Neurohormones (Physiology 2)

Thyrotrophin-releasing hormone (TRH): Stimulates the release of thyroid-stimulating hormone (TSH) from the anterior pituitary.

Gonadotrophin-releasing hormone (GnRH): Stimulates the release of luteinising hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary.

Corticotrophin-releasing hormone (CRH): Stimulates the release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary.

Growth hormone-releasing hormone (GHRH): Stimulates the release of growth hormone (GH) from the anterior pituitary.

Prolactin-inhibiting factor (Dopamine): Inhibits prolactin secretion from the anterior pituitary.

Thyroid-stimulating hormone (TSH): Stimulates the thyroid gland to release thyroid hormones (T3 and T4).

Luteinising hormone (LH): Stimulates ovulation in females and testosterone production in males.

Follicle-stimulating hormone (FSH): Stimulates the growth of ovarian follicles in females and sperm production in males.

Growth hormone (GH): Stimulates growth and cell reproduction.

Prolactin (PRL): Stimulates milk production in females.

Adrenocorticotrophin (ACTH): Stimulates the adrenal cortex to release cortisol.

Vasopressin (ADH): Regulates water balance in the body by promoting water reabsorption in the kidneys.

Oxytocin: Stimulates uterine contractions during childbirth and milk ejection during breastfeeding.

Thyroxine (T4): Regulates metabolism and growth.

Triiodothyronine (T3): More potent than T4, also regulates metabolism and growth.

Calcitonin: Lowers blood calcium levels by inhibiting osteoclast activity.

Parathyroid hormone (PTH): Increases blood calcium levels by promoting osteoclast activity and calcium reabsorption in the kidneys.

Aldosterone: Regulates sodium and potassium balance by increasing sodium reabsorption in the kidneys.

Cortisol: Regulates metabolism and the body's stress response.

Epinephrine (Adrenaline): Increases heart rate, blood flow to muscles, and blood glucose levels during the fight or flight response.

Norepinephrine (Noradrenaline): Increases heart rate and blood pressure, and prepares the body for stress.

Insulin: Lowers blood glucose levels by promoting glucose uptake into cells.

Glucagon: Raises blood glucose levels by stimulating the liver to release glucose.

Somatostatin: Inhibits the release of both insulin and glucagon.

Oestrogens: Regulate the menstrual cycle, promote secondary sexual characteristics, and support pregnancy.

Progesterone: Prepares the uterus for pregnancy and maintains pregnancy.

Testosterone: Promotes sperm production, the development of male secondary sexual characteristics, and the maintenance of male reproductive health.

Fast, restricted

Slow but widespread

Fast, widespread influence

Fast, widespread influence

Slower, widespread influence

Signalling along nerve fibres

Transmission of electrical impulses

Fast communication

Effects are generally short-acting

Mediators travel within blood vessels

Utilizes chemical mediators (hormones)

Slow communication

Effects can be long-lasting

Produced by specialized nerve cells called neurosecretory cells

Released into the blood and can act on distant cells

Can act as neurotransmitters

Can act as autocrine (self) or paracrine (local) messengers

Vary considerably in size

Can be synthesized as a large precursor and processed before secretion (e.g., GH, somatostatin, insulin)

Can be post-translationally modified (e.g., glycosylation)

Can have multiple subunits synthesized independently and assembled (e.g., FSH, LH, TSH)

Mostly derived from tyrosine

Act as neurotransmitters and hormones

Examples include Epinephrine, Norepinephrine, and Dopamine

Derived from cholesterol

Include hormones such as Cortisol, Aldosterone, Testosterone, Progesterone, and Oestradiol

Classified as lipids

Neuropeptides (neurohormones) are functionally important transmitters in the Hypothalamo-pituitary axis

Anterior pituitary

Posterior pituitary

Some peptides act both as hormones and neurotransmitters

In some cases, their endocrine and neural functions are linked, while in others, they are not

Scattered throughout the hypothalamus

Key nuclei include the medial pre-optic, arcuate, and paraventricular nuclei

CRH is a 41 amino acid peptide

It controls the release of adrenocorticotrophin (ACTH)

