Lecture 1-3 – Hormone Synthesis

1. What is a Hormone?
a. Chemical substance (peptide, steroid, or amine) that is secreted into the internal body fluids by cells
and binds to specific receptors on specific target cells and has a physiologic control effect on the body
b. Hormones can be either hydrophilic or hydrophobic
i. Hydrophobic hormones (steroid hormones) travel in the blood with the help of a hydrophilic
carrier protein & are able to pass through the cell membrane to bind receptors within the cell
ii. Hydrophilic hormones (protein hormones) cannot pass through cell membranes on their own
and instead must bind receptors on the surface of the cell membrane
c. Hormone Receptors
i. Composed of protein & have a specific shape/bioelectric configuration for unique binding
ii. Binding results in a chemical chain reaction, often involving the reading of DNA or RNA within
the nucleus resulting in the production of proteins, other hormones, cell growth, or attenuation
d. Chemical Messengers
i. Hormones help regulate the metabolism of cells in a wide variety of ways at specific times
ii. Examples – Sex hormones
1. Testosterone & Estrogen are released in much greater quantities around 12 year old
2. Homeostasis
a. Tendency to maintain various cellular & whole body metabolic condition at  constant optimal levels in
spite of significant environmental changes that want to disrupt it
b. Examples
i. Body temp, BP, BS, brain glucose supply, O2 supply to the tissues etc.
ii. Primary systems involved in homeostasis are the nervous, immune, & endocrine systems
3. Endocrine Glands
a. Hypothalamus, Pituitary, Thyroid, Parathyroid, Adrenal, Pancreas, Ovaries, & Testes
4. Major Hormones & Glands
a. Hypothalamus
i. TRH
ii. CRH
iii. GnRH
iv. GHRH
v. Somatostatin
vi. Dopamine (aka Prolactin Inhibiting Factor)
b. Anterior Pituitary
i. FSH
ii. LH
iii. ACTH
iv. TSH
v. Prolactin
vi. Intermediate MSH
vii. GH
c. Posterior Pituitary
i. Oxytocin
ii. ADH
d. Thyroid
i. T3,T4
ii. Calcitonin
e. Parathyroid
i. PTH
 f. Pancreas
i. Insulin & Glucagon
g. Adrenal Medulla
i. Epi & Norepi
h. Kidney
i. Renin & 1,25-Dihydroxycholecalciferol
i. Adrenal Cortex
i. Aldosterone, Cortisol, Adrenal Androgens
j. Testes
i. Testosterone
k. Ovaries
i. Estrogen & Progesterone
l. Corpus Luteum
i. Estradiol & Progesterone
m. Placenta
i. hCG, Estriol, Progesterone, & HPL (human placental lactogen)
5. Glands & Hormone Types
a. Hypothalamus
i. All are peptide EXCEPT dopamine – which is an amine
b. Anterior Pituitary
i. All are peptide
c. Posterior Pituitary
i. All are peptide
d. Thyroid
i. T3/T4 are amines
ii. Calcitonin is a peptide
e. Parathyroid
i. PTH is a peptide
f. Adrenal Cortex, Testes, Ovaries, & Corpus Luteum
i. All are steroids
g. Placenta
i. Estradiol & Progesterone are steroids
ii. hCG & HPL are peptides
h. Pancreas
i. Insulin & Glucagon are peptides
i. Kidney
i. Renin is a peptide
ii. 1,25-Dihydroxycholecalciferol is a steroid
j. Adrenal Medulla
i. Epi & Norepi are amines
6. Hormones & Types
a. Dopamine, Epi, & Norepi are all amines as well as T3/T4
b. Hypothalamus, Anterior/Posterior Pituitary, Parathyroid, Pancreas area all peptides
c. Calcitonin = peptide
d. hCG & HPL = peptides
e. Renin = peptide
f. Adrenal cortex, Testes, Ovaries, Corpus Luteum = all steroids
g. Estradiol & Progesterone = steroids
h. 1,25-Dihydroxycholecalciferol = steroid
7. Further Broken Down
a. Peptides & Proteins
i. Glycoproteins
1. TSH, FSH, LH, hCG
ii. Polypeptides
1. GnRH, GHRH, CRH, Somatostatin
2. ACTH, MSH, Prolactin, GH
3. Oxytocin, ADH
4. PTH
5. Calcitonin
6. Insulin, Glucagon
7. HPL
8. EPO, GI hormones, IGF, ATII
b. Steroids
i. Aldosterone, Cortisol, DHEA
ii. Testosterone, Estrogen, Progesterone
iii. Estradiol
iv. Vitamin D
c. Amines
i. Norepi, Epi
ii. Thyroxine (T4)
iii. Triiodothyronine (T3)
8. Good Things to Know
a. β-specificity on Glycoproteins
i. All 4 of the Gonadotropins (TSH, FSH, LH, & hCG) have the same α subunit but different β
1. This does however cause some overlap in their effects
b. Which bind intracellular receptors?
