b. Importance of isolated portal system: hormones secreted by hypothalamic neurons reach the anterior lobe relatively undiluted and thus at higher concentrations than would be achieved if they had been released into the general circulation.

c. Further, hypothalamic hormones act on a local rather than distant target.
i. If the portal system is severed or the anterior pituitary is transplanted elsewhere (where it may even become vascularized), secretion of anterior pituitary hormones will no longer be subject to normal hypothalamic control.

5

Hormones leaving the Hypothalamus and traveling to the Ant. Pituitary

a. Hypothalamic hormones are released into the capillary plexus in the median eminence and travel a relatively short distance, for a hormone, to the anterior pituitary.

b. Here, they regulate the secretion of hormones by the anterior pituitary into the general circulation.

c. The hypothalamic hormones are peptides, except for dopamine (DA), which is a catecholamine, and are usually considered in relation to the anterior pituitary hormone's secretion that they influence.

6

Actual hormones released from Hypothalamus to Anterior Pituitary

1. Thyrotropin releasing hormone (TRH)
i. tripeptide
ii. Ant Pit: Increase TSH; Increase PRL

2. Gonadotropin releasing hormone (GnRH)
i. decapeptide
ii. Ant Pit: Increases LH; Increases FSH

3. Corticotropin releasing hormone (CRH)
i. 41 amino acids
ii. Ant Pit: Increases POMC ; Increases ACTH

4. Growth hormone releasing factor (GHRH)
i. 14 amino acids
ii. Ant Pit: Increases GH

5. Somatostatin (GH inhibiting hormone; GIH)
i. 14 amino acids
ii. Ant Pit: decreases GH; decreases TSH

6. Prolactin inhibiting factor (PIH)
i. Dopamine (DA)
ii. Ant Pit: decreases PRL

7

Side notes of these hormones released from Hypothalamus to the Ant Pituitary

a. As suggested by the nomenclature, some of these hormones stimulate while others inhibit the secretion of hormones from the anterior pituitary.
i. In some cases, factors have been identified that stimulate and others that inhibit the secretion of the same hormone, e.g., GHRH and somatostatin stimulate and inhibit, respectively, the secretion of GH.

b. The hypothalamic hormones are peptides, except for dopamine (DA), which is a catecholamine, and are usually considered in relation to the anterior pituitary hormone's secretion that they influence.

1. Thyrotropin releasing hormone (TRH)
i. tripeptide
ii. Ant Pit: Increase TSH; Increase PRL

2. Gonadotropin releasing hormone (GnRH)
i. decapeptide
ii. Ant Pit: Increases LH; Increases FSH

3. Corticotropin releasing hormone (CRH)
i. 41 amino acids
ii. Ant Pit: Increases POMC ; Increases ACTH

4. Growth hormone releasing factor (GHRH)
i. 14 amino acids
ii. Ant Pit: Increases GH

5. Somatostatin (GH inhibiting hormone; GIH)
i. 14 amino acids
ii. Ant Pit: decreases GH; decreases TSH

6. Prolactin inhibiting factor (PIH)
i. Dopamine (DA)
ii. Ant Pit: decreases PRL

8

Hypothalamus Input

The hypothalamus receives inputs from the thalamus, limbic system including:
i. olfactory bulb, hippocampus, habenula and amygdala, the retina,
ii. reticular activating substance and the neocortex
iii. information regarding pain, sleep versus wakefulness, emotions, fright, rage, olfactory sensations
iv. light reaches the hypothalamus and can affect the activity of the neurosecretory neurons.

9

Stimulus-dependent secretion of the hypothalamus

a. Stimulus-dependent secretion of hypothalamic hormones occurs in a manner similar to neurotransmitter release.

b. In brief, appropriate stimulation of a hypothalamic neuron will result in generation of action potentials

c. At the nerve terminal, calcium entry through voltage-dependent calcium channels will lead to liberation of hormone (versus neurotransmitter) from secretory vesicles.

d. Thus, just as for neurotransmitter release, hormone secretion from hypothalamic neurons is calcium-dependent.

10

Cellular mechanisms of action of hypothalamic hormones:

a. At a cellular level, the hypothalamic hormones interact with specific receptors on their appropriate target cells in the anterior pituitary.
i. The intracellular signaling cascades are the subject of much current investigation.

b. One point of agreement is that extracellular calcium is required for the release.
i. Involvement of calcium release from intracellular stores is still debatable.

c. The hormones bind to their respective receptors, which in turn are coupled to various G-proteins.
i. CRH and GHRH receptors are coupled to Gs and, upon activation, stimulate adenylate cyclase to produce cAMP in corticotrophs and somatotrophs, respectively.
ii. In contrast, the interaction of somatostatin with Gi eventually leads to a decrease in cAMP.
iii. Similarly, DA leads to a reduction in cAMP levels in lactotrophs.
iv. CRH also leads to an increase in the rate of transcription of POMC and formation of ACTH.

