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161 Cards in this Set

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What are the 4 broad domains that hormones regulate?
1. Reproduction
2. Growth and Development
3. Energy (production, use, storage)
4. Maintenance of internal environment (homeostasis)
Examples
1. LH, FSH
2. Growth Hormone
3. Insulin, Glucagon
4. Aldosterone, ADH
What is a "hormone"?
Chemical messenger released by endocrine (i.e. ductless) gland that is transported in low concentration to target cells
Endocrinology = cellular communication by means of hormones
What is a "neurohormone"?
Neurohormone= chemical messenger secreted by NEURONS that is transported via circulation to target cell
It is a cross between a neurotransmitter (released by neurons) and a hormone (circulates in blood stream)
What determines the specific action of a hormone?

Where on a cell can these molecules be found?
Receptors on target cells.

They are expressed on cell surface or in cytoplasm/nucleus.
Distinguish between autocrine, paracrine, and endocrine hormones.
Autocrine= cell released a signal that stimulates itself

Paracrine= signal released stimulates nearby cell

Endocrine= signal released travels through blood stream to target distant cell.
What are the 3 general classes of hormones? Give an example for each class.
1. Peptides & Proteins (insulin, GH, prolactin)

2. Amines/ Tyrosine derivatives (thyroid hormones, catecholamines)

3. Steroids/Cholesterol derivatives (cortisol, estrogen, testosterone)
What is the difference between a peptide and a protein?

Give examples of hormones that fall into each category.
Peptide= 3-100 AA: TRH, IGH-1, Insulin

Protein= >100 AA: GH, Prolactin
What is C-peptide?

How is it used clinically?
C-peptide is part of Pro-Insulin. It is cleaved to make the mature Insulin molecule.

Levels of C-peptide can be used as a measure of insulin in the blood.
What is the structure of Insulin?
alpha-chain and beta-chain linked with disulfide bonds
What are some common properties of Proteins/Peptide hormones? (i.e. how are they synthesizes, stored, secreted)
Synthesized: from large precursors, cleaved in RER to prohormone

Storage + Secretion: secretory vesicles that are exocytosed

Mostly water soluble (small peptides can be protein bound).
What are two types of hormones made from Tyrosine?

Where are they made?
1. T4, T3 (Thyroid gland)- from 2 iodinated tyrosines

2. Catecholamines (E, NE, DA)- from single tyrosine precursor
What is the relationship between T3 and T4?

Which is more abundant in the body?
Both are thyroid hormones, named based on # of Iodines

T4 more abundant (10:1 ratio to T3)
Where is T3,T4 stored?

Where is E, NE stored? Which is the more abundant catecholamine?
T3,T4 stored in thyroglobulin (large soluble protein in lumen of follicle)

E > NE (4:1 ratio). Stored in secretory vesicles of adrenal medulla
What molecule binds T3, T4? Are thyroid hormones lipid or water soluble?

What molecule binds E, NE? Are catecholamines lipid or water soluble?
T3, T4= 99% bound to Thyroid Binding Globulin (TBG). Lipid soluble.

E, NE= ~50% bound to Albumin. Water soluble.
What is the structure of a cholesterol ester? What is it's function?
Structure= cholesterol with fatty acid tail

Function= synthesize steroids in adrenal cortex, gonads, and placenta
Are steroids lipid or water soluble?

What are they bound to and what percentage are free molecules?
Lipid soluble (diffuse across cell membrane)

>90% bound to plasma proteins. So 10% or less is free.
Between the free and bound hormones, which is considered active and which is the reservoir?
Free= active

Bound= Reservoir (extends 1/2 life for stable hormone)
T or F

Binding proteins such as albumin and TBG affect the Total but not Free hormone concentration.
True!

Total is affected because it factors in bound and free. Whereas free (unbound) is regulated by negative feedback in the blood.
If you have a mutation in TBG (Thyroid binding globulin), what would you expect the amount of the following to be:

Bound T4
Free T4
Total T4
Bound T4- low
Free T4- normal (blood levels are regulated)
Total T4- low (due to low bound T4)
Increased estrogen causes increased TBG. In a patient with increased estrogen, what would the amount of the following be:

Bound T4
Total T4
Free T4
Bound T4- increased
Total T4- increased
Free T4- normal (amount in blood is regulated)
What is the most common type of feedback mechanism for Hormone control? Give an example.
Negative feedback

ex: Increased T3, T4 will feedback on Hypothalamus and Pituitary causing decreased amounts of TRH/ TSH
What factors besides negative feedback can regulate hormone secretion?
- Positive feedback
- Releasing/ Inhibiting factors (ex: GHRH, SMS)
- Cyclical Variations (diurnal cycle, sleep, etc.)
Why should you always test TSH levels of a patient?
TSH is regulated by T3, T4 levels (negative feedback) and can tell you if there is too much or too little free hormone.

*note: free hormone tests are expensive
What is the relative T4 and TSH level in a person who has:

1. Hypothyroidism
2. Hyperthyroidism
3. Pituitary adenoma
4. Tumor smushing the pituitary
1. Hypo- T4 low, TSH high

2. Hyper- T4 high, TSH low (neg feedback)

3. Adenoma- high TSH (increased production), high T4

4. Tumor- low TSH, low T4 (everything is reduced). " CENTRAL Hypothyroidism"
Where are protein/peptide hormone receptors found? What about steroids?

