C2006/F2402 '11 Outline for Lecture 22 --  (c) 2011 D. Mowshowitz  -- Lecture updated 04/22/11

Handouts:    22A -- Endocrine vs Exocrine Glands, circulation & catecholamines,
                    22B -- Hormones Overall
                    22C -- Thyroid Structure and function; hormone synthesis & regulation (See Sadava figs. 41.9 & 41.10)
                    22D -- Lactation -- on Courseworks

This topic is not covered in Becker. It is covered in Sadava/Purves. If you want a more detailed treatment, any physiology book will do. There are lots of good physiology books available; the one by Sherwood  & the one by Silverthorn have been used here for the last few years.  There is an endocrinology book on line through Pubmed. Go to books to see the list of books available or to search by topic. Also don't forget about Kimball's biology pages.         
 

I. Introduction to Hormones (Endocrines) & Growth Factors

    A. How to describe or classify hormones?

1. Many Possible Classification Schemes -- Hormones can be classified by effect, chemical nature, source (which gland?), target cells, etc. etc. See Topic IV of Lecture 16 for 'How to Keep Track of Hormones.'

2. Today: We will look at (1) the major hormone-producing glands & (2) details for specific hormones.

    B.  Summary of typical hormone roles and examples (A repeat from lecture 16).  See Becker Table 14-3 or Sadava fig. 41.6 (41.5)  for a tabulation of hormones by type of function (Becker) or by source (Sadava).

1. Stress response -- cortisol, epinephrine. Regulate heart rate, blood pressure, inflammation, etc.

2. Maintenance of Homeostasis -- insulin, glucagon, cortisol. Regulate blood glucose/energy supplies and concentrations of substances in general. Maintain more or less constant conditions = homeostasis.

3. Regulation of episodic or cyclic events -- estrogen, insulin, oxytocin -- regulate lactation, pregnancy, effects of eating, etc.

4. Growth/overall regulation -- growth factors, tropic hormones  -- regulate production of other hormones. (Note: not all GF's are endocrines.)

5. Hormones may have more than one function. Note that some hormones are listed twice above, as many have multiple functions. For example, cortisol is constantly made to maintain homeostasis, but it is secreted in larger amounts in response to stress.

    C. Overview of Major Glands & Hormones -- see handout 22B for overview. For a complete list see Sadava fig. 41.6 (41.5)

1. Pancreas

a. endocrine gland -- secretes glucagon and insulin into blood -- These control blood sugar balance, as explained previously.

b. also exocrine gland -- secretes digestive enzymes through duct to GI tract.

What's the difference between endocrine & exocrine glands? See handout 22A.

(1). Exocrine Gland

  • When gland forms, epithelial layer leaves duct to outside.

  • Secretion from gland flows into duct outside or lumen.

  • Examples:

(i) sweat, mammary & tear glands secretion outside
(ii) stomach glands & pancreas → secretion lumen.

(2). Endocrine Gland

  • When gland forms, epithelial layer pinches off leaving no duct

  • Secretion (hormone) from gland enters blood.

  • Example: gonads, pancreas, adrenal.

(3) Both types get precursors for secretions from blood

c. Regulation -- secretion of glucagon/insulin controlled by blood sugar levels and by input from sympathetic (in response to stress).

2.  Adrenal Medulla & Cortex See Sadava fig. 41.12 (41.11).

a. Medulla (nervous)

(1). Stimulated by nerves

(2). Derived from neural tissue; part of autonomic NS.

(3). Secretes compounds that can act as transmitters (when signal cell to cell) but act as hormones (neuroendocrines) here -- are released into the blood.  Note same compound can act as a transmitter or a neuroendocrine.

(4). Major hormone = epinephrine (adrenaline); also secretes some norepinephrine (noradrenaline)For structures see handout 22A. More details below.

(5). Receptors. Receptors for these hormones/transmitters are same adrenergic receptors (α & β) discussed previously.

b. Cortex (epithelial)

(1). Stimulated by a hormone (ACTH)

(2). Derived from epithelial tissue

(3). Produces steroids  = corticosteroids. For structures see Sadava fig. 41.14 (41.12).

(4). Part of HT/AP axis; more details below.