11

Summary of Hypothalmic Hormone effect on the Anterior Pituitary

a. In sum, although release of hormone from anterior pituitary cells is dependent upon calcium, evidence exists implicating several intracellular signaling cascades to different degrees in the various pituitary cells.

b. Membrane conductances also appear to play a role.

c. These intracellular cascades are probably also involved in regulating the synthesis of various pituitary hormones.

12

The Pituitary Gland

Summary

a. The pituitary gland acts as an endocrine control center responding to neural signals, and catering to the needs of various target tissues (e.g.,thyroid, gonads, adrenal gland, bone), coordinating and regulating their functions.

b. The gland is attached to a region of the brain (hypothalamus) by a structure known as the pituitary stalk.
i. This anatomical connection is necessary for the functional interactions between the brain and pituitary.

c. The pituitary consists of two major divisions, the anterior (adenohypophysis) and the posterior hypophysis (neurohypophysis).

d. The anterior pituitary is derived from an embryological structure known as Rathke's pouch (pharyngeal epithelium)
i. the intermediate pituitary is also found within the adenohypophysis, but is extremely small in humans and not thought to be of functional significance.

e. The posterior pituitary is derived from neural tissue arising from an embryological evagination of the diencephalon.

13

What the anterior and posterior pituitary come from

a. The anterior pituitary is derived from an embryological structure known as Rathke's pouch (pharyngeal epithelium)

b. The posterior pituitary is derived from neural tissue arising from an embryological evagination of the diencephalon.

14

Adenohypophysis- the Anterior Pituitary gland

a. The anterior pituitary is comprised of the pars tuberalis, pars intermedia (intermediate lobe) and the pars distalis (anterior lobe).
i. We will focus on the anterior lobe/ pars distalis, since the hormones of the anterior pituitary are secreted from this structure.

b. Six hormones are released from the anterior lobe. Their secretion is under control of the hypothalamic hormones

1. TRH acts on cells called thyrotrophs to stimulate the secretion of TSH

2. GnRH acts on gonadotrophs to stimulate the secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH)

3. GHRH and somatostatin act on somatotrophs to stimulate and inhibit, respectively, the secretion of growth hormone (GH)

4. CRH acts on corticotrophs to stimulate the secretion of corticotropin (ACTH) and proopiomelanocortin (POMC);

5. prolactin inhibiting hormone (PIH, thought to be DA) and prolactin releasing factor (PRF, perhaps TRH?) act on mammotrophs to inhibit and stimulate, respectively, the secretion of prolactin (PRL).

15

Pulsatile Secretion and Endocrine Rhythms

a. The release of hormones from the anterior pituitary is not constant over time but instead is quite varied and described as pulsatile.

b. There are periods of higher release followed by periods of diminished release.
i. Thus, the plasma levels show spikes or pulses.

c. It may be that this type of secretion is directed by pulsatile secretion of the stimulating (or inhibiting) hypothalamic hormone.
i. Evidence for this mechanism is strong for LH, FSH (GnRH pulse generator) and ACTH.

d. Pulsatile, rather than continuous, secretion of hypothalamic hormones is the effective signal guaranteeing appropriate stimulation of the anterior pituitary.

16

Neurohypophysis- the posterior pituitary

Large Summary

a. The posterior pituitary is formed from the evagination of the diencephalon and is thus directly connected to the hypothalamus and brain.

b. It consists of three parts - the median eminence, infundibular stem and the infundibular process (pars nervosa).

c. Posterior pituitary hormones are synthesized in the hypothalamus in two nuclei- the supraoptic nucleus, which and the paraventricular nucleus.
i. These nuclei have two cell types, both of which produce the hormones-
1) the magnocellular neurons, whose processes extend into the posterior pituitary and end in the pars nervosa and
2) the parvocellular neurons, which end at the median eminence close to the endings of hypothalamic neurons that produce the anterior pituitary regulating hormones.

d. Thus, some of the posterior pituitary hormones can reach the anterior lobe where they can have some functions e.g. ADH can act on corticotrophs to increase ACTH production.

e. Cortisol, regulated by ACTH, can in turn, inhibit both ADH function in the kidneys and release at the hypothalamus.

17

Posterior pituitary hormones are synthesized in the hypothalamus in two nuclei

a. Posterior pituitary hormones are synthesized in the hypothalamus in two nuclei- the supraoptic nucleus and the paraventricular nucleus.

b. These nuclei have two cell types, both of which produce the hormones-
1) the magnocellular neurons, whose processes extend into the posterior pituitary and end in the pars nervosa
and
2) the parvocellular neurons, which end at the median eminence close to the endings of hypothalamic neurons that produce the anterior pituitary regulating hormones.

