LECTURE 1

Intro:

Fundamentals of Endocrinology:

• Hypothalamus + pituitary gland → master controllers of the endocrine system

The endocrine system is built on axes and many of the axes involves the hypothalamus and the pituitary gland → control organs then exert a control on the final endocrine gland

which produces a hormone that produces an effect.

ILOs:

1. Describe the links of the hypothalamus to the anterior pituitary and also to the posterior pituitary and to recognize that those are actually very different connections.

2. Describe the role of the regulatory hypothalamic hormones which act on the anterior pituitary in order to cause the release of other hormones. This involves the feedback loops and axes.

3. Be able to name and list the functions of the main hormones of both the anterior and posterior pituitary and know what their target organs.

There are two main systems that control all physiological processes within the body:

The nervous system → this exerts point to point control through the nerves electrically allowing fast control + communication with tissues.

Endocrine system → Sends chemical messengers (hormones) around the body through the bloodstream.

• The body tissues that would be responsive to that hormone must express a receptor that is very specific for that hormone.

• The nervous and endocrine systems are connected and communicate with each other and together coordinate the activities of different body tissues.

• The information that's used by the endocrine system to exert this control can come from both the external environment like the external temperature for example, or the internal environment of the body.

• And this cross talk between the endocrine and the nervous system enables the body to adapt and respond to the environmental changes.

There are many different endocrine glands:

• Pineal

• Hypothalamus

• Pituitary

• Thyroid

• Parathyroids

• Thymus

• Adrenals

• Pancreas

• Ovaries

• Testes

• Adipose Tissue → Largest → present all over body → Secretes many different types of hormones

Hormones can communicate through many basic mechanisms:

Signalling can be:

Endocrine communication:

Where a hormone releases it’s chemical messenger into blood vessels → circulates → picked up by target cell with specific receptor for that hormone.

Local:

Autocrine → cell secretes signaling molecules that bind to receptors on its own surface, leading to changes or responses within the same cell.

Paracrine → Secretes signaling molecules that affect nearby cells in the immediate vicinity. These molecules act on neighboring cells, leading to localized responses.

Neuroendocrine:

A neuronal/nerve cell is capable of producing a hormone, which will then be released from its axon at the nerve terminal into the blood stream and then it can be circulated. Okay. So this is neuroendocrine.

Neurotransmitter:

Neurone secretes a chemical messenger which binds to another neuron, sometimes these can be hormones too, circulating into the bloodstream or working on adjacent cells.

Difference:

Neuroendocrine signaling involves hormones acting at a distance, while neurotransmitters act locally at synapses.

The hypothalamo - Pituitary Axis:

1. Example a change in the temperature in the environment would be picked up by the hypothalamus.

2. The hypothalamus will then sell send a signal via neuroendocrine methods to the anterior pituitary gland.

3. This will then release another chemical messenger into the blood

4. This chemical messenger can either be what we call non - tropic where it has a direct action on tissues in the body

5. Or it can be tropic where that signal goes to another endocrine gland + then endocrine glands will produce another hormone which then has an action on the body so you can see those potentially three different levels of of control, within the axis.

Hypothalamus:

• located just below the thalamus and above the brainstem and it's really important for the control of very basic functions in the body such as hunger, thirst, sleep and for the control of many different hormones that are important for physiology.

Pituitary Gland (aka Hypophysis)

• Sits in this bony cavity.

• Has a bone around it is called the sphenoid bone and the pituitary gland sits inside.

→ If you happen to get a pituitary tumor that tumor would not be able to grow downwards because of the sphenoid bone instead would push up onto the optic nerve → visual symptoms.

→ The pituitary gland dangles down from the hypothalamus + is connected to the hypothalamus by the infundibulum.

→ And I'll talk about the role of the infundibulum n both the anterior pituitary

and the posterior pituitary.

Pituitary gland:

Two different lobes: anterior pituitary + posterior pituitary gland → these have completely different roles in the body and don’t have any direct neuronal connections → joined but don’t communicate.

How the Anterior Pituitary Gland Connects to the Hypothalamus: (Circulatory System Link)

• Parvocellular neurones in hypothalamus secrete regulatory hormones into the portal blood system → control cells in anterior pituitary gland → anterior pituitary will secrete another hormone to rest of body.

• Made of neuronal cells → completely different tissue to posterior.

Communication:

• The hypothalamus exerts control of the anterior pituitary by releasing regulatory (releasing + inhibitory) hormones.

• Does not have a direct nervous connection with the hypothalamus only through capillaries.