3. Additional info on dopamine (DA) & related compounds  = catecholamines

a. Structures: See handout 22A for structures of  catecholamines = epinephrine (aka adrenaline), norepinephrine (aka noradrenaline), and dopamine. These are all modified amino acids derived from tyrosine. All water soluble. (Note thyroxine is also derived from tyrosine but is not a catecholamine; it is lipid soluble -- see below.)

b. Receptors: There are multiple receptors for all of the catecholamines. Receptors are classified by their ligands and responses to drugs.

    (1). Dopamine has its own receptors, separate from the adrenergic receptors (for epi and norepi).

    (2). FYI: All adrenergic receptors  bind to both epi and norepi. Some receptor types bind better to (have higher affinity for) one, some to the other, some equally well to both. 

  • Epinephrine acts mostly through beta adrenergic receptors.

  • Norepinephrine mostly through alpha adrenergic receptors.

c. Mechanism of action: All receptors for all catecholamines are G protein linked; effects of hormones on any particular cell type depend on

(i) what receptors are present

(ii) what G protein each receptor activates. Each G protein does one (or more) of the following:

  • activate adenyl cyclase

  • inhibit adenyl cyclase

  • activate phospholipase C. 

See Previous lectures & problem 6-21 and 6-22 for examples of different responses to epi due to diff. receptors. For an example of the effects of dopamine, see problem 6-24.

4. Hypothalamus (HT) -- neuroendocrine. HT is IC (integrative center) for many homeostatic circuits.

a. Inputs: 3 types of inputs

(1). neuronal

(2). hormonal

(3). local conditions. HT has sensors for some variables such as temperature, osmolarity.)

b. Outputs: To pituitary (also called hypophysis)

(1). To anterior pituitary (AP); also called adenohypophysis

(2). To posterior pituitary (PP); also called neurohypophysis

c. Details of structure and HT hormones below. (For structure, see handout 22B.)

5. Post. Pit. See Sadava fig. 41.7 (41.6).

a. Hormones =  ADH = antidiuretic hormone (aka vasopressin) and oxytocin.

(1). ADH. Affects water retention & vasoconstriction; has 2 names because discovered twice from the 2 different effects. Details of action on water retention to be described when we get to kidney. (Works through IP3 or cAMP.)

(2). Oxytocin. Affects milk ejection, uterine contractions -- works (at least in part) through IP3 to affect Ca2+ and therefore contraction

b. Origin/action of hormones: Peptides are very similar in structure (homologous = share common evolutionary origin)  but bind to different (G protein linked) receptors dif. effects.

6.  Anterior Pit -- Hypothalamus (HT) / Pituitary Axis

a. HT/Ant. Pit -- 3 stages

(1). HT hormones (releasing factors) that signal the AP. Hormones go direct to AP through portal vessel (see handout 22B).

(2). AP (anterior pituitary) → tropic hormones (ACTH, LH, etc.) that signal to glands (endocrine tissue)

(3). Glands lipid soluble hormones (steroids & TH) which control their target organs. Overall:

 HT releasing hormone AP   tropic hormone   TARGET GLAND hormone TARGET TISSUE action.

b. Example: How HT controls adrenal cortex (or see how HT controls thyroid in example on handout)

 HT CRH AP   ACTH   ADRENAL CORTEX corticosteroids TARGET TISSUES action

(1).  HT secretes corticotropin releasing hormone (CRH)

(2.) Ant. Pit responds by secreting ACTH (adrenal cortex tropic hormone; also called adrenocorticotropin) into general circulation

(3). Adrenal cortex produces steroids  = corticosteroids. For structures see Sadava 42.12 (41.11) . Three major types:

(a). Glucocorticoids. Ex: cortisol -- involved in regulation of energy metabolism and long term stress response (after epinephrine wears off) -- has multiple effects/targets, for ex. suppresses immune system. ACTH controls production of cortisol.

(b). Mineralocorticoids. Ex: aldosterone -- regulates salt balance (to be discussed when do kidney). Major control of aldosterone production is by other factors, not ACTH.  ACTH has only a weak effect on aldosterone.

(c). Sex Steroids  -- cortex produces low levels of sex hormones (both androgens and estrogens) in both sexes post puberty. That's how females get 'male' hormones and vice versa.

c. AP also  → "other hormones" (GH, Prolactin, etc.) that signal to nonendocrine tissues. More details below.

7. There are other glands/hormones -- the list so far is not exhaustive but covers most of the major players. See texts for complete lists.

It is worthwhile to memorize most of handout 22B in order to keep all the hormones and glands straight.