Why does this make sense?
Protein- Cell surface (uses 2nd messenger signaling)

Steroids- cytoplasm/ nucleus & affect transcription (lipophilic, so it can get through membrane)
Activation of these receptors causes binding to specific areas of DNA called ______.
Hormone Response Elements (HRE)
What are the three major groups of Cell Surface receptors?

Provide an example of ligands for each group.
1. Receptor Kinases (ex: IGF-I, II)- the receptor is a tyrosine kinase
2. Receptor-linked Kinases (cytokines)
3. GPCR (LH, FSH, TSH, catecholamines, etc.)
Which is more diverse in terms of action, cell surface or nuclear/cytoplasmic receptors?
Cell surface (signal through 2nd messenger, can do many things- trafficking, protein/nucleic acid synthesis, enzyme regulation, etc.)
T or F

Steroid receptor signaling occurs only through gene transcription regulated by nuclear receptors.
False

New data shows that membrane receptors for steroid hormones exist!
What is an SERM? (hint: has to do with estrogen..)

What is it a broad example of?
SERM= selective estrogen receptor modulator

Compounds that bind ERs in breast, bone, uterus. Can be agonists, antagonists, etc.

Ex: Tamoxifen. can be used to fight breast cancer. Also for the cure of Osteoporosis.
Give an example of the following in the context of endocrine DEFICIENCY disorders:

1. Primary
2. Secondary
3. Congenital
4. Acquired
Primary= problem with thyroid gland that decreases hormone production.

Secondary= secondary hypothyroidsm (problem in brain)

Congenital= born without Thyroid hormone

Acquired= Hashimoto (Autoimmune) or cancer
What is an example of a Primary and Secondary Endocrine EXCESS disorder?
Primary= Grave's disease (too much TSH made)

Secondary= Tumor makes too much TSH

*usually tumor or autoimmune
Receptor/ Second messenger defects fall into what category of Endocrine Disorders?
Resistance disorders

Can be congenital or genetic
Why does a pituitary tumor often manifest as vision deficits?
It can squish optic chiasm which it's right behind.
What is the difference in embryological origin and hypothalamic communication between the anterior and posterior pituitary?
Anterior= adrenohypophysis. Rathke's pouch (pharyngeal epithelium). Hypothalamic neurons secrete factors into portal vein to regulate primary hormone synthesis + release.

Posterior= neurohypophysis (neural tissue/ extension of hypothalamus). AXONS from supraoptic & paraventricular nuclei DELIVER hormone to posterior pituitary.
What are the 5 major cell types (in order of frequency) of the Anterior Pituitary and what do they secrete?
1. Somatotrophs- GH (~50%)
2. Lactotrophs- PRL (25%)
3. Corticotrophs- ACTH (15-20%)
4. Gonadotrophs- LH and FSH (10-15%)
5. Thyrotrophs- TSH (<10%)
What is the role of Transcriptional activators?

What causes MPHD (multiple pituitary hormone deficiencies)?
Transcriptional activators- direct embryonic development of anterior pituitary

Inactivating mutations of these transcriptional activators causes MPHD
What is the role of HESX-1 and where is it found?
HesX1- expressed in stem cells, plays a role in optic n. and anterior pituitary development
How are HesX-1, PROP-1, and PIT1 related?
HesX --> PROP --> FSH/LH and PIT-1 --> GH, TSH

PROP1- feedback inhibits HSX-1 and is a precursor for PIT-1
PIT1- activates GH promoter and is expressed throughout life
Why is Prolactin unique from other hormones produces by the anterior pituitary?
2 reasons:
1. It can act DIRECTLY on breast
2. Regulated by DA which INHIBITS Prolactin
What are the 3 Major "Families" of Anterior Pituitary Hormones?
1. GH/Prolactin
2. TSH/ LH/ FSH
3. POMC (pro-opiomelanocortin)
What is the function of POMC?
Pro-opiomelanocortin

Hydrolyzed into ACTH, B-endorphin, MSH (melanocyte stimulating hormone)
What is the structure of GH/PRL?

What about TSH/LH/FSH/ HCG?
*structure determines grouping

GH/PRL= single chain polypeptides with internal S-S bridges

TSH/LH/FSH and HCG- Glycoproteins with alpha and beta subunits. (a-shared, B- unique)
What regulates GH (i.e. stimulates and inhibits) in the hypothalamus?

What regulates GH in the periphery?
Hypothalamus: GHRH- stimulates, SMS (Somatostatin)- inhibits

Periphery: Ghrelin- stimulates, IGF-1 (somatomeidin)- inhibits
Where does GH act and what does it stimulate the release of?
Liver (IGF-1)

Direct effects: Lipolysis (adipose), increase AA transport-muscle anabolism, increase glucose synthesis, inc. INSULIN RESISTANCE

Indirect
Growth Plate
Muscle (anabolism)
Soft tissue growth (connective tissue, tendon, etc.)
Gonads + Lymphocytes (? physiologic role)
Stomach (Ghrelin)
What time of the day do we see intermittent release of GH?