i. Steroids
c. Which are derived from Tyrosine?
i. Amines  Epi/Norepi & T3/T4
d. Specific second messengers?
i. Coming up
e. Steroids are hydrophobic and need to bind to carriers (helps them stay in the blood longer & maintain
consistent plasma levels)
f. T3 & T4 also bind carrier proteins BUT Epi & Norepi do not
g. Generally, smaller peptides have shorter T1/2
h. Glycosylation increases T1/2
i. Among polypeptides, only IGF has plasma binding proteins
9. Four Chemical Classes of Hormones
a. Proteins/Peptides
i. Short chains of AAs (peptides) or longer chains & more complex (proteins)
ii. Because of the protein make up, these can’t be ingested due to H+ & gastric enzymes
iii. This is why insulin must be injected rather than ingested
b. Steroids
i. Distinguished structurally by their 4 ring back backbone – different chemical groups attached
c. Amines
i. Structually simplest, modifying single amino acids forms these hormones
d. Eicosanoids
i. Yep
10. Lipid soluble hormone T1/2?
a. Directly proportional to the affinity of the hormone to it’s plasma protein carrier
b. T4 has the highest affinity for its carrier & thus has the longest T1/2
11. Difference between a polypeptide & a glycoprotein hormone?
a. Glycoproteins have carbohydrate side chains
12. Hydrophillic  peptides/protein hormones
13. Hydrophobic  steroid hormones
a. Bind receptrs in the nucleus – commonly talking about Aldosterone, Cortisol, or T3
14. Peptide/Protein Hormones
a. Fast Facts
i. 3-200 Amino acids long
ii. Synthesized and then STORED in secretory granules before being released in bursts
iii. Generally circulate unbound in plasma
1. Exception is IGFs that do have plasma binding proteins
iv. Bind extracellular receptors & therefore rely on 2nd messengers for signal transduction
1. Effects are very rapid (mins) & the initial effects do not depend on new protein synthesis
2. Cascade of events usually resulting in phosphorylation
b. Important
i. Peptide hormones are large molecules of AAs that may be modified by glycosylation
ii. Generally soluble in blood  don’t need binding proteins (except IGF)
iii. Generally insoluble in lipid  can’t access interior of the cell via diffusion like steroid hormones
iv. Large peptides are unable to be filtered at the glomerulus, small ones (ATII etc) can be filtered
at the PCT & taken up by the cells
v. Stored in vesicles & released upon endocrine cell stimulation
c. Synthesis????
i. Often synthesized as preprohormones
ii. 1° synthesis of the preprohormone occurs on the RER before processed to prohormone in Golgi
iii. Secreted as the hormone
d. Secretion
i. Occurs via exocytosis that is initiated by a stimulus that raises IC Ca2+ levels & usually cAMP
ii. The secretory granules are lined up & translocated to the plasma membrane via activation of
microtubular & microfilament system
iii. Membranes fuse, the common membrane is lysed releasing hormone into the interstitial space
iv. If you have a peptide hormone that is not being released for some reason, could be due to
defect in transport of that hormone to the cell surface
15. Steroid Family Peptides
a. Fast Facts
i. Small lipid molecules derived from cholesterol
ii. These are NOT STORED, but rather synthesized de novo on demand
iii. Circulate bound to globulins & plasma proteins before binding intracellular receptors (nuc/cyto)
iv. Effects are slow (hours to days) as they require gene transcription & protein synthesis
v. Similar MOA for Vit D, Steroids, & Thyroid hormones
vi. Hormones are either diffused into the cell or carried in via membrane receptor
vii. Binds to the C-terminus of a specific IC receptor forming a hormone receptor complex (cyt/nuc)
viii. The hormone receptor complex causes a conformational change in the receptor allowing it to
translocate to the nucleus (if cytoplasmic) or bind to a hormone response element (HRE)
ix. This results in gene transcription (mRNA synthesis) & synthesis of protein (gene translation)
1. Either stimulation or repression of genes
 b. Major Steroid Hormones
i. Cortisol & Aldosterone  21 carbons
ii. Androgens (testosterone)  19 carbons
iii. Estrogen/Estradiol  18 carbons
iv. Also 1,25-Dihydroxycholecalciferol
c. Synthesis
i. Steroid hormones are synthesized on the SER (compared to proteins/peptides of the RER)
ii. 80% of the cholesterol needed is taken up via LDL particle receptor mediated endocytosis
iii. 20% is synthesized de novo (from Acetyl CoA, LDL, VLDL)
d. More Fun Facts
i. Steroid hormones have low solubility in the blood (need plasma binding proteins)
1. There is always some amount that is circulating free and this free fraction is active form
ii. Steroid hormones have high solubility in lipid environments (cell & nuclear membranes)
1. Theyre able to easily diffuse most often, occasionally facilitated diffusion
iii. Again, steroid hormones are generally not stored but rather synthesized de novo PRN and
released into circulation as they are made
1. Generally before release, additional modifications occur in the liver & kidney – sulfation,
glucuronidation – that tend to inactivate the hormone & increase solubility without
need for large binding proteins – in this form they can be eliminated in the urine
iv. Otherwise these hormones are bound to large proteins they are not filtered at the glomerulus