II. Details of HT& Pituitary Set Up

      A. Structure -- Two parts of pituitary (AP and PP) develop and function separately; connected differently to HT.   

1. Ant. Pit. (epithelial)

        a. Blood vessel goes direct from HT to AP. See Sadava  fig. 41.8 (41.7); handout 22B

  • Normally, blood flows from artery in general circulation → some tissue → vein in general circulation. Blood does not normally go direct from one organ to another.

  • Direct (Portal) vessel connects 2 organs.

        b. Release: Hormones released from HT into the blood travel through portal vessel direct to AP.

c. AP is Epithelial. AP consists of epithelial tissue that grows up from mouth.

2. Post. Pit. (nervous) 

a. Cells connect HT & PP. Some cells of HT have bodies in HT and axons/terminals in posterior pituitary.   See Sadava fig. 41.7 (41.6).

b. Release: Hormones (neuroendocrines) are released from nerve endings (terminals) in post. pit →  general blood supply.

c. PP is neural. PP consists of neural tissue that grows down from brain.

    B. Brief Aside on Heart & Circulation -- For set up of general circulation, see Handout 22A, bottom.

1. Overall view of circulation  -- 22A, bottom and Sadava p. 1050 (1049).

a. There are 2 loops of circulation -- to lungs (pulmonary) and to body (systemic) -- see picture on bottom of handout. Different blood vessels of systemic circulation go in parallel to various parts of body.

b. Arteries go away from the heart; don't necessarily carry oxygenated blood

c. Structure:

2. Portal Vessels

        a. Normal Set Up -- No direction connection between two organs. Blood goes through one organ, back to heart, through lungs, back to heart, and to second organ.  

b. Portal Vessels -- provide short cut from one organ to another; connect two capillary beds as in HT and AP. For an example, see handout 22B.

Note:  Gas exchange was discussed briefly in lecture 3 (see the section on the anion exchanger.) A more detailed discussion of Gas Exchange is in Lecture 23 of '05.  The details of this topic will not be covered in lecture and you are not responsible for them. A link is included if you are curious or studying for MCATs.

    C. Hormones of Hypothalamus

1. Outputs (to AP): Some cells in HT release hormones from HT itself. (As vs. cells that connect to post. pit.)

a. Release hormones into portal vessel (see above) that goes direct to anterior pituitary.

b. Hormones are release factors. Hormones released by HT affect production/release of other hormones by ant. pit.

c. Affect on release -- 'release factors' can be stimulatory (RH's such as ACTH-releasing hormone) or inhibitory (IH's such as prolactin release-inhibiting hormone = PIH)

d. All HT hormones (except PIH = dopamine) are peptides/proteins.

2. Outputs (to PP):  Some cells in HT release hormones (ADH & oxytocin) from nerve endings in PP.

a. Hormones are peptides.

b. Hormones made in HT but released from PP.

    D. Hormones of Anterior Pituitary

1. Table of Major Hormones of AP -- details below -- see handout 22B

Tropic (or Pseudo-Tropic) Hormone(s)
All are Peptides

Target Organ

Hormones/Secretions Made by Target Organ

ACTH (adrenal cortex tropic H.) or adrenocorticotropin

Adrenal Cortex

Glucocorticoids, Mineralocorticoids**
Sex steroids*

Gonadotropins -- LH (Luteinizing H.) and FSH (follicle stimulating H.)#

Gonads

Estrogens, androgens & progesterone*

TSH (thyroid stimulating H.) or Thyrotropin

Thyroid

Thyroxine*

GH (Growth H.) = somatotropin

Liver (& others)

Insulin-Like Growth Factors
(ILGF 1 & 2) = somatomedins

Prolactin

Mammary Gland

Milk

* All lipid soluble hormones travel through the blood attached to plasma proteins.
**Production of mineralocorticoids is largely controlled by factors other than ACTH.
Most sex steroids are made by the gonads. Only small amounts are made by the ad. cortex.

#FSH stimulates Sertoli & Granulosa cells; LH stimulates Leydig & Thecal cells.

2. Tropic Hormones

a. Made by ant. pit and influence other endocrine glands. All peptides

b. Release:  controlled by hormones from HT

c. Effect on target tissue

(1). Effect: Usually cause release of another hormone

(2). Mechanism: All tropic hormones work through G protein linked receptors and cAMP.

(3). What is released? Hormones released by targets are steroids or act like them (thyroxine).