TRH is a 3 amino acid peptide

It controls the release of thyroid stimulating hormone (TSH) and prolactin (PRL)

GnRH is a 10 amino acid peptide

It controls the release of luteinising hormone (LH) and follicle-stimulating hormone (FSH)

GHRH is a 44 amino acid peptide

It controls the release of growth hormone (GH)

Somatostatin is a 14 amino acid peptide

It inhibits the release of growth hormone (GH), gastrin, vasoactive intestinal polypeptide (VIP), glucagon, insulin, thyroid stimulating hormone (TSH), and prolactin (PRL)

Dopamine is a monoamine

It inhibits the release of prolactin (PRL)

Gonadotroph cells secrete luteinising hormone (LH) and follicle-stimulating hormone (FSH)

They respond to Gonadotrophin Releasing Hormone (GnRH)

Somatotroph cells secrete growth hormone (GH)

They respond to Growth Hormone Releasing Hormone (GHRH)

Corticotroph cells secrete adrenocorticotrophin (ACTH)

They respond to Corticotrophin Releasing Hormone (CRH)

Thyrotroph cells secrete thyroid stimulating hormone (TSH)

They respond to Thyrotrophin Releasing Hormone (TRH)

Lactotroph cells secrete prolactin (PRL)

They respond to Thyrotrophin Releasing Hormone (TRH), somatostatin, and dopamine

ACTH is a 39 amino acid peptide with a molecular weight of 4.5 kDa

It is derived from a large precursor glycoprotein called pro-opiomelanocortin (POMC)

ACTH stimulates the production of glucocorticoids and sex hormones from the zona fasciculata of the adrenal cortex

Hypothalamic neurons release corticotrophin releasing hormone (CRH)

CRH stimulates pituitary corticotrophs

Pituitary corticotrophs release ACTH into the circulation

Cortisol is a steroid hormone and a type of glucocorticoid

ACTH stimulates the adrenal cortex to produce cortisol, which is also known as hydrocortisone when used as a medication

Glucocorticoid secretion follows a circadian rhythm, with peaks in the morning and troughs throughout the day

Plasma cortisol levels are highest first thing in the morning and decline during the day, reflecting the pattern of ACTH secretion by the anterior pituitary

The circadian rhythm of cortisol affects the timing and effectiveness of replacement therapy

Cortisol replacement therapy must take into account the body's natural rhythm of cortisol secretion, which peaks in the morning after overnight fasting

TRH is released by the hypothalamus and stimulates the anterior pituitary to release thyroid-stimulating hormone (TSH)

TSH acts on the thyroid to increase the secretion of T4/T3 hormones

T4 is converted to T3 by a deiodinase enzyme (DI) found in target tissues

The pituitary also expresses deiodinase to convert T4 to T3, which facilitates negative feedback regulation

Vasopressin

Oxytocin

Both are synthesized in the supraoptic and paraventricular nuclei of the hypothalamus

They are transported to the terminals of the nerve fibers located in the posterior pituitary

They are structurally quite similar

They have very different functions

Also known as Anti-diuretic hormone (ADH)

Release is stimulated by changes in the activity of the osmoreceptor complex in the hypothalamus

Controls plasma osmolality by regulating water excretion and drinking behavior

Stimulates vascular smooth muscle contraction in the distal tubules of the kidney to reduce water loss and raise blood pressure

Normally undetectable but elevated during parturition, lactation, and mating

Released in response to peripheral stimuli such as cervical stretch receptors and suckling at the breast

Regulates smooth muscle contraction (e.g., uterus during labor, myoepithelial cells lining the mammary duct)

Contributes to contraction of the reproductive tract during sperm ejaculation

May also be involved in responses to stroking, caressing, and grooming

Kidneys secrete renin

Renin converts Angiotensinogen to Angiotensin I

Angiotensin I is converted to Angiotensin II

Angiotensin II is detected by the subfornical organ

Subfornical organ projects to vasopressin cells and neurons in the lateral hypothalamus, affecting kidney function

Estradiol (from ovaries) activates oxytocin receptors on the uterus

Oxytocin (from fetus and mother's posterior pituitary) stimulates the uterus to contract

Oxytocin also stimulates the placenta to produce prostaglandins

Positive feedback occurs, stimulating more contractions in the uterus

This cycle continues to amplify until labour is completed

Antipsychotic

Antidepressant

Social cognition enhancement

Hypnotic

Induces trust

Anxiolytic

Treatment for autism and anti-OCD

Peptide and protein hormones bind to surface receptors on the target cell.