v. Most but not all involve hormone receptor complexes binding to DNA HREs
1. Causes increased or decreased transcription of particular genes  changes protein expr.
vi. The lag time (mRNA & protein synthesis) as well as the need to be synthesized de novo means
the full effect from steroid hormones may take hours to occur (prednisone, etc)
16. Amine Hormones
a. Fast Facts
i. Synthesized from Tyrosine & stored for instant release upon stimulation
ii. Thyroid Hormone (TH aka T3)
1. Thyroglobulin molecules are produced in the thyroid & contain Tyrosine
2. Iodine is chemically bound to these tyrosines & packaged together to form T3
3. Circulates >99% bound & thus has a very long T1/2 (days)
4. Initial transport into the cell via plasma membrane transporter but binds intracellular
receptors
5. Effects are slow (hours to days) as gene transcription is required
6. Can also be formed in the cytoplasm from free Tyrosine & stored & secreted from
secretory vesicles similar to peptide hormones
a. Have extracellular receprors that act through various 2nd messengers
iii. Epi/Norepi
1. Circulate unbound
2. Very short T1/2 – 2-3 minutes
3. Bind to extracellular receptors
17. Feedback Loops
a. Idea is that all hormones have some sort of negative feedback
i. Exception is Oxytocin & Estrogen that can have sometimes have positive feedback
b. Negative Feedback
i. Most common method of hormone regulation, self-limiting
ii. Hormone with biologic activity directly or indirectly inhibits further secretion of itself
c. Positive Feedback
 i. Rare, explosive, & self-reinforcing
ii. Example
1. Just prior to ovulation, estrogen increases & acts on AP to secrete more LH
2. The additional LH acts on the ovaries to produce more estrogen
iii. However, Oxytocin is the only TRUE positive feedback
d. Long Loop
i. Hormone produced by the AP acts on a target organ to increase hormone production
ii. That hormone then feeds back to the AP or HP to decrease release from AP or HP
iii. HP releases TRH  AP releases TSH  TH increases T3/T4 – once high enough inhibit AP/HP
e. Short Loop
i. Hormone produced by the AP due to stimulation by a HP hormone feeds back to the HP
ii. ACTH feeds back to the HP to inhibit CRH
f. Ultra-Short Loop
i. Hormone released by the HP acts directly on the HP to inhibit its own production
ii. GnRH from HP to HP
18. Endocrine Defects
a. Primary
i. Target gland itself is affected
b. Secondary
i. Occurs when the initial disorder is in the pituitary & the problem is seen in the target organ
c. Tertiary
i. Disorder originates in the hypothalamus
d. VERY IMPORTANT
19. Abnormal Normal
a. Hormones act with positive or negative feedback with appropriate up or downregulation of hormone
b. Example
i. When you give cortisol, should see a fall in ACTH
ii. If ACTH does not decrease as would be expected, you have an abnormal normal value
20. Regulation of Receptors
a. Hormones determine the sensitivity of the target tissue by regulating the # or sensitivity of receptors
b. Sensitivity = hormone concentration that produces a 50% max response
i. Can be changed by changing either the # of receptors or the affinity of the receptors
c. Downregulation of Receptors
i. Ex: in the uterus, progesterone down-regulates it’s own receptor & the receptor for estrogen
d. Upregulation of Receptors
i. In the ovary, estrogen upregulates its own receptor and the receptor for LH
21. Hormone Regulation & Feedback
a. Induction of a Counteracting Hormone
i. Insulin is secreted during nutrient excess resulting in decreased glucagon (prevents  sugar)
b. Modified to be Inactive
i. TH (T3) can be iodinated in different places
ii. Vitamin D can by hydroxylated & inactivated
c. Hormone is Degraded & Excreted
i. Usually by the liver and/or kidney
ii. More rapid degradation allows more rapid up/down regulation of hormone levels

Lecture 2 – Regulation of Hormone Receptors, & MOA/Second Messengers of Hormones

1. Cell Signaling
a. Endocrine Signaling – circulating hormones in the blood, disseminates widely, far away target cells
 b. Paracrine Signaling – cells secrete local chemical mediators or local hormones & are quickly destroyed
c. Autocrine Signaling – local hormones bind to and affect only the cell that secreted them (seconds long)
d. Synaptic Signaling – NT released into clefts from their presynaptic knobs, generally affect only 1 neuron
2. Mechansims of Action
a. Note the differences
i. ADH via V2 receptor is Gs AC cAMP
ii. ADH via V1 receptor is Gq PLC IP3/Ca2+
3. Steps in G-protein  AC  cAMP pathway
a. Three Subunits
i. α, β, & γ
ii. α subunit can bind either GDP or GTP
iii. When GDP is bound to the α subunit, the G protein is inactive
iv. When GTP is bound to the α subunit, Gαs dissociates and is active