(4). Question: Where are the receptors (for the appropriate hormone) on the AP? Endocrine glands? Target cells?

d. Three major tropic hormone types -- each type named after its target -- see handout 22B & table above.

See problem 7-4. (Skip choice 5 for now.)

3. 'Other Hormones 'of ant. pit.

a. GH and prolactin -- "pseudo tropic" hormones -- both peptides.

(1). Structure & mechanism: Similar in structure to each other (homologous) and use a special type of TK receptor

(2). Release: Release regulated by release/inhibitory factors from HT.

(3). What is released from target cells? Stimulate production of secretions, but not from endocrine glands.

(a). GH stimulates secretion of ILGFs

  • GH stimulates liver (& possibly other tissues) to produce insulin-like growth factors (ILGF 1 & 2).

  • ILGF's from liver are released into blood (act as endocrines).

  •  ILGF's from other tissues act as paracrines.

  • GH has other effects as well.

(b). Prolactin stimulates secretion of milk

PL stimulates mammary (exocrine) gland to produce milk. (Need oxytocin to eject the milk.)

Hormone (from AP)   Receptor & 1st Target   Secretion by 1st Target   Final Target
Tropic Hormone GPCR in endocrine gland endocrine (steroid or TH.) blood
Pseudo Tropic Hormones            
    GH (somatotropin) TKR in Liver* ILGFs blood
    Prolactin TKR in exocrine gland milk outside

* GH also effects other tissues -- some respond directly and some make ILGFs that affect other tissues/cells. ILGFs make by tissues other than liver are paracrines.
TKR = Tyrosine kinase receptor; GPCR = G protein coupled receptor

Try problems 7-1 & 7-13.

b. MSH (melanocytye stimulating H), endorphins & enkephalins.

(1). Common source: All come from cleavage of single peptide precursor (pro-opio-melanocortin or pomC) that is cut up to give ACTH and MSH etc.

(2). Alternative ways of cleavage: Same precursor can be cut up different ways in different tissues and/or species. Note: this is alternative processing of a protein, not an RNA.

(3). Function: Function of these hormones is relatively obscure. MSH may be involved in control of body weight as well as pigmentation.

(4). Protein Precursors: 'pro-hormones' & 'pre-pro-hormones':

(a). Many hormones are made as inactive precursors = pro-hormones. Example: pro-insulin. 

(b). 'pre-pro-hormone' = pro-hormone with its signal peptide still attached = sequence that gene codes for.

(c). Some enzymes are also made in an inactive forms (called zymogens) -- for example, trypsinogen, fibrinogen. Zymogen or pro-hormone has amino acids that must be removed to give fully active product (insulin,  typsin, fibrin, etc.).

Try Problem 7-2 & 7-4 if not yet done, but skip choice 5 (of 7-4) for now.

  III. Thyroid and Regulation

    A. Regulation of HT/AP Axis      

1. General case:  See Sadava fig. 41.9 (41.8)

a. The cascade: 

 HT RH AP   tropic hormone   TARGET GLAND hormone TARGET TISSUE action.

b. Negative FB: Hormone from target gland (thyroxine, cortisol, etc.) has negative feedback effect on  AP (& also in some cases on HT).

2. Specific case: thyroxine production (See handout 23B)

a. The cascade:

 HT TRH AP TSH TARGET GLAND TH TARGET TISSUE increase in BMR, etc. 

b. Regulation

(1). Negative Feedback: TH inhibits production of both TSH and TRH. (Where are the receptors? On cell surface or intracellular??) Primary effect is at AP -- reduces response to TRH.

(2). Two different types of goiter (enlarged thyroid)

(a). When TH is low (hypothyroidism) -- Lack of iodine or other factor low level of  TH

Low level of TH lack of negative feedback to HT &/or AP overproduction of TSH goiter. See Sadava fig. 41.10 (41.9)

(b). When TH is high (hyperthroidism): Have high level of TH but still have too much stimulation of thyroid. Problem can be

i. over production of TRH and/or TSH (due to tumors, failure of feedback, etc.), or

ii. over stimulation of TSH receptors by other factors. See Graves disease below.

(3). Graves disease = antibodies to TSH receptors act as agonists of TSH. (Case of (b -ii) above). Reminder:

  • agonist = acts like -- or has same effect as -- normal ligand

  • antagonist = blocks action of -- or effect of -- normal ligand

(4). What regulates hormone levels? It's different for TH & insulin.