This activates intracellular signalling mechanisms that lead to changes in target protein and/or enzyme activities.

These actions result in the alteration of cellular functions.

Insulin and growth hormone bind to cell surface receptors, causing receptor dimerization.

This dimerization recruits tyrosine kinases (e.g., JAK2 or MAPK).

The kinases phosphorylate target proteins (e.g., STAT), triggering biological responses.

Mutations in the GH receptor gene can cause defective hormone binding or reduced receptor dimerization.

This results in GH resistance, such as in Laron syndrome.

G-protein coupled receptors (GPCRs): Largest group of cell surface receptors with over 140 members; characterized by 7 transmembrane domains.

Hormone binding: Binding of hormone to GPCR causes conformational changes, leading to GTP exchange for GDP and activation of adenylate cyclase.

Activation of adenylate cyclase: Increases intracellular cAMP levels, activating protein kinase A (PKA), which phosphorylates target proteins (e.g., CREB).

Activating mutations of TSH receptor: Can cause thyroid adenomas (constitutive ON).

Inactivating mutations of TSH receptor: Lead to resistance to TSH.

Hormone binding: Oxytocin and GnRH bind to cell surface GPCRs.

Activation of phospholipase C: Stimulates conversion of phosphatidylinositol bisphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG).

IP3 effects: Stimulates Ca2+ release from intracellular stores (particularly the endoplasmic reticulum).

DAG effects: Activates protein kinase C (PKC), which leads to phosphorylation of proteins and altered enzyme activities to initiate a biological response.

Loss-of-function mutations in GnRHR: Lead to sex hormone deficiency and delayed puberty (hypogonadotropic hypogonadism).

Hormone diffusion: Steroid and thyroid hormones diffuse across the plasma membrane of target cells.

Receptor binding: The hormones bind to intracellular receptors in the cytoplasm or nucleus.

Transcriptional function: These receptors act as hormone-regulated transcription factors, controlling gene expression.

Transcriptional activation domain (AF1): A domain involved in transcription activation.

Zn2+ finger DNA binding domain: A structural feature for binding to DNA.

Ligand binding/dimerisation domain: A domain for binding to the hormone (ligand) and dimerising with other receptors.

Gigantism: Excess GH in children leads to abnormal growth, particularly in height.

Acromegaly: Excess GH in adults leads to thickening of bones and tissues, especially in the hands, feet, and face.

Loss of visual field: Pressure from the adenoma on the optic nerve can cause loss of vision.

Hormone imbalances: Pituitary adenomas can cause excessive secretion of hormones such as ACTH, GH, or PRL.

Cushing syndrome: Excess ACTH leads to increased cortisol secretion, causing symptoms such as weight gain, high blood pressure, and a round face.

Hyperprolactinaemia: Excess PRL can cause symptoms such as infertility and irregular menstrual cycles in women and erectile dysfunction in men.

Reduced pituitary function: This condition involves a decrease in the production or secretion of one or more pituitary hormones, affecting various bodily functions.

Hypothyroidism: A condition where there is too little thyroid hormone in the body.

Effects: Can lead to mental retardation, slow growth, cold hands and feet, lack of energy, and other symptoms.

Causes: The most common cause is Hashimoto's disease, an autoimmune disorder where the immune system attacks the thyroid.

Risk Factors: More common in women, those with a family history of thyroid disease, or following radioactive iodine treatment, thyroid surgery, or pituitary dysfunction.

Goitre: Swelling of the thyroid gland.

Heart failure: Due to the effects on heart function.

Depression: Commonly seen in older individuals with hypothyroidism.

Slowed mental functioning: Can lead to cognitive decline.

Mental retardation and slow growth: If untreated, hypothyroidism can cause developmental delays.

