Intro to Endocrinology

Question 1

Group 1 Hormones:

• Types
• Solubility
• Transport proteins?
• Plasma half-life
• Receptor
• Mediator

Answer 1

• Types
  
  • Steroids, iodothyronines
• Solubility
  
  • Lipophilic
• Transport proteins?
  
  • Yes
• Plasma half-life
  
  • Long (hours to days)
• Receptor
  
  • Intracellular
• Mediator
  
  • Receptor-hormone complex

Question 2

Group 2 Hormones:

• Types
• Solubility
• Transport proteins?
• Plasma half-life
• Receptor
• Mediator

Answer 2

• Types
  
  • Polypeptides, proteins, glycoproteins, catecholamines
• Solubility
  
  • Hydrophilic
• Transport proteins?
  
  • Rarely
• Plasma half-life
  
  • Short (minutes)
• Receptor
  
  • Plasma membrane
• Mediator
  
  • cAMP, cGMP, Ca2+, metabolites of complex phosphinositols, kinase cascades

Question 3

Examples of Group 1 hormones:

• Steroids –
• Thyroid hormone –

Answer 3

• Steroids – e.g. cortisol, aldosterone, testosterone (androgens), estrogens, progestins, calcitriol
• Thyroid hormone – thyroxine (T₄) and triiodothyronine (T₃)

Question 4

Examples of Group 2 hormones:

• Peptides
• Proteins
• Glycoproteins

Answer 4

• Peptides:
  
  • oxytocin, vasopressin (ADH), angiotensins, somatostatin, thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (GnRH), gastrin
• Proteins:
  
  • insulin, glucagon, ACTH, growth hormone, prolactin, CRH, GHRH, PTH, calcitonin, CCK, secretin
• Glycoproteins:
  
  • TSH, and the gonadotropins (FSH, LH, hCG)

Question 5

Pearls

1. Steroids all synthesized from some form of ________
2. Thyroid hormones contain ______
3. ________ generally do not have tertiary structure whereas ________ do.
4. Glycoproteins all have same _____ subunit – specificity is in ____ subunit

Answer 5

1. Steroids all synthesized from some form of cholesterol
2. Thyroid hormones contain iodine
3. Peptides generally do not have tertiary structure whereas proteins do
4. Glycoproteins all have same alpha subunit – specificity is in beta subunit

Question 6

Pearls: Describe the transport (bound or free) of the following hormones

1. Thyroid hormones
2. Steroid hormones
3. Peptides

Answer 6

1. Thyroid hormones are bound >99.5% to TBG, transthyretin, and albumin
   
   • plasma half-life is VERY long (T4 is 6 days),
   • metabolic clearance very slow
2. Steroid hormones are bound 90-98% to plasma proteins (e.g. cortisol to CBG; testosterone to SHBG)
   
   • half-life (~30-60 min) is shorter than thyroid hormones but still longer than most peptides and proteins
3. Most peptides and proteins circulate only in the free form
   
   • half-lives are very short (e.g. <15 min)
   • clearance rate is high

Question 7

Pearls: Steroidogenesis

1. What is the rate-limiting step for all steroidogenic pathways?
2. Expression of different enzymes determines ….
3. G-protein coupled receptor expression on the cell membrane determines ….

Answer 7

1. Rate-limiting step for all steroidogenic pathways is steroidogenic acute regulatory (StAR) protein mediation of cholesterol uptake from the cytosol to the inner mitochondrial membrane where P450scc is located
2. Expression of the different enzymes determines the major steroid product of each gland
3. G-protein coupled receptor expression on the cell membrane determines which circulating secretagogue the gland will respond to
   
   • e.g. ACTH, Angiotensin II, FSH, LH

Question 8

What are the different types of cell signaling?

Answer 8

1. Endocrine
   
   • seretion into a blood vessel
2. Paracrine
   
   • secreted hormones act on adjacent cells
3. Autocrine
   
   • secreted hormones act on orignal cell
4. Neurotransmitter
5. Neuroendocrine

Question 9

Pearls: Hormone Mechanism of Action

1. What does the chemical nature determine?
2. What determines the specificty of hormone action?
3. What mediates thyroid hormones?
4. What mediates steroid hormones?
5. What mediates peptides?