v. Can either have Gαs or Gαi – stimulatory or inhibitory
b. Basic Steps
i. Ligand binds G-protein coupled receptor
ii. GDP is released to allow GTP to bind (now in the active state)
iii. Gαs protein binds AC which will now convert ATP  cAMP
iv. 4 cAMP molecules will then bind PKA
1. PKA has 2 regulatory subunits & 2 catalytic subunits
2. The 2 regulatory subunits are activated & phosphorylate downstream enzymes
v. cAMP is eventually inactivated to 5-AMP by phosphodiesterase enzymes
vi. Gαs has intrinsic phosphatase activity
c. Gq-PLC Mechanism
i. Hormone bind G protein, GDP is released allowing GTP to bind the αq subunit
ii. The αq subunit stimulates PLC which converts PIP2  IP3 & DAG from the membrane lipids
iii. IP3 mobilizes Ca2+ from the ER which together with DAG activates PKC
iv. PKC then phosphorylates proteins & causes specific physiologic effects
4. Tyrosine Kinase Receptors
a. All TyrK Receptors use some form of autophosphorylation inside the cell after the ligand binds
b. May also result in receptor dimerization or may already be in a dimer
c. Main point  no AC & no PLC acting as second messengers
d. Most TyrK is some sort of growth factor mediated mechanism
i. Insulin, IGFs, Leptin, & GH (GH does act on Jak/Stat)
5. Catalytic Receptors (Enzyme Linked Receptors)
a. Jak-Stat pathway, important in Leptin signaling & in GH signaling as well as many immune pathways
b. Example
i. Leptin binds the extracellular portion of the homodimer receptor
ii. This causes phosphorylation & activation of the intracellular janus kinase Jak2
iii. This causes phosphorylation of Signal Transducer & Activator of Transcription (STAT) protiens
which then activate the transcription of target genes & synthesis of proteins
iv. JAK2 phosphorylation also activates several other enzymes systems that mediate some of the
more rapid effects of Leptin
6. Calcium-Calmodulin
a. Hormone binds G-protein coupled receptor
b. Results in the opening of the cell membrane Ca2+ channels & release of Ca2+ from the ER
c. Increased intracellular [Ca2+] allows Ca2+ binding to Calmodulin to form a complex – produces actions
7. Things to Know
 a. Hormones bind the extracellular receptor (first messenger or primary messenger)
b. Messenger acts on enzymes or channels to alter
i. Formation of cAMP or cGMP (2nd messenger)  amplification of the signal
ii. Alter phosphorylation of patterns on enzymes
iii. Alter cystoplasmic Ca2+ levels
iv. Alter breakdown of membrane lipids to form IP3 & DAG
c. May occur many times in order to amplify the initial effect (1 hormone induce 100s of phosph. protein)
d. Initial effects are very rapid – minutes
i. Generally do not depend on new protein synthesis (although later effects do in many cases)
e. Primary effects are to activate/inactivate existing proteins (phosphorylation/dephosphorylation)
8. Steroid Hormones
a. Bind protein receptors that have specific domains (
i. Ab binding region, DNA binding domain, Zinc fingers, Hormone binding region
b. Mutations in parts of these domains can cause disease
i. Hormone dependent or Independent cancers
c. Hormone-receptor complex dimerizes where it binds steroid response elements
9. Steroid Hormone & Thyroid Hormone Mechanism
a. Step 1 – Steroid or T3 diffuse across the cell membrane to bind their receptor
b. Step 2 – Hormone receptor complex enters the nucleus & dimerizes
c. Step 3 – Hormone receptor dimers are transcription factors that bind to steroid-responseive elements
(SREs) of DNA
d. Step 4 – Initiation of DNA transcription
e. Step 5 – New mRNA is produced, leaves the nucleus, & is translated to synthesize new proteins
f. The new proteins have specific physiologic actions
10. Measuring Hormone Levels
a. Development of RadioImmunoAssa (RIA) about 35 years ago
i. Very sensitive
ii. Disadvantage is measures antigenic activity which doesn’t always equal biological activity
iii. Need to know that RIA is used to measure hormone levels, but doesn’t give you activity
b. Can also do ELISA or other immunoassays

Lecture 3 – Hypothalamic-Pituitary Relationships

1. Hypothalamus
a. Links the nervous system to the endocrine system via the pituitary gland (hypophysis)
b. Responsible for certain metabolic processes & other activities of the ANS
c. Controls
i. Body temp, hunger
ii. Parenting & attachment behaviors
iii. Thirst, fatigue, sleep, circadian rhythms
d. Regions
i. Medial Preoptic Nucleus
1. Regulates gonadotrophic hormone release from the adenohyphysis
2. Contains the sexually dimorphic nucleus which releases GnRH
ii. Supraoptic Nucleus
1. Vasopressin release (ADH)
iii. Paraventricular Nucleus
1. TSH, CRH, Oxytocin, & Somatostatin release
iv. Suprachiasmitic Nucleus
