Endocrine System 2

What is meant by hormones of the hypothalamic-anterior pituitary-peripheral target axes?

Hormones that originate from the hypothalamus, signaling the anterior pituitary to release another hormone. The anterior pituitary hormone then stimulates peripheral endocrine glands to release hormones that elicit effects on target organs in the body.

What is the general mechanism of hormone action in the hypothalamic-anterior pituitary axis?

1) Hypothalamic neuroendocrine cells release Hormone 1 into the blood.

2) This hormone stimulates the anterior pituitary, which then releases Hormone 2 into general circulation.

3) Hormone 2 acts on either endocrine or non-endocrine target tissues.

4) If released into endocrine tissues, it stimulates the release of Hormone 3 into general circulation. If released into non-endocrine tissues, it directly causes a tissue response.

What are the characteristics of the pituitary gland?

• It is physically connected to the hypothalamus through a stalk-like structure called the infundibulum.

• The whole gland is protected by bone.

• The anterior pituitary (adenohypophysis) functions as an endocrine gland, and it is split into three components.

• The posterior pituitary (neurohypophysis) is an extension of neural tissue

What are the three components of the anterior pituitary?

1) Pars distalis: Make up the lobe itself.

2) Pars tuberalis: A sheath of tissue that partially wraps around the infundibulum.

3) Pars intermedia: Strip of tissue that lies between the two lobes, but it only exists in the fetus.

What are the two components of the posterior pituitary?

1) Pars nervosa: The main portion of the posterior pituitary, in contact with the infundibulum.

2) Infundibular stalk: Connects the pars nervosa to the hypothalamus.

How is the posterior pituitary connected to the hypothalamus?

The posterior pituitary is connected to the hypothalamus through nerve cells. The cell bodies are located in the hypothalamus, while axons travel through the infundibulum and project into the posterior lobe. This allows for a very fast and efficient connection.

How is the anterior pituitary connected to the hypothalamus?

The anterior pituitary is connected to the hypothalamus through blood vessels only (blood vessel network).

What is the role of neurosecretory cells in hormone release?

Neurosecretory cells release hormone 1, which travels to the anterior pituitary, stimulating the release of hormone 2. Hormone 2 then enters general circulation to reach its target cells and elicit a response.

What are some examples of hormones released by the anterior pituitary?

1) TSH (Thyroid-Stimulating Hormone)

2) ACTH (Adrenocorticotropic Hormone)

3) FSH & LH (Follicle-Stimulating Hormone & Luteinizing Hormone)

4) GH (Growth Hormone)

5) PRL (Prolactin)

6) Endorphins

What are some hypothalamic hormones that stimulate the pituitary?

Releasing Hormones:

• Thyrotropin-releasing hormone (TRH) – Stimulates TSH (thyroid-stimulating hormone) release

• Corticotropin-releasing hormone (CRH) – Stimulates ACTH (adrenocorticotropic hormone) release

• Gonadotropin-releasing hormone (GnRH) – Stimulates LH (luteinizing hormone) & FSH (follicle-stimulating hormone) release

• Growth hormone-releasing hormone (GHRH) – Stimulates GH (growth hormone) release

• Prolactin-releasing hormone (PRH) – Stimulates prolactin release

Inhibitory Hormones:

• Dopamine (PIH) – Inhibits prolactin release

• Somatostatin (GHIH) – Inhibits GH release

What is the mechanism of Hypothalamic -anterior pituitary- adrenal cortex axis which is also known as the stress axis?

1) When the body is stressed, the neurosecretory cells of the hypothalamus release corticotropin-releasing hormone (CRH).

2) CRH travels through the network of blood vessels connecting the hypothalamus to the anterior pituitary, where it stimulates the cleavage of pro-opiomelanocortin (POMC) to produce adrenocorticotropic hormone (ACTH).

3) ACTH then enters circulation and reaches the adrenal cortex of the adrenal glands, which sit on top of the kidneys. This stimulates the adrenal cortex to secrete increasing amounts of glucocorticoids, primarily cortisol.

4) Glucocorticoids stimulate catabolism, which is the breakdown of substances (opposite of anabolism). This includes the breakdown of muscle proteins and fat. Cortisol also stimulates the liver to convert amino acids into glucose via gluconeogenesis, leading to a rise in blood glucose levels, providing more energy.

5) Additionally, cortisol suppresses the immune system, reducing immune responses. This is why people sometimes get sick after prolonged periods of stress.

6) This process follows a negative feedback mechanism. Once the stressful period is over, cortisol signals the anterior pituitary and hypothalamus to stop secreting CRH and ACTH, preventing excess cortisol production.