When in life do we see an increased spurt of circulating GH? What is it's normal course during aging?
Night (peaks in GH)

Puberty (growth spurt)
Normal to decline with aging
What is the Direct and Indirect action of GH?
1. Direct: Metabolic- lipolysis, protein synthesis, insulin resistance (fat/muscle)

2. Indirect: Growth (IGF-1)
When GH-binding protein binds to the GH-receptor, what happens?

What physiological states ACTIVATE GH release?
Dimerization of GHBP and GH-Receptor --> signal transduction in liver --> IGF and IGFBP synthesis

Hypoglycemia, Starvation, Exercise, Stress, Sleep
T or F

The only hypothalamic factor that regulates release of Prolactin in DA.
False!

TRH also oddly stimulates the release of Prolactin.

*note: prolactin INCREASES DA via negative feedback
What is the action of PRL in the body?
Puberty: Proliferation + branching of mammary ducts.

Pregnancy: Growth + development of mammary alveoli.

Milk production (stimulated by suckling/ breast feeding)
What is neurophysin?
A carrier protein that transports hormones to nerve terminals in the posterior pituitary (which are then released into circulation).
What hormones are stored in the Posterior Pituitary and what are their roles?
Vasopressin (ADH)- water, BP
Oxytocin- milk letdown (into sinuses from which it can be excreted in the nipple), uterine contraction

*note: Oxytocin does NOT PRODUCE milk
What physical parameters controls Vasopressin (AVP) and what detects these changes?

What is structure of AVP?
AVP= 9 AA peptide stored in posterior pituitary

1. Osmolality (osmoreceptors in hypothalamus)
2. Vascular volume/ pressure (baroreceptors in heart)
What 3 major receptors respond to AVP and what physiological effect do they produce when stimulated?
V1 (vessels: vaso-constriction)

V2 (renal tubule: water re-absorption = ADH, increases factor VIII)

V3 (corticotrophs- increase ACTH secretion, thus cortisol)
Why do hemophiliacs or some patients undergoing surgery get AVP supplementation?
It increases factor VIII of the clotting cascade (so helps promote clotting)

Specifically V2, renal tubule receptor
What is ADH more sensitive to- arterial pressure changes or osmolality?
Osmolality (small changes cause large increase in ADH).
Describe the defects in water regulation in the case of:

1. Central/acquired DI
2. X-linked nephrogenic DI
3. AR nephrogenic DI
1. Central DI: not enough ADH produced, so receptor is not stimulated

2. X-linked nephrogenic DI: mutation in the ADH receptor (normal ADH produced)

3. AR nephrogenic DI: mutation in aquaporin-2 (regular receptor and ADH)
Describe how in development, the gonads, kidneys, and adrenal gland get into close proximity?
1. Adrenal gland and kidney are at opposite ends of urogenital ridge and come inwards during development.

2. Germ cell migrate to UG ridge early on as well.

* Numerous genetic factors are important for this process.
What are "mullerian structures"?
1. uterus
2. fallopian tubes
3. upper 1/3 of vagina
What role do the following genes play in gonad differentiation?

SF-1
WT-1
SF-1 (steroidogenic factor)- TF for adrenals and gonads. Regulates UG development and AMH

WT-1 (Wilms tumor)- TF for kidney and gonads.
What is the role of SRY in gonad differentiation?
testis determining factor on Y chrom.

DNA binding protein to-
1)induce sertoli cell differentiation
2) formation of genital ridge
3) male-specific vasculature in testis

*if missing, no testes!
A young boy develops a hernia and is operated on to correct it. During the operation, a piece of a rudimentary uterus is discovered in his peritoneal cavity. How is this possible if he is a genetically 46XY male?
He has a mutation in AMH (antimullerian hormone) that prevents it from fully causing mullerian duct regression (so the boy develops a uterus).
When do germ cells begin to migrate?

Why do women (XX) develop a uterus, fallopian tube, and upper 1/3 vagina whereas men (XY) do not?
germ cell migration 5-6 weeks

Women don't have SRY gene and AMH secretion so default = women parts.
How is the Wolffian Duct different in XX vs. XY?
Wolffian duct in male differentiates into epididymis, vas def, etc (due to presence of testosterone)

In Women, this degenerates (no testes/ testosterone)
What hormone regulates the development of the UG sinus?

What does the UG sinus develop into in XX and XY?
Testosterone regulates the UG sinus.

In males it becomes the urethra. In females it becomes the urethra + vagina.
Describe the stages of External Genitalia Differentiation starting from 8wks to 14 wks.

When is differentiation complete?
8 wks: bipotential genital tubercle
9-10 wks: external genetalia differentiates (raphe beginning to close)
12 wks: testes descend
~13 weeks: differentiation complete
T or F

Like males, females require hormones for external genetalia differentiation.
False

Males require 1) Testosterone --> DHT, 2) androgen receptors

Females are the default.
A patient with ambiguous external genitalia is brought to your attention in the ER. The baby has an enlarged, phallus-like clitoris, but imaging shows normal ovaries, uterus, and fallopian tubes.Furthermore, no testes are found. It is exhibiting signs of shock (arrhythmias, dehydration, low bp) for which it was brought to the ER.

What do you suspect to be the problem? How would you treat it?
Suspect Congential Adrenal Hyperplasia: enzyme defect causing back up of steroid precursors (convert to DHT --> virilized external genetalia) and lack of mineralocorticoids and glucocorticoids (causing shock)

Treatment = surgical reconstruction of ext. genitals (raise child as female), and hormone replacement (GC and MC)
What hormone triggers release of LH and FSH from the pituitary?

