Physiology Lectures 12-17

Hormone

Chemical signals secreted into the bloodstream that act on tissues

Endocrine

Hormone secreted into blood binds distant target cells

Paracrine

 Hormone acts locally by diffusing from its source to target cells in the neighborhood

Autocrine

Hormone acts on same cell that produced it

Steroids, protein/peptide hormones, amino acid analogues and derivatives

What are the three classes of hormones?

Ovaries, testes, adrenal cortex

Organs that secrete steroids

Mineralocorticoids, glucocorticoids, testosterone, estradiol

Examples of steroids

Anterior pituitary, thyroid, parathyroid, pancreas

Organs that secrete protein/peptide hormones

Insulin, prolactin, anti-diuretic hormone, oxytocin

Examples of protein/peptide hormones

Steroids

Which class of hormone originates from a cholesterol precursor?

Thyroid and adrenal medulla

Organs that secrete amino acid analogues and derivatives

Thyroxine, norepinephrine, and epinephrine

Examples of amino acid analogues and derivatives

External stimuli, internal stimuli, feedback loops

How are hormones regulated in the body?

Fright, cold, light cues

Examples of external stimuli

Blood sugar levels, hormonal signals from another gland

Examples of internal stimuli

Anterior

The hypothalamus synthesizes and releases regulating hormones that act on the ___ pituitary.

Posterior

The hypothalamus synthesizes hormones that are released from the ___ pituitary.

Oxytocin, antidiuretic hormone (ADH)

What hormones are synthesized by the hypothalamus and released from the posterior pituitary?

Releasing and inhibiting hormones

What hormones are synthesized and released from the hypothalamus to act on the anterior pituitary?

Peptide

What class do most hypothalamic releasing hormones belong to?

Dopamine

What is the only non-peptide hypothalamic releasing/inhibiting hormone?

Corticotropin releasing hormone (CRH)

1. Acts on corticotrophs in the anterior pituitary to stimulate production of ACTH

2. 41-amino acid protein is highly conserved (e.g., identical in humans and rats)

Gonadotropin releasing hormone (GnRH)

1. Acts on gonadotropes in the anterior-pituitary to stimulate production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH)

   1. AKA luteinizing hormone releasing hormone (LHRH)

2. 10 amino acids

3. Very similar in different species

Growth hormone releasing hormone (GHRH)

1. Acts on somatotrophs in the anterior pituitary

2. Stimulates production of growth hormone (GH)

Growth hormone inhibiting hormone (GHIH)

1. AKA somatostatin

2. Acts on somatotrophs in the anterior pituitary

3. Inhibits production of GH

Thyrotropin releasing hormone (TRH)

1. TRH acts on thyrotrophs of the anterior pituitary to stimulate thyroid stimulating hormone (TSH)

2. 3-amino-acid peptide

Prolactin releasing hormone (PRH)

1. Acts on lactotrophs in the anterior pituitary

2. Stimulates production of prolactin (PRL)

Dopamine or prolactin inhibiting hormone (PIH)

1. Distinct ___-secreting neurons in hypothalamus

2. Enters portal vessels and is transported to the anterior pituitary

3. Acts on lactotrophs to inhibit production of prolactin by the anterior pituitary

Dopamine

What is the only non-peptide hormone?

Oxytocin

1. Stimulates smooth muscle contraction in the uterus and mammary glands

2. Uterine contraction and milk let-down

   1. Works with estrogen

   2. Inhibited by progesterone

   3. Short half-life

   4. Essential role in activating maternal behavior

   5. Role in social attachments and affiliations

   6. Positive interactions between humans and dogs linked with increase in oxytocin levels

   7. May increase trust among humans

Pitocin

Analogue of oxytocin

Used clinically to facilitate parturition and milk let-down

Has a short half-life and must be given repeatedly or continuously

Secreted at time of ejaculation; promotes contraction of ductus deferens (needed for contraction); may play a role in prostate function in dogs

Effects of oxytocin on males (even though role in males is unclear)