1. Circadian rhythm
 v. Arcuate Nucleus
1. GHRH, Feeding, Dopamine
2. Anatomy
a. Pituitary is Divided into 2 Lobes
i. Anterior lobe  adenohypophysis  funnel like extension of 3rd ventricle (ectoderm derived)
ii. Posterior lobe  neurohypophysis  protrusion of nerve tissue from hypothalamus
(neuroectoderm derived)
b. Empty Sella Syndrome
i. Condtion of shrinkage or flattening of the pituitary gland, can’t be seen on MRI
ii. Sella appears empty but isn’t  CSF leaked in pressing on & flattening pituitary
iii. Often asymptomatic
iv. If symptoms due occur, may include HA, ED,  libido, irreg. menses, fatigue, nip discharge, blah
3. Neurohypophysis
a. Posterior lobe of the pituitary
b. Acts as both the anatomic & functional connection between the HP & pituitary (primarily neural)
c. Hormones of the Posterior Pituitary (considered neuropeptides)
i. Oxytocin – synthesized in the paraventricular nuclei of the hypothalamus
ii. Vasopressin (ADH) synthesized in the supraoptic nuclei of the hypothalamus
d. These hormones (OT & ADH) are transported into & stored in the posterior pituitary
e. Clinically  someone with a head injury can disrupt this connection & lose control over the hormones
4. Hypothalamus Hormones
a. TRH  stimulates secretion of TSH & prolactin
b. CRH  stimulates secretion of ACTH
c. GnRH  stimulates secretion of LH & FSH
d. GHRH  stimulates secretion of GH
e. GHIH  inhibits secretion of GH
f. VIP/TRH  induces prolactin release
g. PIF  inhibits secretion of prolactin (DOPAMINE TONICALLY INHIBITS PROLACTIN)
5. Anterior Pituitary Hormones
a. ACTH  act on the adrenal gland to secrete glucocorticoids, mineralocorticoids, & androgens
b. FSH  acts on the gonads for growth of the Repro system
c. LH  Acts on the gonads, induces sex hormone production
d. GH  acts on liver & adipose tissue, promotes growth as well as lipid/CHO metabolism
e. TSH  acts on the thyroid, promotes secretion of thyroid hormones
f. Prolactin  acts on ovaries, mammary glands  results in secretion of estrogen, progesterone, milk
g. These are generally stimulated by the secretion of the hypothalamic hormones into the median
eminence & pituitary stalk and into the blood
h. There is retrograde blood flow in the AP-HP region  important for down regulation
6. Sheehan’s Syndrome
a. Occurs in post-partum women
i. There is an increase in pituitary size during pregnancy due to estrogen signaled  in prolactin
ii. The vessels of the pituitary do not grow in the same manner so more tenuous blood supply
iii. If lots of blood is lost in delivery  necrosis of the pituitary
iv. Vessels of the anterior pituitary necrose & blood supply is unable to reach the anterior pituitary
v. Hormones from the AP aren’t produced (FSH, LH, GH, TSH, PRL, & ACTH)
b. Presenttion
i. Won’t be able to lactate, amenorrhea, 2° adrenal insufficiency (pituitary issue)
ii. Hypothyroid (low TSH), cold intolerance, & tired (due to low glucose)
7. Hormonal Rhythms
a. Pulsatile & Episodeic or ??? can be tonic???
b. Frequency & Amplitude can vary  estrogen monthly vs cortisol daily vs T3 which is constant
8. Circadian Rhythms
a. Yep

Lecture 4: Anterior Lobe Hormones

1. 6 Major Hormones
a. Glycoproteins
i. LH, FSH, TSH
ii. Glycoprotein hormones all have the same α chain but differ in their β chains
iii. hCG also has the same α chain
iv. GLycosolation of these hormones increases their T1/2
b. Polypeptide Hormones
i. GH, ACTH, Prolactin
2. Pituitary Gene Defects
a. Prop-1 Gene
i. Expressed soon after Rathke’s pouch forms
ii. Promotes lineages  lacking this gene results in MR, dwarfism, infertility
iii. Somatotropes, Lactotropes, Thyrotropes, Gonadotropes
b. POUF1
i. Transcription factor for GH, TSH, & Prolactin
c. SF-1
i. Steroidogenic factor-1 lose gonadal function
d. Tpit
i. Transcription factor for POMC (could cause isolated 2° adrenal insufficiency)
3. Multiple Endocrine Neoplasia (MEN) gene ★
a. Gene produces menin (a nuclear protein)
b. MEN type 1 (Wermer’s syndrome)
i. Rare hereditary autosomal dominant endocrine cancer
ii. Tumors of PT glands (95% of cases), Pancreas (30-80% of cases), and AP (15-90% of cases)
iii. Overproduce GH and prolactin)
iv. Many endocrine tumors in MEN1 are benign & symptoms d/t overproduction of hormones
c. MEN type 2 (Sipple’s syndrome)
i. Occurs in thyroid, parathyroid, and adrenals
ii. MEN2 derive from a variation in the RET proto-oncogene (tyrosine kinase-gain of function)
iii. Inherited in an autosomal dominant pattern
iv. Mainly associated with medullary thyroid carcinoma
v. May also show have high epinephrine and calcium
d. PPT Notes:
i. MEN 2 is different from MEN 1 in one very important way...those with MEN 2 will almost
certainly develop thyroid cancer.