What are the individual roles of FSH and LH on the ovaries and the testes?
GnRH (Gonadotropin releasing hormone)

FSH- Testis: stimulate spermatogenesis & sertoli cell fxn.
Ovary: stimulate growth of follicle

LH- Testis: stimulate leydig cell- testosterone secretion
Ovary: Make precursor that becomes estrogen, stimulates progesterone
What is the role of Kisspeptin in sexual development?

What hormone regulates it?
It is a protein (gene= Kiss-1) that initiates the secretion of GnRH at puberty.

It binds to GPR54 (a GPCR) and triggers release of GnRH and thus LH and FSH. Regulated by LEPTIN.
If a patient has a deletion in the gene for GPR54, what phenotype do you expect?

What about if they had a gain of function mutation in this gene?
Deletion of GPR54 = delayed puberty (no sex hormone surge at puberty)

Gain of function mutation- precocious puberty
Explain why an athletic olympic gymnast might not have reached menarch till 16 years of age (delayed)?
Tend to have little body fat, so leptin is very low (leptin is the "full" hormone). Leptin regulates Kisspeptin, which is necessary for the GnRH burst that initiates puberty.
Should you be worried if you see a 6 mo old boy with the testosterone level of a pubescent boy? What about a toddler with breast buds?
No! This is natural.

After birth FSH>LH increases (loss of neg. feedback because no connection to placenta which made estrogen/progesterone).
Why do some boys in early puberty have a little breast development?
FSH and LH surge increase estrogen levels (in men secreted by testes and adrenal gland). Breast tissue in early puberty is very sensitive to E2.
What physical changes are seen in puberty in females (list them in the order they occur)?
1. Breast development
2. Growth spurt
3. Menarche

*note: Pubic hair is not controlled by Hypothal/Pit/Gonadal axis
What is the role of the theca cells and granulosa cells in the ovary?

What stimulates each?
Theca: produces androsteindione which acts on granulosa (gets converted to E2) and progesterone. Stimulated by LH.

Granulosa: feeds and nurtures egg. Also helps make E2. Is sensitive to FSH.
What are the 2 phases of the menstrual cycle and how long do each start? When does ovulation occur during this time?
2 phases- each 14 days

14 days follicular
Ovulation
14 days luteal
Describe what happens in the Follicular phase of the menstrual cycle.
FSH--> 8-12 follicle growth, theca cells, granulosa cell (make E2 and Inhibin B)

LH--> stimulate theca cell (androsteindione)
What is the role of Inhibin B and in what cell is it made?

How does it play a role in the "dominant follicle" maturation?
Feeds back and inhibits FSH. Made in granulosa cells

Dominant follicle will have more FSH receptors ('tears out of the gate, ahead of the pack'). So it is thought that Inhibin B, by neg feeding back, will decrease FSH so other follicles will not be stimulated as much and only one will dominate.
Describe what happens on a hormone level to elicit ovulation.

What type of feedback mechanism is important in this process?
Prior to ovulation: dominant follicle produces E2 which inhibits FSH

E2 rise positively feeds back on LH (and slight FSH) and LH surge results --> follicle swell and rupture.

LH stimulate progesterone synthesis from granulosa cell.
Describe what happens in the Luteal phase if fertilization occurs and if it doesn't.
1. collapsed follicle forms CL
2. CL makes inhibin A, PG, E2

w/out fertilization: CL involutes, E2 and PG production decline, necrosis of cells and desquamation (you bleed!)

w/ fertilization: E2 from CL promotes gland/blood vessel growth, nutrients mucous, etc. Fertilized egg implants and voila you have a baby!
What physiological changes occur at Menopause?

Does FSH/LH rise or decline?
12 mo after last period
- ovarian follicles fall below threshold (rapidly decline with age)

-follicle loss, E2 and Inhibin A decline.

FSH rise 1st, then LH increase (remember loss of neg. feedback from E2!)
What is the role of Leydig and Sertoli cells?

Which sex hormone triggers which?
Leydig- trigger by LH (make testosterone and E2. DHT controls virilization)

Sertoli- proliferate and surround spermatogenesis in tubules, make ABP (androgen binding protein) and Inhibin B. Trigger by FSH.
What are the main physical changes seen in boys during puberty (in order of appearance)?
1. Testes enlarging (first FSH)
2. Virilization (next LH- testosterone-DHT)
3. Growth spirt
What is the role of ABP?
ABP= androgen binding protein (made in sertoli, binds testosterone and presents in to germ cells).

*another binding protein we've learned is IGFBP (helps IGF-1 circulate)
Describe the timeline of puberty in boys (in terms of hormone action).
1. FSH acts on Sertoli- grow and testes enlarge
2. LH act on Leydig- testosterone is formed- virilization (DHT)
3. Spermatogenesis begins mid puberty (need FSH & testosterone + ABP)

*growth spirt late in puberty
Describe the role of Estrogen on epiphyseal plates.
Early on in puberty E2 enhances growth.

High E2 at end/ after puberty- fuses growth plate.
What is SHBG?

How do it's levels change in girls vs. boys during puberty?
Sex Hormone Binding Globulin (binds T and E2).

At puberty, it decreases in boys (more free T), and increases in girls (less free T, so protection against effects of testosterone).
Women with Complete Androgen insensitivity have what karyotype?