Stillbirth or premature birth: Babies may be born with lower IQ and developmental issues later in life.

Unclear: The exact brain mechanisms underlying the changes in function due to hypothyroidism are not well understood.

Hyperthyroidism: A condition where the thyroid gland produces too much thyroid hormone.

Cause: The most common cause is Graves' disease, an autoimmune disorder where antibodies attack the thyroid gland and mimic TSH, causing excessive thyroid hormone production.

Risk Factors: More common in women, especially between ages 20-50, and those with a family history of thyroid disease.

Goitre: Enlarged thyroid gland.

Difficulty breathing: Due to the enlarged thyroid.

Anxiety and irritability: Emotional symptoms.

Difficulty sleeping: Related to the overstimulation of the body.

Fatigue: Despite the hyperactive thyroid.

Rapid or irregular heartbeat: Increased heart rate due to excess thyroid hormones.

Trembling fingers, excess perspiration, heat sensitivity, weight loss: Despite normal food intake.

Heart failure: Due to excessive strain on the heart.

Osteoporosis: Weakening of bones due to hormone imbalance.

Pregnancy complications: Increased risk of miscarriage, premature birth, and low birth weight in babies.

Graves' ophthalmopathy: Rare condition causing bulging eyes if untreated.

Adrenal insufficiency (Addison’s disease): A condition where the adrenal glands do not secrete enough steroids.

Cause: The most common cause of primary adrenal insufficiency is an autoimmune disorder.

Fatigue and muscle weakness: Common due to lack of cortisol.

Decreased appetite and weight loss: Resulting from hormonal imbalance.

Nausea, vomiting, and diarrhea: Gastrointestinal symptoms.

Muscle and joint pain: Affects mobility.

Low blood pressure and dizziness: Due to insufficient cortisol.

Low blood glucose: As cortisol is involved in glucose regulation.

Sweating and darkened skin: Particularly on the face, neck, and back of the hands.

Irregular menstruation: Hormonal disruptions in women.

Cushing's syndrome: A condition caused by excess cortisol secretion.

Exogenous Cushing's syndrome: Caused by taking cortisol-like medications (e.g., prednisone) for treating inflammatory disorders, asthma, rheumatoid arthritis, or after organ transplants.

Endogenous Cushing's syndrome (Cushing's disease): Occurs when a pituitary tumor produces too much ACTH, leading to excess cortisol production.

Weight gain and rounded face: Often seen in the upper back and face.

Excess fat on the upper back and above the clavicles: Characteristic fat deposits.

Diabetes and hypertension: Resulting from high cortisol levels.

Osteoporosis: Bone weakness due to cortisol excess.

Muscle loss and weakness: As a result of protein breakdown.

Thin, fragile skin: Bruising easily and purple-red stretch marks.

Facial hair in women and irregular menstruation: Hormonal disruptions in females.

Homeostasis: The maintenance of the body's internal environment within a narrow physiological range.

Regulation: The hypothalamus is the prime regulator of homeostasis.

Neurohormones: Hormones produced by nerve cells and secreted directly into the blood circulation.

Examples: Vasopressin and noradrenaline.

Hypophysiotropic hormones: Hormones produced by endocrine cells in the hypothalamus.

Production location: These hormones are released at a capillary bed called the median eminence.

Transport: They are conveyed directly to the adenohypophysis (anterior pituitary) via the hypophyseal portal vessels.

Hypothalamic-pituitary portal circulation: A system of blood vessels in the microcirculation at the base of the brain, connecting the hypothalamus with the anterior pituitary.

Main function: To quickly transport and exchange hormones between the hypothalamus (specifically the arcuate nucleus) and the anterior pituitary gland.

Addison’s disease: A disorder that occurs when the body produces insufficient amounts of hormones from the adrenal glands.

Symptoms: Progressive anaemia, low blood pressure, great weakness, and bronze discoloration of the skin.

Hormones affected: Insufficient cortisol and aldosterone levels.

Cushing’s syndrome: A metabolic disorder caused by overproduction of corticosteroid hormones by the adrenal cortex.

Common features: Obesity, high blood pressure, and other metabolic complications.