• Hormones secreted by the hypothalamus reach the target cells of the anterior pituitary by the hypothalamic - pituitary portal system.

• How the Posterior Pituitary Gland Connects to the Posterior Pituitary Gland: (Direct - Neuro endocrine link).

• Magnocellular neurons in the hypothalamus have long axons which extend down into the posterior pituitary lobe.

• Made of nervous tissue.

Communication:

• Posterior hormones produced in hypothalamus + transported down long axon + stored at nerve terminals in the posterior pathway.

• Stimulus causes release of these hormones from end of axons + into blood supply of posterior pituitary gland.

Look at slide 13 table

Hormones released by hypothalamus effect either:

• Directly on tissues like prolactin on the breasts and growth hormone on the liver

and other cells throughout the body

or

• those hormones from the anterior pituitary will act on other endocrine glands to cause the release of other hormones.

Function of the anterior pituitary hormones → The Tropins (FLAT)

• Regulate function of other endocrine glands to produce effector hormones:

FSH - Secreted + synthesised + stored by gonadotropins →

- Stimulates the ovaries to produce estrogen + testes to produce testosterone.

LH - Secretes + synthesised + stored by gonadotropins →

- Role in ovulation + in the growth of corpus luteum during menstruation.

- Stimulates androgen secretion by interstitial cells in testes.

ACTH - synthesised + stored + secreted from corticotropes →

- Stimulates the adrenal gland cortex region to produce the corticosteroids

such as aldosterone and cortisol

- involved in the stress response in the body

TSH - Synthesized + stored + secreted from the thyrotropes in the anterior pituitary →

- Stimulates thyroid gland to produce thyroid hormones such as T3 and T4.

Example -

Thyroid hormone → Low temp → reduction in core temp → detected by neurones in the hypothalamus → release of thyrotropin - releasing - hormone - travels in blood → stimulates anterior pituitary to produce thyroid stimulating hormone → enters blood + acts on thyroid gland to produce thyroid hormones → T3 act on cells with correct receptors → increases metabolism → produces heat as byproduct - elevates core body temp.

• Heat is produced in the body that's going to have a physiological feedback effect.

• Hypothalamus will no longer be detecting that the body temperature is too low.

• Helps to reduce the amount of thyroid hormone TSH and the regulatory hormones that are produced so that the body can stabilize.

BUT there are also other feedback mechanisms that you need to be aware of which are actually really important for the control of the hypothalamus and pituitary and these are the short Loop feedback which comes from T3 acting on the anterior pituitary gland to reduce production of TSH.

then

Long Loop feedback which jumps in on this control system so that the T3 will actually inhibit the hypothalamus from producing TRH as well.

Three feedback loops for CRH + ACTH:

1. Ultra short feedback Loop: (Only seen in this system) → Cortisol produced inhibits the release of both CRH and ACTH. It's a more direct and localized feedback loop compared to the positive feedback system.

2. Short Loop Negative Feedback: After cortisol is released by the adrenal glands, it can inhibit the release of both CRH from the hypothalamus and ACTH from the pituitary gland. This negative feedback loop helps regulate the levels of cortisol in the body.

3. Long Loop Negative Feedback: In this loop, cortisol produced by the adrenal glands can also act on the hypothalamus and pituitary gland to inhibit the release of CRH and ACTH, respectively. This long loop negative feedback helps maintain the balance of cortisol in the body.

Function of anterior pituitary hormones: Non - Tropic Hormones → prolactin and

growth hormone.

Prolactin →

• Prolactin is produced by the lactotrophs in the anterior pituitary.

• Roles and functions are actually quite complex, but they include effects on the breast tissue for and lactation.

• Most common pituitary tumor is actually a prolactinoma and it's known that one, but it may treated quite easily using dopamine receptor agonists.

• As it's the dopamine from the hypothalamus which is usually responsible for suppressing the secretion of prolactin and examples of dopamine receptor agonists are bromocriptine and cabergoline.

Growth hormone →

• Synthesized and stored by the somatotropin cells in the anterior pituitary growth hormone.

• Stimulates growth cell reproduction and also, regeneration of some cells as well.

• If you get over secretion of growth hormone, it can cause two different types of syndromes.

• The first one is known as gigantism → when hypersecretion of growth hormone in childhood causes excess growth,

• whereas if you get hyper secretion of growth hormone in adults, it causes something different known as acromegaly and the difference in the two is because when you're n your late teens your long bones fuse and won't actually grow anymore.

• So if you have an excess growth hormone before the long bones have fused then you will get increased rapid growth of those long bones.