1. Suckling

2. Sight, sound, or smell of an infant

3. Dilation of the cervix

4. Orgasm

Stimulatory factors affecting oxytocin secretion

Opoids (endorphins)

Inhibitory factors affecting oxytocin secretion

Antidiuretic hormone (ADH) or Vasopressin

1. Acts on kidney tubules

   1. Decreases urine output

   2. Increases water resorption

2. Acts on sweat glands

   1. Decreases sweating

3. Acts on arterioles

   1. Constricts arterioles

   2. Increases blood pressure

4. Secreted in pulsatile fashion

Decreases, increases

ADH/Vasopressin acts on kidney tubules, which ___ urine output and ___ water resorption.

Decreases

ADH/Vasopressin acts on sweat glands, which ___ sweating.

Constricts, increases

ADH/Vasopressin acts on arterioles, which ___ arterioles and ___ blood pressure.

Fear, thirst, preanesthetic and anesthetic agents, the opioid methadone

Stimulating factors affecting ADH secretion

Satiation of thirst

Inhibitory factor affecting ADH secretion

V1

ADH receptor subtype on blood vessels

V2

ADH receptor subtype on renal collecting duct epithelial cells

V3

ADH receptor subtype on mediating ACTH secretion from the anterior pituitary

Hypertonic renal medulla

ADH facilitates diffusion of water from the collecting ducts into the ___.

V2

Which receptor subtype does ADH bind when facilitating diffusion of water into the hypertonic renal medulla

Adenylate cyclase, phosphorylation of proteins

What does ADH stimulate while facilitating diffusion of water into the hypotonic renal medulla

Aquaporins (AQP)

Permit water to pass from cell to interstitium

Diabetes insipidus

1. Abnormalities (lack) of ADH production or response

2. Little or no stimulation of ADH release due to sustained and excessive drinking

3. Significant disease in veterinary medicine

Central diabetes insipidus

Insufficient ADH release

Characterized by:

Dilute urine despite osmotic stimuli for ADH secretion

Absence of renal disease

Rise in urine osmolality following administration of ADH

Nephrogenic diabetes insipidus

Insufficient response of the kidney to ADH

Rarely congenital (more common in huskies than other dogs due to low affinity V2 receptor)

Acquired by down-regulation of AQP-2 due to tumors or endocrine disorder

Little/no response to desmopressin

Inter-cranial tumor in middle-aged and elderly animals, non-pituitary lesion, idiopathic form in young animals

Causes of central diabetes insipidus

Polyuria, polydipsia, near continuous demand for water, huge urine volume

Clinical manifestations of central diabetes insipidus

Diagnosis, treatment, and prognosis of central diabetes insipidus

Measure plasma ADH during osmotic provocation by hypertonic saline infusion

Treat with vasopressin (ADH) analogue (desmopressin)

In absence of tumor, long-term prognosis is good.

Treatment of nephrogenic diabetes insipidus

Treat with anti-diuretic drugs to increase water permeability in kidneys

Primary polydipsia

Occurs primarily in dogs

Marked increase in water intake that cannot be explained as a compensatory mechanism for fluid loss

Change in environment for young dogs

Control water access

Syndrome of inappropriate antidiuresis

1. Elevated or normal ADH in presence of low plasma osmolality

2. Characterized by water retention, cellular over hydration

3. Only a few cases in dogs (with and without polyuria)

   1. Idiopathic

   2. Encephalitis

   3. Dirofilaria immitis infestation (heartworm)

   4. Tumor in thalamus and dorsal hypothalamus

   5. Excessive ADH administration

Plasma hypotonicity and hyponatremia

1. Leads to brain compression, cerebral edema

   1. Weakness

   2. Lethargy

   3. Nausea

   4. May lead to resting tremor, generalized seizures, and coma

2. Restrict fluid intake and/or give V2 receptor antagonists

Lactotrophs (PRL), gonadotrophs (FSH, LH), thyrotrophs (TSH), corticotrophs (ACTH), somatotrophs (GH)

What are the five distinct cell types and their associated hormones?