ii. The type of thyroid cancer these people get is considerably more aggressive than when thyroid
cancer develops in non-MEN patients
1. First of all, the type of cancer which develops is a more aggressive type
2. Secondly, this cancer begins early in life in MEN 2 patients and grows quickly.
4. Feedback of hormones
a. PPT Notes: Feedback regulation of HP-AP (three types)
 b. Long loop
i. Hormone produced by the AP acts on target organ (endocrine gland)  increased production
of a hormone. This hormone then feeds back to the AP or HP to decrease release from AP or HP
1. HP releases TRH
2. AP then releases TSH
3. TSH acts on the thyroid to increase T3,T4
4. Once T3, T4 levels increase enough they have a negative feedback on the HP & AP.
c. Short loop
i. Hormone produced by AP due to HP stimulation feeds back on HP to stop it from releasing
1. ACTH to decrease CRH from HP.
d. Ultra-short loop
i. Hormone released by the HP acts directly on HP to inhibit its own production.
1. GnRH (also called LHRH) from HP to HP.
e. If the hormone effects target organ and there is defect there, it is called primary disease. If the
pituitary is problem it is called secondary disease. If the defect is HP it is called a tertiary disease
5. Secretion of Hormones
a. All pituitary gland hormones, GH is secreted in bursts (pulses, episodic)
b. There is a dominant daily rhythm where secretion increases shortly after sleep (within 2 hours)
6. Regulation of GH
a. GHRH
i. Synthesized in the arcuate nucleus & released into the median eminence
ii. Binds somatotrophs in the AP (Gs) to release GH (can also activate PLC pathway as well)
b. GHIH (Somatostatin)
i. Synthesized in the periventricular nucleus & released into the median eminence
ii. Binds somatotrophs in the AP (Gi) to inhibit release of GH
7. GH Mechanism
a. IGF has a similar structure to GH and are probably the hormones that carry out GH effect on cells
b. IGF-1 is the only peptide protein that is bound to a carrier protein
c. IGF is also known as somatomedins, produced in the liver
d. Most likely GH acts on the liver to produce IGF which carry out actions on target cells
e. Notes
i. IGF 1 is similar to insulin & its actions parallel GH release
ii. IGF 2 is not really all that well known
8. GH Excess
a. Acromegaly
i. Due to an over secretion of GH after puberty (adulthood) – usually due to SOMATOTROPHS
ii. Wide nose, spade hands, enlarges with age
iii. Linear bone growth stops but cartilaginous doesn’t  stimulated to grow (hands, feet, chin)
iv. Presentation  HA, arthritis, carpel tunnel, enlarged heart, HTN, DM, HF, kidney failure
v. Bitemporal hemianopsia is possible
vi. Increased palmar sweating & sebum production indicative of GH producing pituitary tumors
b. Gigantism
i. Childhood over secretion of GH (usually SOMATOMAMOTROPHS)
ii. Linear growth of bones is accelerated prior to the closure of the epiphyseal plates
iii. May also have glucose intolerance & hyperinsulinism, diabetes, & cardiac hypertrophy
iv. Often caused by a pituitary adenoma
1. If MAMMOTROPHS (prolactin secreting cells) involved, can have gynecomastia &
lactation & delayed puberty???
2. Can also arise if due to GH having some PRL like effects (structurally similar)
9. GH Deficiency

Lecture 5 & 6: Sexual Differentiation

1. Jost Paradigm
a. Chromosomal sex – XX or XY
b. Gonadal Sex – presence or absence of SRY (present  testes, absent  ovaries)
c. Phenotypic Sex – external genitalia male or female
2. TDF & SRY
a. SRY or sex determining region of Y is located in the Y chromosome
b. It is a DNA binding protein that enhances transcription factors
i. SRY upregulates SOX9 which upregulates FGF9
ii. FGF9 is necessary for Sertoli cell differentiation
c. Thus, expression of SRY directly or indirectly causes the development of primary sex cords that will
later become seminiferous tubes (forming in the center of the undifferentiated gonad  testes)
d. Mistake
i. If there is a crossover event where the Y chromosome doesn’t receive SRY  Swyer Syndrome
1. A 46XY that doesn’t create SRY/TDF  genotypic male, phenotypic female
3. Before Differentiation
a. Mammalian embryos have two pairs of genital ducts
i. Mesonephric (Wolffian Ducts)
1. Progress in males to form epididymis, vas def, seminal vesicles, ejaculatory duct
ii. Paramesonephric (Müllerian Ducts)
1. Regress in males (form oviducts, uterus, cervix, upper vagina in females)
4. Sertoli Cells
a. Sertoli cells produce MIF that degrades the Müllerian ducts in males
i.