What happens when our body cannot keep up with the stress that we are experiencing?

During acute stress, the body enters the resistance phase, attempting adaptation. However, if stress persists and the body cannot return to baseline, chronic stress leads to prolonged adaptation efforts. Over time, this results in failed adaptation and exhaustion.

Where exactly does CRH come from?

From the hypothalamic paraventricular nucleus.

What is the name of the cell that produces CRH?

Parvocelular neuroendocrine cells.

What type of control is CRH under?

1) CRH is under central stimulatory control, specifically noradrenergic control.

2) Noradrenergic signals stimulate the pre-proCRH gene and protein expression (196 AA).

3) This precursor is then processed into CRH (41 AA).

4) The processed CRH stimulates the pulsatile release of CRH.

What are the CRH inhibitory influences?

Physiological levels of cortisol inhibit CRH release and sometimes the pre-proCRH gene.

How does CRH stimulate the release of ACTH

1) CRH is released from neurosecretory nerve terminals at the median eminence (base of the brain) into blood vessels in the hypothalamic-pituitary portal system.

2) These blood vessels transport CRH peptides to the anterior lobe of the pituitary.

3) CRH stimulates corticotropes in the anterior pituitary to secrete adrenocorticotropic hormone (ACTH).

How is proopiomelanocortin (POMC) cleaved?

By enzymes called convertases.

What are the major products derived from POMC?

1) ACTH: Adrenocorticotropic hormone (regulates adrenal cortex function)

2) MSH: Melanocyte-stimulating hormone (skin pigmentation in response to UV radiation)

3) β-Endorphin: Analgesic role in the central nervous system

4) Enkephalin (ENK): Analgesic role in the fetus

5) MC3, MC4, MC5 receptors: Involved in hypothermia, hypotension, feeding behavior, and appetite

What are the two parts of the adrenal glands?

1) Adrenal cortex: secretes steroids

2) Adrenal medulla: secretes catecholamines (e.g., epinephrine), functioning as modified sympathetic ganglia.

Where does ACTH go after being released from the anterior pituitary?

ACTH travels to the adrenal glands, which are paired glands located on top of the kidneys. Each adrenal gland consists of an outer cortex and an inner medulla, functioning as separate glands. The adrenal cortex responds to ACTH by releasing steroid hormones called corticosteroids, such as glucocorticoids.

What are the three main types of corticosteroids?

1) Glucocorticoids (e.g., cortisol) – Controlled by ACTH; regulate the metabolism of glucose and other molecules.

2) Mineralocorticoids (e.g., aldosterone) – Controlled by the renin-angiotensin system; regulate sodium and potassium balance.

3) Sex steroids (e.g., testosterone) – Controlled by ACTH; supplement sex hormones secreted by the gonads.

What are the three categories of corticosteroids that are released from the adrenal cortex derived from?

Cholesterol

What are the different zones of the adrenal cortex and the hormones they produce?

1) Zona glomerulosa → Produces mineralocorticoids

2) Zona fasciculata → Produces glucocorticoids eg. cortisol

3) Zona reticularis → Produces androgens

What is the difference between the dominant glucocorticoid in humans and rodents?

In humans, it is cortisol, and in rodents, it is corticosterone.

Why is cortisol so important?

1) It protects against hypoglycemia (low blood sugar)

2) It promotes gluconeogenesis (increase in blood sugar)

3) Plays a role in immune system (suppresses it and is used clinically to regulate inflammatory response; they are used as anti-inflammatory agents)

4) It causes the breakdown of skeletal muscle for gluconeogenesis

5) Causes bone catabolism

6) Affects brain functions (such as mood, memory, and learning)

What happens when the blood corticosteroids are too high for too long?

Cushing’s syndrome (primary hypersortisolism) and Cushing’s disease (secondary hypersortisolism)

What is the difference between primary and secondary hypersortisolism?

Cushing’s syndrome (primary)

• Caused by taking glucocorticoid drugs or diseases that result in excess cortisol

• Causes changes in carb and protein metabolism, glycemia, hypertension, and muscular weakness

• They cause a puffy appearance and cause CNS disorders such as depression.

Cushing’s disease (secondary)

• Pituitary dependent, so a tumor in the pituitary gland produced large amounts of ACTH, causing the adrenal glands to make excess cortisol

ACTH levels are going to be lower in Cushing’s syndrome.

How to treat Cushing’s?

1) Surgery to remove pituitary or adrenal gland

2) Medical management

If not treated, it can lead to stroke or heart attack.

What happens when the blood corticosteroids are too low?

Addison’s disease (primary hypocortisolism)

What are some factors that lead to Addison’s disease (primary hypocortisolism) and the common symptoms that come with it?