Stimulates LH and FSH (gonadotrophs)

What does the gonadotropin releasing hormone (GnRH) regulate in the anterior pituitary?

Gonads (ovary and testis)

What tissues does the gonadotropin releasing hormone (GnRH) regulate?

Stimulate PRL (lactotrophs)

What do the prolactin releasing factors (TRH and PRH)  regulate in the anterior pituitary?

Inhibits PRL (lactotrophs)

What does the prolactin inhibiting factor (dopamine) regulate in the anterior pituitary?

Mammary glands

What tissues do the prolactin releasing factors (TRH and PRH) and the prolactin inhibiting factor (dopamine) regulate?

Stimulates TSH (thyrotrophs)

What does the thyrotropin releasing hormone (TRH) regulate in the anterior pituitary?

Thyroid gland

What tissue does the thyrotropin releasing hormone (TRH) regulate?

Stimulates GH (somatotrophs)

What does the growth hormone releasing hormone (GHRH) regulate in the anterior pituitary?

Inhibits GH (somatotrophs)

What does the growth hormone inhibiting. hormone (GHIH or somatostatin) regulate in the anterior pituitary?

Bone, liver, muscle

What tissues do GHRH and GHIH/somatostatin regulate?

Stimulates ACTH (corticotrophs)

What does the corticotropin releasing hormone (CRH) regulate in the anterior pituitary?

What tissue does the corticotropin releasing hormone (CRH) regulate?

Adrenal cortex

Prolactin

1. Single-chain protein, produced by lactotrophs in the anterior pituitary

2. Peptide hormone, structure is close to GH and differs only by 8 amino acids

3. Is inhibited by dopamine from the hypothalamus

4. Synthesis is remarkably increased during pregnancy and augmented by oxygen

5. Secretion is stimulated by suckling

Functions of prolactin

1. Mammary gland development (during pregnancy)

   1. High estradiol allows ductal network to grow and promotes alveolar epithelia cells differentiating into secretory cells

   2. High progesterone suppresses milk production

2. Milk production

   1. Induces lactogenesis or milk production

   2. Triggered by stimulus of suckling and drop of progesterone levels at the end of pregnancy

Prolactin

Anterior pituitary

Mammary gland development (pregnancy)

Acts on alveolar epithelial cells

Milk formation (lactation)

Oxytocin

Posterior pituitary

Acts on myoepithelial cells

Milk release (milk-ejection reflex, lactation)

Estrogen, progesterone

During pregnancy, ___ increases prolactin production and secretion (mammary gland development), while ___ inhibits milk formation.

Suckling

What is the major stimulator of prolactin secretion during lactation?

Role of prolactin in males

1. Low but measurable levels in males

2. PRL receptors present in male reproductive and non-reproductive organs and tissues (e.g., Leydig cells in testes)

3. Role of PRL in male mammals is unclear

4. May help maintain normal production of testosterone

Hyperprolactinemia

1. May or may not be associated with tumor of the anterior pituitary

   1. Often causes infertility due to secondary inhibition of gonadotropin secretion (by inhibiting the secretion of GnRH) and ovarian function

   2. Dogs: pseudopregnancy with galactorrhea

2. Treated with dopamine agonist— bromocriptine (Parlodel, Cyclist)

Pseudopregnancy

1. Extended nonpregnant ovarian cycles

2. Extremely high PRL level due to a rapid decrease in progesterone secretion

3. No treatment is best

Glycoprotein hormones (FSH, LH, TSH)

1. Composed of two subunit structures, alpha and beta linked by non-covalent bonds

   1. FSH = follicle stimulating hormone

   2. LH = luteinizing hormone

   3. Beta subunit is unique to each hormone

   4. Beta subunit confers specificity

   5. Alpha subunit is common to LH, FSH, and TSH

Endocrine control in males

1. FSH and LH act on the testes to maintain spermatogenesis and product testosterone and inhibin

2. Testosterone and inhibin inhibit GnRH and gonadotropins

Primary hypogonadism

1. Problems in the gonads, leading to elevated FSH/LH levels (reduced/no negative feedback)

   1. Premature ovarian failure

   2. Castration

   3. Testicular failure

Secondary hypogonadism

1. Problems in the brain with normal or low FSH/LH levels (no response to negative feedback)

   1. Hypothalamic suppression

   2. Hypopituitarism

   3. Hyperprolactinemia

   4. Gonadotropin deficiency

Prl, FSH, LH, GH, TSH, ACTH

What are the six main types of trophic hormones?