b. Leydig cells produce the testosterone causing internal male development
5. Persistent Müllerian Duct Syndrome
a. Males that have persistent müllerian duct structures fallopian tubes, uterus, cervix
i. Caused by deficient MIS or MIS receptor defect
ii. But can still have kids (have all the important parts for reproduction are present)
6. Development of Müllerian Ducts
a. In XY males, MIS is produced by the testes and works to eliminate Müllerian ducts
7. Cell Types
a. Germ Cells
i. Spermatogonia in males
ii. Oogonia in females
b. Coelomic Epithelium
i. Sertoli cells in males  produce MIS
ii. Granulosa cells in females  no MIS produced
c. Mesenchymal Cells
i. Leydig cells in males  produce androgens in males
ii. Theca cells in females  no androgen production in females????
8. Important to Know
a. Need to know SRY, TDF, SOX9, FGF9
b. XO – turners – streak gonad
c. DHT role in utero
d. 5α-reductase in utero?  converts testosterone to DHT
 e. MIS involutes/degrades the Müllerian ducts
9. Hormone Production
a. Around 8 weeks gestation
i. Leydig cells in the testes begin to produce testosterone (initially stimulated by hCG, then LH)
ii. Sertoli cells in the testes produce MIS to cause involution of the Müllerian ducts
1. hCG & LH also continue to growth & differentiate the Wolffian ducts
10. Male Development
a. 9th-12th weeks external genitalia begin to diverge & finish diverging around week 13
b. The genital folds fuse over the urethral groove to form the penile urethra (line = penile raphe)
i. Incomplete fusion  hypospadias
c. Look for hotdog on US for male, hamburger for females
d. Virilization
i. Occurs during the last ⅔ of gestation
ii. External genitalia differentiate to male by conversion of testosterone to DHT via 5α-reductase
1. Penis, scrotum, prostate, urethra
2. MUST OCCUR BY 12 WEEKS
iii. DHT binds same androgen receptor as testosterone but is more active (500x???)
1. Added activity of DHT is necessary for external genitalia but not for Wolffian duct devel.
iv. If you have a 5α-reductase deficiency it is a Type 2 deficiency???
v. BIG POINTS
1. Testosterone is needed for testes descent & elongation of the vas deferens
2. DHT is needed for urethra, shaft, seminal vesicle, & prostate
11. Female Development
a. Internal female reproductive tract is formed by the müllerian ducts
i. Absence of MIS (no Sertoli cells because no TDF/SOX9/FGF9) allows the müllerian ducts to
differentiate to into fallopian tubes, uterus, & upper ⅔ of the vagina
ii. After week 10, the genital tubercle swells to form the clitoris & the genital folds  labia minora
12. External Genitalia (without androgens, with androgens)
a. Genital Folds
i. Labia minor
ii. Urethra & shaft of the penis
b. Genital Swellings
i. Remains open for females
ii. Scrotum in males
c. Genital Tubercle
i. Glans clitoris
ii. Glans penis
d. External genitalia appear male or female dependent on the presence of androgens, not SRY
i. In females, if androgens are inappropriately elevated  virilization occurs
ii. Corrollary in males
13. X Chromosome Abnormalites
a. Barr Body – all females should have a dense, inactivated X chromosome on microscopy
i. Normal = 46XX female with one Barr Body
ii. Abnormal = 47XXX with two Barr Bodies
iii. Klinefelter = 47XXY with one Barr Body
b. In female somatic cells – should see one active X chromosome & one Barr Body
c. In germ cells = need to have both X chromosomes (one will inactivate later)
i. If only 1 X chromosome in the germ cell  will result in Turner’s???