1) Adrenal insufficiency

2) Many causes, such as genetic, autoimmune, destruction of the adrenal cortex, etc.

3) Can be acquired due to high-dose steroids given for more than a week, as they suppress adrenal glands.

Common symptoms: hair loss, blurry vision, abdominal pain, decreased appetite, skin darkening, shaking, tremors, and depression.

What is the normal pattern of adrenal cortisol secretion?

• Pulsatile secretion throughout the day

• Follows a circadian rhythm

• Peak levels in the early morning (around 6-9 AM)

• Lowest levels at night (around 6-9 PM)

What is pituitary pars intermedia dysfunction (PPID)?

Happens in horses; typically older but can be diagnosed as young as 10 years

Caused by:

• Impaired pituitary (hyperplasia and hypertrophy of pars intermedia)

Leads to:

• Increased secretion of cortisol by adrenal glands

• High blood pressure

• Suppression of immune system

Common signs in horses:

• Hypertrichosis, which is excessive hair growth

• Abnormal hair

• Muscle atrophy

• Excessive sweating

• formation of foot pads on top of neck, tail head, and around the eyes

• Pot-bellied appearance

How is pituitary pars intermedia dysfunction (PPID) diagnosed in horses, and what are the treatments?

It is diagnosed by measuring the resting ACTH and fasting insulin

Treatment:

• Medication that acts on the pituitary gland to decrease circulating ACTH, e.g., pergolide.

• Management such as exercise, weight loss, and low starch/sugar diet

What is the mechanism od the hypothalamus-pituitary-thyroid axis?

1) Thyrotropin-releasing hormone is going to be released from the hypothalamus.

2) Then it's going to travel down the vascular system to the anterior pituitary.

3) This stimulates the anterior pituitary to release thyroid-stimulating hormone (TSH).

4) Thyroid-stimulating hormone (TSH) will then travel down to the thyroid gland, where it is going to stimulate the secretion of T3 and T4.

This is a negative feedback because T4 inhibits the secretion of TRH from the hypothalamus, and it is going to decrease the responsiveness of the anterior pituitary to TRH stimulation.

Key facts about the thyroid gland.

• Sits below the larynx (voice box)

• It has two lobes, which are positioned on either side of the trachea

• The two lobes are connected by an isthmus

• Very fibrous in cows and horses

• Indistinct in dogs and cats

• Largest purely endocrine gland by mass in the human body (20-25g)

Thyroid gland histology

• The thyroid gland is made up of follicles, which are small sac-like structures.

• These follicles take up iodide (I⁻) from the blood.

• Inside the follicle, the colloid contains thyroglobulin, which is essential for thyroid hormone synthesis.

• Thyroid peroxidase enzyme (TPO) in the colloid helps attach iodide to tyrosine residues in thyroglobulin, a crucial step in producing thyroid hormones (T3 and T4).

What is thyroglobulin protein?

• Long peptide chain with lots of tyrosine side chains

• Made by the follicular cells themselves

• Found in colloid

• The thyroid follicles are actively accumulating iodide from the blood and releasing it to the colloid by a transporter called pendrin

• Thyroid peroxidase enzyme removes an electron from iodide to produce iodine

How are T3 and T4 made?

When iodine binds to tyrosine residues in thyroglobulin, one of two outcomes is possible:

• MIT (Monoiodotyrosine): A tyrosine molecule with one iodine attached.

• DIT (Diiodotyrosine): A tyrosine molecule with two iodines attached.

Then within the colloid, there are enzymes that modify the structures of MIT and DIT, joining them together:

• T3 (Triiodothyronine) = MIT + DIT

• T4 (Thyroxine) = DIT + DIT

How are T3 and T4 released into the blood?

1) TSH (Thyroid-Stimulating Hormone) stimulates follicular cells in the thyroid gland.

2) Thyroglobulin undergoes hydrolysis, releasing T3 and T4 from its backbone.

3) T3 and T4 are then secreted into the bloodstream.

4) Since they are lipophilic (fat-soluble), they must bind to carrier proteins (e.g., Thyroxine-Binding Globulin (TBG)) to travel in the blood.

5) Once at the target tissues, T3 and T4 dissociate from the carrier protein to exert their metabolic effects.

How are thyroid hormones transported in the blood?

• Over 99% bind to plasma carrier protein TBG

• Less than 1% is free and unbound, and they need to lose the carrier protein to elicit their effects in target cells

How do thyroid hormones act on cells?

1) T4 travels in the bloodstream attached to thyroxine-binding globulin (TBG).

2) T4 dissociates from TBG and enters the cell via transporters.

3) Inside the cell, T4 is converted to active T3.