18

The neurohypophysis (post pituitary) secretes two nonapeptides

a. The neurohypophysis secretes two nonapeptides, antidiuretic hormone (ADH) and oxytocin.
i. Both are synthesized in the cell bodies of large hypothalamic neurons known as magnocellular neurons.

b. ADH and oxytocin are synthesized as part of a larger prohormone.
i. The prohormone is packaged into secretory vesicles and cleaved into the hormone and a protein called neurophysin (function unknown) as the vesicles travel down the axon of the neuron to the posterior pituitary.

c. The vesicles are released when an action potential invades the terminal, activating calcium channels.
i. Calcium influx occurs, leading to a rise in intracellular calcium and neurosecretion.

19

Antidiuretic hormone (ADH)

a. ADH is secreted in response to an increase in plasma osmolarity or a decrease in blood pressure.

b. ADH acts on the cells of the renal tubule and collecting ducts to alter water permeability and conserve water.

c. At high concentrations it is a powerful pressor agent, acting to increase blood pressure; for this reason, it was originally called vasopressin.

d. There are two kinds of ADH receptors:
i. V1 coupled to Gq and the Phospholipase C pathway, mediates the vasopressive action of ADH
ii. V2 coupled to Gs and the cAMP pathway regulates the effects of ADH on glomerular filtration rates in the kidney.

20

There are two kinds of ADH receptors:

a. Two Receptors:
1. V1 coupled to Gq and the Phospholipase C pathway, mediates the vasopressive action of ADH

2. V2 coupled to Gs and the cAMP pathway regulates the effects of ADH on glomerular filtration rates in the kidney.


b. ADH acts on the cells of the renal tubule and collecting ducts to alter water permeability and conserve water.
i. At high concentrations it is a powerful pressor agent, acting to increase blood pressure; for this reason, it was originally called vasopressin.

21

Oxytocin

a. Oxytocin is secreted in three interpersonal situations:
1. During the passage of the infant through the cervix at childbirth.

2. During sexual intercourse.

3. In response to suckling by the infant during breast-feeding. This neuroendocrine reflex can be conditioned.

b. Oxytocin acts on the uterus around the time of birth to cause contraction of the myometrium.
i. In the lactating woman it causes contraction of myoepithelial cells, producing milk ejection.

22

Hypothalmic Pituitary Axis

a. Hypothalamus contains cell bodies (neurons) that will communicate with the Pituitary. These hypothalmic neurons are in the Median Eminence
i. posterior pituitary is part of the hypothalamus; axons will travel from the hypothalamus to carry hormones to the post. pituitary
ii. anterior pituitary is seppearte from the hypothalamus; it developed from Rathke's pouch

b. There is not a direct connection between the anterior pituitary and the hypothalamus
i. This is solved by the Hypothalamo-Hypophyseal portal system
ii. Critical portal system that allows high concentration of hormones to the ant. pituitary

23

Median Eminence Phsyiology

a. The median eminence is a part of the hypothalamus from which regulatory hormones are released.

b. It is of great physiological importance, as it is integral to the hypophyseal portal system, which connects the hypothalamus with the anterior pituitary gland.

c. The pars nervosa (part of the posterior pituitary gland) is continuous with the median eminence of the hypothalamus via the infundibular stalk.

d. Parvocellular neurons from the hypothalamus terminate in the median eminence of the hypothalamus.

e. To be specific, it is in the median eminence that the secretions of the hypothalamus (releasing and inhibiting regulatory hormones, known as "hypophysiotropic hormones") collect before entering the portal system. Such hypophysiotropic hormones include: CRF (corticotropin-releasing factor), GnRH (gonadotropin-releasing hormone), TRH (thyrotropin-releasing hormone), GHRH (growth hormone-releasing hormone), and DA (dopamine).

f. These hypophysiotropic hormones go on to stimulate or inhibit the release of hormones from the anterior pituitary.

24

Median Eminence and the Ant. Pituitary

a. Median Emincence is of great physiological importance, as it is integral to the hypophyseal portal system, which connects the hypothalamus with the anterior pituitary gland.

b. To be specific, it is in the median eminence that the secretions of the hypothalamus (releasing and inhibiting regulatory hormones, known as "hypophysiotropic hormones") collect before entering the portal system.

c. Such hypophysiotropic hormones include: CRF (corticotropin-releasing factor), GnRH (gonadotropin-releasing hormone), TRH (thyrotropin-releasing hormone), GHRH (growth hormone-releasing hormone), and DA (dopamine).

d. These hypophysiotropic hormones go on to stimulate or inhibit the release of hormones from the anterior pituitary.