What is the problem in these women?
46 XY
abnormal/ no androgen receptor (so testosterone is made but doesn't bind).

Phenotypically female but no secondary sex characteristics. They will have testis.
What type of receptor is the Androgen receptor?

Where is it expressed?
It is a nuclear receptor (transcription factor)- coded on X chromosome

Highly expressed in reproductive organs (penis)> skin>muscle
What are the 3 stages of Sexual Function? Briefly describe what controls each.
1. Libido (testosterone levels in BOTH sexes. DA and E2 promote, PRL inhibits)

2. Arousal- parasympathetic, NO and Ach release- inc. blood flow, secretions

3. Orgasm- Sympathetic, NE released. 5-HT is inhibitory. orgasm results.
What are some genetic and acquired causes of Primary Hypogonadism (aka. Hypergonadotrophic)?
GONAD Failure. Hypergonadotrophic because no feedback.

Acquired= drugs, irradiation, autoimmune.
Genetic= Turner, Kleinfelter, etc.

*also menopause
What are some congenital, genetic, and acquired causes of Secondary Hypogonadism (aka. Hypogonadotrophic)?
CENTRAL failure.

congenital: MPHD
genetic: Kallman's, Prader-Willi
Acquired: anorexia, chronic disease, prolactinoma, morbid obesity.
What is the difference between Gender Assignment, Gender Identity, Gender Orientation, and Sexuality?
Gender Assignment: boy/girl assigned by medical staff

Identity: what a person's perception is of their gender *may not occur for many years

Orientation: what gender a person is attracted to

Sexuality: a person's erotic desires, practices, sexual orientation
What is the role of the adrenal gland in the fetus?
It is made up of a fetal zone that shuttles androgens to placenta which makes estrogen.

After some time it also begins to make cortisol in the fetus.
What are the layers of the adrenal cortex (from outside to in). What is the function of the three outermost layers?
Out --> In
Glomerulosa: regulates salt (aldosterone/ mineralocorticoid)
Fasciculata: regulates sugar, glucocorticoids
Reticularis: makes adrenal androgens at puberty

*note: Medulla (sympathetic ganglion)- only 10-20% of the cortex volume
Trace the cortisol cycle from the hypothalamus down.

If there is a tumor compressing the adrenal gland, what would you expect the relative CRH level to be?
CRH (in hypothalamus) --> ACTH (in pituitary) --> cortisol (adrenal glands)

Tumor compress adrenal (squish it) -> ACTH decrease -> loss of neg. feedback so CRH increase
What critical hormone regulates salt in the body?

Describe how this process occurs when someone has low bp.
Aldosterone!

1. drop in bp= low blood volume (sensed by kidney JGA)
2. JGA secretes renin which convert angiotensiongen --> angiotensin I
3. Angiotensin I converted to A II by enzyme in vascular endothelial cells
4. A II stimulate aldosterone release
5. Aldosterone increases Na and H20 reabsorption, excretes K
What is another name for ACTH?

What is another name for CRH?

Why does it make sense that AVP is secreted concomitantly with CRH and amplifies ACTH secretion in situations of stress?
ACTH= corticotropin
CRH= CSH

AVP also released from pituitary because under stress you need to retain body fluids.
What us the major function of Cortisol?

What are it's other functions?
Glucocorticoid- maintains blood sugar.

Also
1. metabolism of carbs, proteins, fat (gluconeogenesis). makes you a little insulin resistant so you're not using glucose as quickly.
2. vital response to stress
3. controls inflammation (mobilize leukocytes)
What molecule does ACTH come from?

How does ACTH stimulate cortisol production/secretion?
POMC ('cortin' part is the ACTH).

ACTH activates GPCR to increase cholesterol transport & conversion of pregnenolone to cortisol.
At what time does cortisol peak? What time is its nadir?

How does cortisol circuate in the bloodstream?
Peak ~6am, Nadir ~midnight

Cortisol circulates bound to CBG (cortisol binding globulin)- 75% and albumin 15%

*only 10% is fee to get into cell & activate transcription
What enzyme normally inactivates cortisol in the kidney? Why does this need to happen?

Why can you become hypertensive eating a lot of licorice?
Cortisol inactivated to cortisone in kidney by HSD-2 (11B hydroxysteroid dehydrogenase). Cortisol normally binds aldosterone receptors which would further retain salt. Not needed in normal situation, but needed in high stress situation.

Licorice inactivates HSD-2, so you basically increase binding of aldosterone receptors and salt retention (increase bp).
T or F

Cortisol inhibits amino acid utilization in the body.
True!

By inhibiting AA utilization for protein synthesis, more can be converted to glucose via gluconeogenesis.
What is DHEAS?

What physical characteristics are seen during Adrenarche?
Adrenal androgen --> androsteindione --> Testosterone (and E2) in the periphery

Adrenarche- sweat glands, pubic and axillary hair (unclear role of other pituitary factors, ACTH plays a role too)
What is the rate-limiting enzyme of NE and E biosynthesis?