(a). Levels of TH  production (& levels of TSH & TRH) are regulated by the hormone itself (TH). Same for cortisol, FSH, LH. 

(b). Levels of insulin production are regulated by [Glucose] levels in blood, not the hormone (insulin) itself.

    B. Production of Thyroid Hormone (aka Thyroxine or TH) -- see handout 23B or Sadava fig. 41.10 (41.9).

1. What does thyroxine do? Raises BMR and is needed  for normal alertness and reflexes. Needed during childhood for brain development.  See In Raising the World’s I.Q., the Secret’s in the Salt This article is part of a series from the NY Times (2006). Articles in this series examine diseases that hover on the brink of eradication, and the daunting obstacles that doctors and scientists face to finish the job.

Here are two more recent articles on Thyroid Function from the NY Times:
    Prenatal Testing of Thyroid Debated
    Raising the World's IQ (an op ed)

2. Biochemistry: Structure of TH -- How modification and rearrangement of tyrosines in thyroglobulin (TG) leads to TH. (See handout.)

3. Cell Biology: How is thyroxine made & stored?  How (& where) TG is made & TH released from it. 

1. TH made in follicle of thyroid gland

2. protein (TG) made on RER Golgi vesicles

3. exocytosis of vesicles releases TG into lumen

4. Iodine taken up into gland;

5. Iodine added to tyrosines of TG in lumen; one modified tyrosine added to OH of another. 

6. Modified TG stored in lumen of gland = reservoir of TH

7. TG taken up by cell from gland by RME.

8. TG is degraded in lysosomes releases T4 or T3 (= TH)

9. TH  diffuses out of cell across membrane. Acts like a steroid. (For structures see handout or texts.)

4. TSH stimulates virtually all of the steps listed above.

5. How does thyroxine travel through the blood? All lipid soluble hormones are attached to plasma proteins, either to general proteins or specific binding proteins for that hormone. T4 and T3 are transported by thyroxine-binding globulin, which is specific for thyroxine. Note: thyroglobulin is not the same as thyroxine-binding globulin. (Globulin just means globular, soluble protein.)

Try problem 7-5 & 7-9. (If you have time, there are additional problems on this topic -- most of problem set 7. )

IV. Examples of how hormones and nerves co-operate to run a circuit. See handout 22D -- two representations of the circuit. These may not be discussed in class, but you should be able to follow the processes in both cases.

   A.  Lactation

1. Overall Loop: Suckling by baby milk ejection ("letdown) more suckling   more milk ejection etc. Loop continues until baby stops nursing.

2. Signaling Pathway: Suckling by baby stimulates nerve endings in nipple nerve signal to HT release of oxytocin and prolactin as follows:

a. Oxytocin: HT release of oxytocin from neuron endings post. pit. contraction of myoepithelial cells (similar to smooth muscle)  surrounding alveolus (milk producing section of mammary gland) milk ejection from lumen of alveolus more suckling etc.

b. Prolactin: HT  PIH (= DA) down and PRH (?) up in portal vessel  AP releases prolactin (PL) stimulates inner layer of cells surrounding lumen of alveolus   promotes milk production and secretion of milk into lumen of gland.

3. Receptors. Oxytocin uses a GPCR; PL & GH (the pseudo tropic hormones) use tyrosine kinase receptors (TK receptors or RTKs).

Question to think about: what does the circuit look like here? What's the IC? The effector? Etc.

Try problems 7-15 & 7-19.

    B. Stress response  

1. Phase one -- Nerve (Sympathetic) activity stimulates target organs (that are not glands) Direct response of heart, liver, lungs, etc.

2. Phase two -- Nerve (Sympathetic activity) activation of glands

a. Stimulate pancreas glucagon release stimulated; insulin release inhibited secretion of glucagon additional stimulation of some of same target organs

b. Stimulate adrenal medulla release of epinephrine stimulation of same targets as sympathetic nerve activity & some additional targets -- hormones can reach where nerves can't go.

3. Phase three -- stimulate HT/AP axis to produce cortisol

 HT in brain releases CRH AP releases ACTH adrenal cortex produces cortisol target organs stimulation of breakdown of fats & protein for energy (sparing glucose for brain); inhibition of immune system.

Note that each additional phase is slower but involves additional degrees of amplification due to second messengers, transcription, etc.