4) T3 binds to thyroid hormone receptors (TRs) in the nucleus.

5) The T3-TR complex forms a dimer with RXR, a vitamin A derivative, for enhanced DNA binding.

6) The T3-TR-RXR complex binds to DNA, initiating transcription of new mRNA, new protein, and a new cellular response.

How is TSH secretion regulated?

• Pulsed secretion from the hypothalamus.

• Young animals secrete more than older animals.

• Stress & cold increase secretion levels.

• In humans, secretion is highest between 10 AM – 2 PM.

• In rodents, secretion is higher at night rather than during the day.

What is the physiological action of thyroid hormones in the body?

• Elevate basal metabolic rate

• Needed for normal gonadal development and function

• Needed for fetal development, especially the CNS

• Production impaired with age

• Deficiency or excess cause serious consequences

What are hypothyroidism and hyperthyroidism?

Hypothyroidism: abnormally low basal metabolic rate (weight gain and intolerance to cold)

Hyperthyroidism: abnormally high metabolic rate (weight loss, and protruding eyes)

What causes hypothyroidism and hyperthyroidism?

• Insufficient dietary iodide

• Thyroid gland defect

• impaired thyroid hormone pathway

• Insufficient TSH from anterior pituitary or hypothalamus

• Mutant TSH or TRH receptors

• Mutant TH transport proteins

• Autoimmunity

What is cretinism?

• Congenital deficiency of thyroid hormones

• Due to innate maternal hypothyroidism, or iodine deficiency

• Reduced physical growth and development delays

• Treated with T4 soon after birth (before 1 month), completely or almost completely restores mental development by age 5.

Why are thyroid hormones so important?

• Thyroid hormone-dependent brain development begins in utero and is completed after birth

• Important for dendritic and axonal growth, myelin formation, and synapse formation.

• Important for neural migration

• Maternal thyroid hormones are the first supply for the needs of the embryo.

What causes goiters in hypothyroidism?

Goiters result from abnormal thyroid growth due to hypothyroidism, caused by:

1. Low iodide intake, leading to reduced thyroid hormone production.

2. Low plasma thyroid hormones, triggering increased TRH release.

3. High TRH levels, stimulating excessive TSH secretion.

4. High TSH levels, causing excessive thyroid growth, leading to goiter formation.

What causes Graves' disease and its key features?

Autoimmune antibodies stimulate the thyroid gland, leading to excessive T3 and T4 production.

High thyroid hormone levels suppress TRH and TSH secretion.

What are the key differences between natural and synthetic thyroid hormone medications?

• Synthetic Thyroid Medications:

  • Contain only T4 (e.g., Synthroid), which must be converted to T3 by deiodinase enzymes.

  • Some individuals may have enzyme deficiencies, making conversion inefficient.

  • In such cases, Cytomel (T3) is added to improve symptom control.

• Natural Thyroid Medications:

  • Contain both T3 and T4, along with small amounts of T2, T1, and Calcitonin.

  • More closely mimics the natural thyroid gland function.

  • May be preferred for patients who struggle with T4-to-T3 conversion or have had a thyroidectomy, which removes C cells responsible for Calcitonin production.

What are the common signs of hyperthyroidism in cats?

• Weight loss despite increased appetite

• Increased thirst (polydipsia)

• Increased urination (polyuria)

• Increased heart rate (tachycardia)

• Vomiting & diarrhea

• Restlessness or hyperactivity

• Greasy or matted fur

What are the common causes of primary hypothyroidism in dogs?

• Lymphocytic thyroiditis: Immune infiltration leading to thyroid destruction (affects ~50% of Doberman Pinschers).

• Idiopathic atrophy of the thyroid: Loss of thyroid tissue replaced by adipose (fat) cells.

What are the causes of secondary hypothyroidism in dogs?

• Thyroid destruction due to neoplasia: Affects ~40% of dogs with cancer.

• Congenital hypothyroidism (cretinism/pituitary dwarfism): Insufficient thyroid hormone from birth.

• At least 75% of both lobes must be non-functional before symptoms appear.

• Severe hypothyroidism can lead to myxedema (tissue swelling), stupor, and coma.

What are the treatment options for thyroid disorders?

• Surgery – Partial thyroid removal (e.g., hemithyroidectomy).

• Hormone supplementation – Start with a low dose.

• Radiation therapy – Used for thyroid cancer.

• Blockers – Thiouracil derivatives & thiocarbamides inhibit iodination & T4-to-T3 conversion.

• Stimulants – Some drugs (e.g., furosemide) increase T4-to-T3 conversion.

• Supportive care – Diet, electrolyte infusions, and symptom management.