Describe the sequence in which NE and E are made.
Rate limiting= Tyrosine Hydroxylase (TH)

L-Tyr --> L-Dopa --> DA --> NE --> E

*NE to E conversion happens in the adrenal medulla. Cortisol activates PNMT to make Epinephrine (Paracrine action!)
If you wanted to measure levels of L-Dopa, DA, NE, and E in the body, what metabolites would you measure?
L-Dopa -> vanillactic acid (VNA)

Dopamine --> Homovanillic acid (HVA)

Norepi --> Vanillymandelic acid (VMA), normetanephrine

Epi--> Metanephrine
The majority of catecholamines produced in the adrenal medulla is ____.
Epinephrine (80% of catecholamine production)

major "fight or flight" hormone
Mutations in what three genes can lead to adrenal dysgenesis/hypoplasia?

hint: think of embryological factors
SF-1
DAX-1
ACTH-receptor
What are the 6 major causes of adrenal destruction?

Which are the two most common of these?
Autoimmune **
Metastatic **
Adrenoleukodystrophy
Infections (TB)
Hemorrhagic
amyloidosis (sarcoidosis?)


**= two most common
A patient comes into the ER, obtunded and febrile. PMHx is unremarkable except for a 6mo. course of dexamethosone which they recently ran out of and stopped taking. Endogenous steroid levels are taken and barely detectable.

What is going on here? What is the treatment!
Exogenous GC overload. During this time, the body produces less ACTH (because of feedback inhibition). Immediate removal rather than tapering causes low levels of cortisol because ACTH is low and will take some time to bounce back.

Treat with cortisol!
What percentage of the body's calcium is contained in bone?

Which is greater- the concentration of extracellular or intracellular calcium?
99% of body Ca2+ is in bone

[intracellular Ca] <<<< [extracellular Ca]
A patient getting a blood transfusion is loaded with citrate for anti-coagulant effects. 10 minutes into the surger, the patient has tetanic contractions. Explain this phenomenon.
Citrate and phosphate etc. can bind with free Ca2+ and thus decrease free calcium conc.

This causes a change in gradient, lowers threshold for action potential so cell starts to fire away.
What percent of Extracellular Calcium is ionized? what percent is bound and what is it bound to?
50% is free/ ionized

40% is bound (mainly to albumin)

The rest is complexed with anions such as citrate, etc.
What are the three organs that regulate Calcium?

What two hormones regulate calcium (briefly give their effects).
1. Bone (formation/resorption)
2. Intestinal mucosa (absorption via vit D/ secretion)
3. Kidney (filtration/ 99% reabsorption)

PTH (increases blood Ca2+)
Vitamin D (increases absorption of Ca2+)
What is the matrix of bone composed of?
Scaffolding= Type I collagen (organized in triple helix).

Osteoid= polymerized proteins such as osteocalcin and osteonectin bound to Ca2+. They get converted into HYDROXYAPETITIE (calcium phosphate crystals)- aka "the cement"
What are the three major cells of bone?
1. Osteoblasts- bone formation. Matrix formation. Have receptors for E2, PTH, vit D.

2. Osteoclast- bone remodelling: multinuclear macrophages. Have acid and protease enzymes to dissolve hydroxyapetite and collagen respectively.

3. Osteocyte- following calcification of osteoblasts- mature bone cells.
At what age does bone mass peak?

What happens to normal bone during aging?
Peaks in twenties, then declines.

Normally mineralized bone declines with age (becomes more hollow- more spaces).
How can PTH and VitD activate osteoclasts if they don't have receptors for the hormones on them?
Indirect activation (through secretion of soluble factors from osteoblasts).

Remember- they have receptors on Osteoblasts.
What does estrogen do to osteoblasts?

What about to osteoclasts?
Activates osteoblasts to make IGF-1 and OSTEOPROTEGERIN (inhibits osteoclast activation)

OPG inhibits osteoclast activation. E2 also suppresses IL-6 which has same effect.
What is the role of GH on bone growth/remodeling?
Direct effects and indirect via IGF-1

regulates bone turnover/remodeling
stimulates proliferation of articular chondrocytes (cartilage) & matrix production
What receptor on the Osteoclast does OPG bind to?


What else binds to this receptor?
RANK receptor (OPG is a RANK-ligand decoy)

Osteoblast also expresses a RANK-L that binds to RANK on osteoclasts and stimulates differentiation.
What are biochemical markers of bone formation? of bone reabsorption?
Bone formation= products of osteoblasts
-alk phos (makes hydroxyapetite)
-osteocalcin
-cleavage products of type I collagen

Bone resorption= break down products of osteoid
- urine excretion substances (collagen, hydroxyproline, etc.)
Describe the regulation of Ca2+ in blood by PTH and Calcitonin (CT), if you started with low serum Ca2+ levels...
1. Parathyroid stimulated to release more PTH
2. PTH promotes Ca2+ resorption from bone matrix into blood. Prevents loss of Ca2+ in urine.
3. PTH stimulates kidneys to release Calcitriol (1,25 OH-D)
4. 1,25 OH-D stimulates increased absorption of Ca2+ in gut
5. high levels of Ca2+ stimulate release of Calcitonin (CT)
6. CT inhibits osteoclasts (decreases Ca2+)
Where is Calcitonin made and what does it do?

Does it have an essential function in the human body?
Parafollicular cells of thyroid. It tones down blood calcium (inhibits osteoclasts).

Not essential function. If it's removed, blood calcium does not sky rocket. Same with if it's supplemented, blood calcium does not drop.
Where is PTH produced (be as specific as possible)?