14. Overview of Disorders
a. Turner’s Syndrome
i. 45 XO
ii. Ovaries absent or defective, sterile, external female genitalia remains infantile
iii. No pubertal development, no menses
iv. Rarely taller than 5 feet
b. Triple X Syndrome
i. 47XXX
ii. No sexual abnormalites
iii. Able to have children
iv. Some are mentally retarded
c. Klinefelter’s Syndrome
i. 47XXY
ii. Internal & external genitals are male but testis are small & produce low sperm counts
iii. Underdeveloped pubic, facial, & body hair
iv. Gynecomastia, decreased libido, tall, possible MR
d. 47XYY Syndrome
i. 47XYY
ii. Tall, may show impulsive behavior
iii. Sperm count may be reduced, may be sterile
15. Gonadal Hormone Production
a. Hypothalamus releases GnRH which acts on the Anterior Pituitary to release LH & FSH in both M/F
b. LH & FSH act on the gonads of males & females differently
i. LH
1. Males  stimulates Leydig cells to produce testosterone (neg. feedback to HP/AP)
2. Females  stimulates ovarian production of steroids,
 surge occurs at midcycle to trigger ovulation (follicle  corpus leuteum)
ii. FSH
1. Males  stimulates sertoli cells to produce ABP (stimulating spermatogenesis)
 stimulates sertoli cells to inhibin (negative feedback on FSH from AP)
2. Females  stimulates ovary to produce steroids
 surge at midcycle along with LH to trigger ovulation
16. Lifetime Patterns of Hormonal Prodction
a. After initial bursts during fetal life & again during 1st year of life, hormone production is quiescent
b. At puberty there is a resetting of the gonadostat with increases in GnRH, LH, FSH, & sex hormones
i. Females  cyclic pattern emerges
ii. Males  simple increase in androgen levels that lasts until the 7th-8th decade
c. As gonadal output of Androgens/Estrogens goes down, (post-menopause or old males) LH & FSH 
d. Gonadostat happens at night, pulses of GnRH & others are timed properly throughout puberty
17. Female Cycle
a. FSH stimulates eggs primordial follicles to enter the growing pool, once there are no more follicles, FSH
remains elevated  gotta look out for estrogen acting as a negative feedback inhibitor of FSH prod.
b. When you get old & run out of eggs you don’t produce any more estrogen & will increase your FSH
c. When you have few eggs left, takes longer for eggs to mature, have more FSH trying to recruit cells
d. Childhood  FSH>LH
e. Adult Reproductive Age  LH>FSH
f. Post-menopausal  FSH>LH
18. Hermaphrodites
 a. True Hermaphrodites are very rare  involves presence of both ovarian & testicular tissue present
i. 50% are 46XX – not sure how as they have no Y as far as we can tell
ii. 25% are 46XY
iii. 25% are 45X/46XY
19. Pseudohermaphroditism
a. Refers to the chromosomal & gonadal genotype not matching external phenotype
i. Male pseudos = 46XY with testes but female like external genitalia
ii. Female pseudos = 46XX with ovaries but male like external genitalia
20. Male disorders
a. Vanishing Testes Syndrome
i. 46XY
ii. Endocrine function of the testes was normal at some point in embryonic differentiation but lost
iii. Usually occurs around 12-14 weeks
iv. Penis & scrotum form (provided DHT is present) & continue to develop but have no testes
v. Symptoms appear at puberty – later than expected, absence of 2° sex characteristics
vi. Could have complete female phenotype???
b. Pure Gonadal Dysgenesis
i. 46XY or 46XX
ii. Bilateral streak gonads with immature female phenotype
1. Defect occurs prior to testosterone & MIS production
iii. If 46XY  Swyer syndrome
1. Due to an absence of both testosterone & MIF in males
2. Genotypic male but internal & external phenotypic female
c. Klinefelters
i. 47XXY (male phenotype)
ii. Testis have  sperm counts & azoospermia is due to damanged seminiferous tubules
iii. Usually noted at puberty due to infertility, gynecomastia (d/t low T), incomplete virilization but
TALLER
iv. Endocrine findings
1. Low to low normal testosterone
2. Elevated estradiol (from increased body fat)
3. Elevated FSH & LH (no testosterone or inhibin negative feedback)
v. The extra X is detrimental to spermatogenesis & testicular function
vi. Increased height is due to the decreased testosterone/estrogen production
1. Test/est increases the rate of epithelial plate closure thus delayed  long arms/legs
vii. Also have reduced facial hair, body hair, OP, feminine fat distribution, small testes
d. Super Male
i. 47XXY
ii. Most often the extra Y chromosome has no clinical effect
iii. Often increased growth velocity with expected height 7cm above average (NFL/NBA)
iv. Testosterone levels are NORMAL both prenatal & postnatal
v. Not associated with increased incarceration or low IQ
vi. Not heritable, usually due to incident during anaphase II (of meiosis II)
21. Female Disorders
a. Pseudohermaphroditism
i. Most commonly associated with a 21-hydroxylase deficiency
ii. Present with virilization of the newborn
 iii. Caused by a defect in Cortisol production, increased ACTH due to no feedback inhibition, results
in a shunt toward adrenal androgen production & build up testosterone, DHT, & DHEA
iv. Typically not a complete deletion, mild to severe
22. 17β-Hydroxysteroid Dehydrogenase Deficiency
a. Males born with almost completely female external genitalia but marked virilization occurs in puberty
b.