Decreased glucose concentration, decreased fatty acid concentration, arginine, fasting or starvation, hormones of puberty (estrogen, testosterone), exercise, stress, stage III and IV sleep, alpha-adrenergic agonists

What are stimulatory factors of GH?

Increased glucose concentration, increased free fatty acid concentration, obesity, senescence (hibernation), somatostatin (GHIH), somatomedins (IGFs), growth hormone, beta-adrenergic agonists, pregnancy

What are inhibitory factors of GH?

Stimulates

GH ___ local IGF-1 production in many organs.

The 1950s GH/IGF-1 hypothesis proposed that the liver was the sole source where GH ___ IGF-1 production, but this turned out to be an oversimplification.

Insulin-like growth factor 1 (IGF-1)

Structural resemblance to insulin but functional differences compared to insulin

Produced in liver, which was initially thought to be essentially the sole source

GH stimulates ___ by liver

Bovine somatotropin (BST)

1. Commercial versions have small amino acid differences

2. Administered to dairy cows by injection every 14 days– 60 days after calving until end of lactation

3. BST acts to increase milk yield

4. BST has no therapeutic use

5. Average increase in milk production of up to 40% over lactation

6. 20,000 # x 40% = 8000 # of extra milk → serious money

Porcine somatotropin (PST)

1. Produced naturally by the anterior pituitary gland of the pig

2. Acts as a growth regulator

2. ___ injections

   1. Increase cell division in muscle tissue

   2. Decrease fat storage

   3. Increase protein accumulation

   4. Improve feed efficiency

Acromegaly

Adulthood hypersecretion of GH

Abnormal body proportions

Affects soft tissue of face and bones of face, limbs (prominent forehead, enlarged nose, enlarged lips and tongue, prominent chin and jaw)

Effects differ from developmental hypersecretion because long bones have fused

Gigantism

Developmental hypersecretion of GH

Rapid, prolonged bone growth and normal body proportion

Panhypopituitarism

Dwarfism, slow bone and organ growth, reduced adult size, and abnormal body proportions

GH-responsive dermatosis

Alopecia (hair loss) due to GH deficiency; if diagnosed as an adult, this condition can be treated, but patients will likely need to be on GH replacement therapy for the rest of their lives

Diabetes mellitus

Too much GH is frequently associated with ___.

Raises, inhibits

GH ___ blood glucose and ___ insulin from regulating blood glucose levels

Hormone signaling steps

1. Synthesis of the hormone in the secreting cell

2. Release of the hormone by the secreting cell

3. Transport of the hormone to the target cell

4. Recognition of the hormone by a specific receptor on their target cell

5. Signal transduction within the target cell triggered by the hormone-receptor complex, resulting in a change in cellular metabolism, function, or development

6. Removal of the hormonal signal, terminating the cellular response

Short-lasting signal

1. Quick-acting but ___

2. Stored in secretory vesicles and released upon stimulation-caused exocytosis

3. Affects various protein kinase cascades

4. Signals are terminated by degradation by blood and tissue proteases

5. Examples: peptide hormones

Long-lasting signal

1. Slow-acting but __

2. Produced on demand

3. Need to be converted from precursor and the release takes from hours to days

4. Transported by carrier proteins and not rapidly degraded

5. Regulates gene expression

6. Examples: steroid hormones

Desensitization/adaptation

1. Receptor activation triggers a feedback signal that shuts off the receptor or removes it from the cell surface

   1. Ex. FSH receptor