Answer 9

1. Chemical nature of a hormone or a drug determines its mechanism of action
2. Expression of the appropriate receptor in tissue determines which hormones will act on that tissue ​
   
   • specificity of hormone action
3. Thyroid hormones act via nuclear receptors
   
   • increase transcription and translation (slow)
4. Steroid hormones act on cytoplasmic (e.g. cortisol) or nuclear (e.g estrogen) receptors
   
   • increase transcription and translation
5. Peptide hormones and catecholamines act on cell surface receptors and activate secondary messengers (rapid).

Question 10

Give an example of how hormones are activated peripherally:

Answer 10

• T₄ activated to T₃ in target tissue
• Testosterone (T) activated to dihydrotestosterone (DHT) in target tissue
• Conversion of androgen to estrogen in tissue
  
  • e.g. breast tumors and adipose tissue

Question 11

Describe peripheral actvivation of thyroid hormone:

Answer 11

• Thyroxine (T₄) and triiodothyronine (T₃) readily diffuse through the cell membrane
• Much of the T₄ is deiodinated to form T₃:
  
  • which interacts with the thyroid hormone receptor of the thyroid hormone response element of the gene.
  • bound as a heterodimer with a retinoidX receptor
• This causes either:
  
  • increases or decreases in transcription of genes that lead to formation of proteins
  • thus producing the thyroid hormone response of the cell
• Thyroid hormone acts on several different systems via mRNA

Question 12

What is the precursor to estrogen?

Answer 12

androstenedione (A)

Question 13

1. What is the function of aromatase?
2. What is the function of 17ß hydroxysteroid dehydrogenase?

Answer 13

1. Aromatase mediates androstenedione (A) ⇒ estrone (E₁)
2. 17ß hydroxysteroid dehydrogenase mediates estrone (E₁) ⇒ estrodial (E₂)

Question 14

How is estrogen important in breast cancer?

Answer 14

• Aromatase expression and enzyme activity in extraovarian tissues increases with advancing age
• Aromatase activity in skin and subcutaneous adipose fibroblasts ⇒ formation of systemically available estrone (E₁)
  
  • some estradiol (E₂)
• Circulating A to E₁ conversion in undifferentiated breast adipose fibroblasts
• Subsequent conversion of E₁ to E₂ in malignant epithelial cells provide high tissue concentrations of E₂ for tumor growth

Question 15

What is a potential therapy for breast cancer in postmenopausal women?

Answer 15

1. aromatase inhibitors
2. selective estrogen receptor modulators (SERMs)

Question 16

What blocks the production of DHT?

Answer 16

• antiandrogens
• 5-α reductase inhibitors

Question 17

Describe the simple negative feedback loop for hormone control:

Answer 17

• A sensor detects some regulated variable and responds by modulating its secretion of a hormone
  
  • pancreatic islet cell senses glucose and releases insulin
• This hormone, in turn, acts on a target to modulate its production of another hormone or a metabolite, which may affect a second target
• In addition, the other hormone or metabolite feeds back on the original sensor cell

Question 18

Describe negative feedback via hierarchical control:

Answer 18

• Under the influence of the cerebral cortex, the hypothalamus releases CRH, which stimulates the anterior pituitary to release ACTH, which, in turn, stimulates the adrenal cortex to release cortisol
• The cortisol acts on certain effector organs
• In addition, the cortisol feeds back on both the anterior pituitary and the hypothalamus

Question 19

When would positive feedback occur?