25

Hormones released from Hypothalamus to Anterior Pituitary

*Great list

Hormones released from the median eminence to the Ant. Pituitary
*RH ---> releasing hormone
1. TRH
i. only 3 amino acid size
ii. works on Thyrotroph cells to cause TSH release

2. CRH
i. is 40 amino acid size
ii. Works on Corticotrophs to release ACTH

3. GnRH
i. Works on gonadotrophs to release LH and FSH

4. GHRH
i. works on Somatotrophs--> will release growth hormone

5. Somatostatin
i. works on Somatotrophs---> will Decrease Growth hormone

6. PIH (prolactin inhibiting hormone)--> Dopamine
i. Decrease prolactin release

These hormones are all peptide hormones (except dopamine)

26

The six hormones from the Median Eminence will act upon the Ant. Pituitary

a. All 6 hormones act upon G-protein coupled receptors
i. disassociated g-proteins will cause the effect
ii. Will lead to downstream effects

b. Types of G-proteins
1) Gs---> lead to increase of Adenylate Cyclase---> increase cAMP
i. will increase protein kinase a and other proteins

2) Gi--> leads to decrease of Adenylate Cycle---> lower cAMP
i. Somatostatin and Dopamine have this effect

3) Gq--->PIP2---> increase IP3 and DAG
i. IP3 ill increase Ca2+ amount
ii. DAG will increase protein Kinase C

27

Great G-protein review

1) Gs---> lead to increase of Adenylate Cyclase---> increase cAMP
i. will increase protein kinase a and other proteins

2) Gi--> leads to decrease of Adenylate Cycle---> lower cAMP
i. Somatostatin and Dopamine have this effect

3) Gq--->PIP2---> increase IP3 and DAG
i. IP3 ill increase Ca2+ amount
ii. DAG will increase protein Kinase C

28

Prolactin

a. Prolactin is a protein hormone that is released by Lactorophes in the anterior pituitary
i. released by Ca2+ dependent exocytosis

b. Prolactin is carried mostly freely in blood (still researched), short half-life due to proteases (30 min half life)

c. Prolactin Target: Will reach target cell membrane receptor (Prolactin Receptor). This receptor belongs to the Cytokine family
i. Cytokine family are large membrane receptors, will have 2 binding sites for prolactin

d. Binding of Prolactin to the Prolactin receptor (Cytokine receptor) will activate Janus Kinase
i. Janus kinase is a tyrosine kinase, will phosphorylate a bunch of signal transducers that lead to transcription inside the nucleus
ii. also Janus kinase will phosphoralte Activates of Transcription (STATS)
iii. Called JAK-STAT activation in total

29

When Prolactin reaches its target-
Cellular Mechanism

a. Prolactin Target: Will reach target cell membrane receptor (Prolactin Receptor). This receptor belongs to the Cytokine family
i. Cytokine family are large membrane receptors, will have 2 binding sites for prolactin

b. Binding of Prolactin to the Prolactin receptor (Cytokine receptor) will activate Janus Kinase

c. Janus kinase is a tyrosine kinase, will phosphorylate a bunch of signal transducers that lead to transcription inside the nucleus
i. also Janus kinase will phosphoralte Activates of Transcription (STATS)
ii. Called JAK-STAT activation in total

d. JAK-STAT is the major tyrosine kinase pathway of cytokine receptors

30

Prolactin effect on Mammary Gland

a. Primary function is to regulation milk release from mammary gland

b. Prolactin will cause 3 process:
1. Mammogenisis--> growth of mammary gland
2. Lactogenesis--> getting glands ready for milk production
3. Galacoporesis---> synthesis and release of milk

c. Dysfunction of prolactin--> dysfunction in milk production

d. Dopamine will inhibit the production of Prolactin
i. Dopamine will cause increased Gi protein function at Ant Pituitary, lower porlactin production

e. It appears TRH (thyroid releasing hormone) will cause increased prolactin release

f. Estrogen and Progesterone will modify the different functions of prolactin
i. They will increase the effect of Mammogenisis (mamillary gland devlopment)
ii. They will decrease lactogenesis and galacoporesis
*will allow breast to get ready for milk developing during pregnacy

31

Main inhibitor of prolactin release

PIH (prolactin inhibiting hormone)--> Dopamine
i. Decrease prolactin release

Dopamine will inhibit the production of Prolactin
i. Dopamine will cause increased Gi protein function at Ant Pituitary, lower porlactin production

32

Dysfunction of Prolactin

a. Hyper-Prolactin
i. Overgrowth of mamallary gland
ii. Amenorrhea (disruption of mentral cycle)
iii. Loss of Libido

b. Hypo-Prolactin
i. Sheehan's Syndrome--> failure to lactate