How are calcium levels in the blood sensed?
Chief cells of the parathyroid gland.

Ca-sensing receptor on parathyroid cells is what controls PTH synthesis/release.
Describe the sequence of events when PTH activates it's 2 principle organs.
1. Bone: increased Ca, P resorption via osteocyte and osteoclast (PTH receptor on bone)

2. Kidney: inc. Ca, decreased P absorption, activates GPCR in kidney- conversion of 25 OH-D to 1,25 OH-D
What is the effect of PTH on phosphate?

If a person has a cancer expressing PTH-rp, what would you expect their Ca2+, Phosphate, 1,25-vit D, and PTH levels to be relative to normal?
PTH decreases Phosphate.

PTH-rp (related peptide) binds PTH receptor. Ca2+ inc, Phosphate dec, 1,25 vit D increase, PTH levels DECREASE (*negative feedback)
What is the structure of the Ca-sensing receptor?

How does it work to control the levels of PTH?
7 transmembrane GPCR.

Signals through PLC to inhibit PTH. High Ca2+ will prevent PTH activation. As Ca2+ level fall, inhibition is released.

*note: CaR is found in brain, skin, bone, thyroid C cells, renal distal tubule.
An inactivating mutation in CaR in the kidneys and parathyroids would result in what clinical state?
Hypercalcemia.

CaR can't sense calcium, so removal of tonic inhibition on PTH. PTH will upregulate Calcium production and Ca2+ levels with skyrocket.
What percentage of phosphate is in bones?

Which is more, the amount of Phosphate inside or outside the cell?
85 % in bone

14% in cells > 1% extracellular fluid
What is NPT2a and where in the body is it found in abundance?
Transporter of PO4, found in Kidney (major site of PO4 homeostasis).

NPT2a mediates PO4 reabsorption in the renal tubule.
What is FGF23 and what is it's role in the regulation of phosphate?
FGF23 is a phosphatonin (tones down phosphatae). It (along with PTH) DECREASES NPT2a expression.

FGF23 found in bone and acts on kidney to inhibit PO4 absorption. **cofactor Klotho needed to activate it's FGFR1 receptor.
Start with absorption from sun and trace the production of ACTIVE vitamin D.

What are the three major target tissues of vit D?
1. cholesterol derivative Chlecalciferol (D3) converted to 25OHD in liver (storage form).

2. Activated by PTH in kidney to active form 1,25 OH D

Bone: remodeling, mineralization

Small Intestine: Ca, P, Mg absorption

Skin: keratinocyte differentiation
What is the role of Mg on PTH?
High [Mg] inhibits PTH synthesis and release

however, Low [Mg] stimulates PTH (complicated mechanism)
How does vit D get around in the body and how does it get into and activate a cell?
Vit D is bound to DBP (D-binding protein).

VitD-receptor + Vitamin D enter cell and dimerize with Retanoid X receptor (RXR). This promotes transcription of Osteocalcin, Osteopontin, Alk phos, etc.
What is the level of Insulin during the Fed and Fasting states?

What is it's role in each state?
FED-HIGH, Anabolic (energy storage, growth, maintenance, Glucose disposal, AA synthesis). Synthesis of:
- Glycogen (liver, muscle)
- Fat (Liver, adipose)
- Protein (muscle)

FASTING-LOW (energy utilization, prevent hypoglycemia). Breakdown of
- Glycogen (L,M)
- Fat (Adipose tissue)
- Protein (M) for gluconeogenesis
What hormones regulate Fasting (Catabolic) states?

Why is it that when you haven't eaten for a while, your blood sugar might be completely normal but you will be jittery and feel sweaty?
Counter-regulatory (glucagon + Stress Hormones, i.e. Catecholamines, Cortisol, GH)

Your insulin drops to make sure you're not hypoglycemic, but low insulin will mean high Counter-regulatory hormones (so high catecholamines produce shakyness).
Describe how insulin is secreted once glucose enters the B cell?
1. Glucose enters via passive diffusion (gluT)
2. Phosphorylated (can't leave)
3. Glycolysis, Krebs, ATP forms
4. High intracellular ATP binds to and closes K+ channel
5. Membrane depolarizes and opens voltage gated Ca2+ channels. Ca2+ pours into cell
6. This allows fusion of granules containing insulin with cell membrane and release
What is the glucose sensor of the Beta cell?
Glut2 Receptor
Sulfonylurea drugs were used for diabetes treatment. Describe how?

Diazoxide is a drug that binds to K+ channels and opens them. What goes it do to Insulin? Would the person taking this drug be hypo or hyperglycemic?
Sulfonyl urea drugs: bind to partner protein on K+ channel and closes it faster. This means more depolarization, more Ca2+ intake, and greater insulin secretion response.

Diazoxides bind to the K+ channel and open it. This makes it harder to depolarize cell, open Ca++ receptors, and secrete insulin granules. So Insulin is low. A person would be hyperglycemic (aka diabetic!)
What part of the islet has exocrine function? What part has endocrine function?

What are the products of the three cell types in the Islets of Langerhan?
Outside= exocrine (GI system), Inside= endocrine (hormones)

alpha= glucagon
beta= insulin
delta= somatostatin
What is insulin synthesized from?

Describe the process by which mature insulin is made.
Made from pre-proinsulin.