Answer 19

• Late follicular and ovulatory phases of the menstrual cycle
• Oxytocin release during pregnancy and parturition

Question 20

Describe the positive feedback in the late follicular and ovulatory phases of the menstrual cycle:

Answer 20

• high levels of estradiol
• cause greater secretion of the hypothalamic releasing hormone and trophic hormones in that system
• results in surge in pituitary hormone release
• responsible for ovulation at midcycle

Question 21

Describe the physiologic effects and regulation oxytocin release:

Answer 21

• release of oxytocin is stimulated by:
  
  • distention of the cervix toward the term of pregnancy
  • contraction of the uterus during parturition
• signals are transmitted to the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus
  
  • provide a positive feedback regulation of oxytocin release
• responsiveness of the uterine muscle is enhanced by:
  
  • increased number in oxytocin receptors
  • increase number in gap junctions between smooth muscle cells
  • increased synthesis of prostaglandins
• suckling of the nipple of the lactating breast also stimulates oxytocin release
  
  • afferent sensory signals elicit an increase in oxytocin release into the circulation

Question 22

What is primary hyperfunction?

Answer 22

• **too much production of the target **gland hormone that exerts the important systemic effect
  
  • usually caused by a neoplasm (often a benign adenoma) of the gland of origin that has lost its normal control
  • produces too much of its hormone in the absence of its normal stimulation (autonomous secretion)
  • Because of negative feedback, the normal controller of the hormone is suppressed

Question 23

What are examples of primary hypersecretion?

Answer 23

1. Adrenal Cushing’s syndrome:
   
   • cortisol overproduction from the adrenal adenoma (usually) that suppresses ACTH release from the pituitary
   • Therefore, diagnosis is made by measuring an increased cortisol and decreased ACTH
     
     • also called “ACTH-independent Cushing’s syndrome”
2. Graves’ disease (primary hyperthyroidism):
   
   • Excess thyroid hormone production independent of TSH
   • Therefore, diagnosis is made by measured increased thyroid hormone and decreased TSH

Question 24

What is secondary hyperfunction?

Answer 24

• too much production of the hormone that exerts the important systemic effect because it is being “told” to by an overproduction of the normal stimulator of that hormone
• IMPORTANT:
  
  • Although the normal stimulator of the hormone can be increased, it is often “within the reference range” for that hormone.
  • However, it should be suppressed if the target gland hormone is increased, so the normal hormonal stimulator of the target gland is “inappropriately normal” or “inappropriately not suppressed”

Question 25

What is an example of secondary hyperfunction?

Answer 25

* **Cushing’s disease** (pituitary hypersecretion of ACTH causes **ACTH-dependent Cushing’s syndrome**) * Because cortisol is increased, pituitary secretion of ACTH should be suppressed just like in adrenal Cushing’s syndrome * However, **ACTH is not suppressed** (although _often in the reference range_ for ACTH) * This **“inappropriately not suppressed”** ACTH secretion **maintains cortisol hypersecretion and adrenal hypertrophy**

Question 26

What is **primary hypofunction**?

Answer 26

* This is due to **loss of target gland function** due to a **pathophysiological process directly in the gland** * autoimmune destruction or surgical removal * In this case, the **target gland hormone will be low and the normal stimulator of that hormone will be increased** in an attempt to restore target gland function

Question 27

Examples of primary hypofunction:

Answer 27

1. **Primary adrenal insufficiency** (sometimes incorrectly given the generic name “Addison’s disease”) 2. **Primary hypothyroidism** (e.g. Hashimoto’s thyroiditis) 3. **Menopause** 4. **Male primary hypogonadism**

Question 28

What is **secondary hypofunction**?

Answer 28

* **normal stimulator of the target gland is inadequate,** and the target gland **does not produce a normal amount of its hormone** * often atrophies as a result * **IMPORTANT:** * Although the normal stimulator of the target gland is inadequate to maintain target gland function, it is **often “in the reference range”** * That is, it is **“inappropriately normal” or “inappropriately not increased”**

Question 29

What are examples of secondary hypofunction?

Answer 29

**Hypopituitarism** (also known as panhypopituitarism) Examples: 1. **Secondary adrenal insufficiency** 2. **Secondary hypothyroidism** 3. **Secondary (hypogonadotropic) hypogonadism**

Question 30

Describe the effect on the **target gland function** and **controlling hormone/factor:** 1. **Primary hypofunction** 2. **Secondary hypofunction** 3. **Primary hyperfunction** 4. **Secondary hyperfunction**

Answer 30