• Whereas later on in life. Those long bones aren't going to grow anymore. No matter how much growth hormone you throw at them and instead you'll get other symptoms such as enlargement of the head.

• Acromegaly and gigantism can be treated using somatostatin which is the natural inhibitor of growth hormone.

• It will regulate the production of growth hormone and also reduce the amount of cell proliferation

• and growth via the somatostatin receptors the synthetic synthetic analogues like octreotide which have much longer Half-Life than somatostatin and these can be used to treat those conditions.

• However, if the overgrowth is caused by a tumor then quite often they'll be surgery to remove that tumor to stop the over secretion of growth hormone.

Pituitary Dwarfism:

Insufficient production of growth hormone, which can be due to a tumor mutation of growth hormone genes or it can be from growth hormone resistance A syndrome. That's known as Laron syndrome (GH resistance).

Posterior Pituitary gland:

• Magnocellular neurones in the hypothalamus pass through the infundibulum and end in the posterior pituitary gland.

• These neurones synthesise and secrete oxytocin + vasopressin (ADH).

• The hormones are remarkably similar → differ in 2 AAs → Vasopressin = Phe + Arg → Oxytocin = Ile + Leu.

• The hormones are released at axon terminals, where they diffuse into the capillary network of the posterior lobe.

• Do not go through the portal system.

Functions of oxytocin what's got three main functions:

• Stimulation of milk ejection from the lactating mother + then prior to that obviously the stimulation of uterine muscle contraction at birth.

• Establishment of maternal Behavior.

• When the baby presses on the cervix here it activates Sensory neurons, which go back to the hypothalamus where it triggers the release of more oxytocin.

• So that oxytocin is then secreted from the posterior pituitary + binds to receptors that are found in the uterus to cause the uterus to contract.

• When you contract that uterine muscle it's going to push the baby's head on to the cervix and then trigger that sensory neuron back to the hypothalamus again to cause the release of more oxytocin so you can see this is an example of a positive feedback mechanism where secretion of the hormone is going to lead to more secretion of the hormone.

Obviously once the baby's born you stop getting pressure on the cervix. And so that positive feedback loop will be broken and the oxytocin won't be released anymore. So although oxytocin isn't the initial trigger for labor. It can actually be use for induction of artificial labor. Usually the membranes of the of the pregnant woman are swept first to break the membranes and then if that doesn't trigger labor then Artificial oxytocin will be given as well. It can be quite dangerous though. Because if the uterine muscle correct contract too much and doesn't stop Contracting it will actually stop the blood supply to the baby and that can cause Cerebral Palsy.

Vasopressin: (DH) →

• Role of vasopressin — water regulation in the body. So it will bind to receptors on cells in the collecting ducts of the kidney.

• leads to the synthesis of aquaporins aquaporin which is a water Channel.

• So once the aquaporin has been produced it's inserted into parts of the kidney to allow water re-absorption from the filtrate in the kidney go back into the blood. So that vasopressin is going to promote water reuptake into the body into the blood.

• In absence of vasopressin those parts of the kidney tubule are virtually impermeable to water which means that more water will flow out of the body as urine. So it's actually controlled by the osmolality of the blood as to whether vasopressin is secreted or not secreted.

• If you have a defect in the secretion or action of vasopressin, it leads to a disease called diabetes insipidus and this is where you get it's not related to diabetes mellitus whatsoever.

• So somebody who has diabetes insipidus could be producing as much as 16 liters of urine per day and you can → dehydration very quickly.

So the two main causes of diabetes in peace insipidus are hypothalamic or Central or nephrogenic →

Hypothalamic central:

Deficiency in vasopressin secretion and that can be caused by head trauma.

Infections or tumors that involve the hypothalamus and will stop the posterior pituitary from releasing vasopressin. It's quite easy to treat this form of diabetes insipidus because all you need to do is give exogenous vasopressin and that can be in tablet form or injection and that cures the condition completely because you're just replacing the vasopressin.

Nephrogenic diabetes insipidus:

The kidney is insensitive to the effects of vasopressin and this can be caused by various renal disease, but perhaps more often through mutations in the vasopressin receptor gene or actually in the genes which encode that aquaporin which is inserted into the membrane after vasopressin has bound to its receptor.

The only way to treat nephrogenic diabetes insipidus is by increasing water consumption. So unfortunately the person with nephrogenic Like diabetes insipidus is going to need to urinate quite frequently. But as longas they have a good access to water then they shouldn't get dehydrated and it won't be life threatening.