It gets cleaved in secretory granule to proinsulin, and matures. When granule fuse with membrane, C peptide is cleaved and insulin is released.
What is the structure of insulin?
1 alpha, 1 beta chain joined by three disulfide bonds.
Why should you never give hyperglycemic or diabetic people IV bolus of insulin?
Because insulin has a half life of 3-5 minutes. It will be more effective if given constant infusion of insulin (or a pill that has modified the insulin so it is constantly released).
What is amylin? What is the ratio of amylin to Insulin?
Amylin is co-secreted with Insulin (1:100 ratio).

Suppresses post-prandial glucagon and slows down gastric emptying (basically helps with anabolic state).
When the Insulin receptor is activated, what signaling effects does it have?
Insulin binds to it's receptor- tyrosine kinase on intracellular domain phosphorylates Insulin Receptor Substrates.

- Activates downstream signaling pathways (protein synthesis, fat synthesis):
- Ras complex- gene transcription
- Also activates PI-3 kinase which regulates the movement of GLUT4 (in muscle or fat cell) to membrane (ACTIVE glucose transporter).
Where are the following glucose transport proteins found and what is each of their role?
Glut 1- all tissues (mediates glucose uptake esp. in brain)

Glut 2- "glucose sensor" in Beta cell, liver, GI, kidney- passive glucose uptake

Glut 3- All tissues, high affinity for neurons

Glut4- Skeletal and Adipose tissue, Insulin regulated, active glucose transporter
Describe the role of Insulin in each of the following tissues:

Liver
Muscle
Adipose
Brain
Liver: Stimulate glycolysis, FA synthesis. Inhibit gluconeo and ketogenesis

Muscle: Stimulate glucose uptake (Glut 4), stimulate glycolysis, increase protein synthesis

Adipose: Stimulate glucose uptake (Glut 4), FA uptake (for storage as TG)

Brain: NOT insulin requiring for glucose!!!!!!!!!
T or F

Insulin has a lot more roles than just to regulate blood sugar.
True!

Has functions in brain including satiety, appetite, maybe even alzheimers
What three compounds in the body provide energy during the Catabolic process?
Glucose (from Liver, and gluconeogenesis)

Fatty Acids (from TG in adipose, release of Hormone sensitive lipase) * NOTE: Brain doesn't use this

Ketone bodies: Made in liver from FA, used by all the tissues except liver (including brain!)
How does the brain get energy?

What one compound is not used by the brain as a source of energy?
Brain LOVES glucose, it steals it from the bloodstream. Does not require insulin for glucose (Glut 1 mediates uptake).

Does NOT use FA as a source of energy
What besides low glucose (hypoglycemia) stimulates the release of glucagon?

How does glucagon signaling work?
Catecholamines stimulate glucagon release

Signaling: acts through GPCR, signals via cAMP
If a person hasn't eaten for a while, what are the major sources of energy and which order do they occur in?
Glycogenolysis (minutes)
Gluconeogenesis (hours- from lactate and alanine, need ATP)
Ketogenesis (last)

*remember, muscle does provide glucose maintenance over long periods of time, that is the role of the liver
What is GLP-1? What is GLP-2?
Normally when proglucagon is cleaved it is made into glucagon. BUT, glucagon cleaved by a special prohormone convertase 1/3 into glucagon-like peptides (GLP-1 and GLP-2)

GLP-1: secreted from intestinal L cell after meals (increases insulin!)

GLP-2: secreted with GLP-1 and increases absorption, decreases motility).
Why is it that when a person is given food parenterally, their insulin is not as elevated as when they are given food enterally (my mouth)?
When food is taken by mouth, GLP peptides in the L cells of intestine are activated and will help increase Insulin levels (promote anabolism).

Whereas, this does not occur when sugar is given directly into blood stream.
If the dipeptidyl peptidase IV (DPP-IV) was inactivated, would you become hungrier or would you become more satiated?
DPP-IV = enzyme that inactivates circulating GLP-1. GLP-1 helps signal satiety to the brain. So if there is something inactivating the enzyme that breaks down GLP-1, it would stay active for a longer period of time and this would

INCREASE SATIETY. (hmmm diet pill?)
Where in the body is Somatostatin synthesized?

Which SMS is responsible for inhibitory effects on GH, insulin and glucagon?
Hypothalamus, pancreatic delta cells, GI
- At least 5 receptors (tissue specific). Different SMS in different tissues.

SMS-14 pancreas (more potent inhibitor of GLUCAGON)

SMS-28 gut (more potent inhibitor of GH, INSULIN)
What are the 3 major Counter-regulatory hormones and what are their actions?
1. Catecholamines (NE,E): stimulate glycogen breakdown, GN in liver, lipolysis (via Hormone-sensitive lipase)

2. Cortisol: proteolysis, GN, insulin resistance

3. GH: lipolysis, insulin resistance (though not as potent as cortisol)
What is the "dawn phenomenon"?
At Dawn, your body is in a fasting state and needs to get more energy. It's also the physiologic peak time of cortisol.

Cortisol increases and so does GH to regulate blood sugar.
Why does a person get diabetic ketoacidosis?
Insulin deficiency (diabetes) causes a person to be in a catabolic state. Ketone bodies are being formed in liver as a result of fatty acid breakdown. Also counter-reg's are higher and are promoting ketogenesis.