Week 3: Anterior/ Posterior Pituitary

What is the feedback control for the thyroid gland?

hypothalamus → TRH → (+) anterior pituitary (thyrotrophs) → TSH → (+) thyroid gland → T4/T3 → has its effects on the body

T4/T3 → (-) anterior pituitary thyrotrophs & (-) hypothalamus

TRH in excess can stimulate lactotrophs to release PRL

What are the 3 effects of stimulating TSH-R on the thyroid gland?

1. growth of thyroid gland

2. increased T4/T3 synthesis

3. increased Na⁺/ I^- symporter activation

What is the importance of I^- ?

iodine is important for making thyroid hormone (T4/T3)

What is the feedback control for prolactin?

hypothalamus → DA → (-) anterior pituitary lactotrophs → prolactin → (+) milk production

estrogen → (+) anterior pituitary lactrotrophs → prolactin → (+) milk production

excess TRH can also stimulate (+) anterior pituitary lactrotrophs → prolactin → (+) milk production

What is hyperprolactinemia?

high levels of PRL in blood

What are the 5 cell types of the anterior pituitary?

1. corticotrophs

2. gonadotrophs

3. somatotrophs

4. thyrotrophs

5. lactotrophs

What do each of these 5 cell types release when stimulated by hypothamalic releasing hormones?

1. corticotrophs → ACTH

2. gonadotrophs → FSH/LH

3. somatotrophs → GH

4. thyrotrophs → TSH

5. lactotrophs → PRL

What are the 2 hypothamalic releasing hormones that act on lactotrophs?

TRH (excess) → stimulatory

DA → inhibitory

Describe the roles of TRH, DA, and ER (estrogen receptor) on lactotrophs

TRH → in EXCESS amounts, can stimulate secretion of PRL

DA → MAJOR regulatory hormone; inhibits PRL secretion

ER → stimulates secretion of PRL

What are the 5 major causes of hyperprolactinemia?

1. prolactinoma (lactrotroph adenoma/tumor)

2. decreased DA inhibition

3. increased ER stimulation

4. increased TRH receptor stimulation

5. other drugs

How does prolactinoma contribute to hyperprolactinemia?

something is wrong with the lactotroph that is causing it to make more of a hormone it typically means (excess PRL)

What are the 3 things that can cause decreased DA inhibition, leading to prolactinemia?

1. pituitary stalk damage

2. hypothamalic damage

3. D2 receptor antagonists/anti-psychotics/other drugs

Why does pituitary stalk damage lead to increased PRL secretion?

the pituitary stalk is what carries DA from the hypothalamus to the anterior pituitary

if the pit stalk is damaged, DA can’t get to the lactotrophs in the ant pit to inhibit

What are the 2 things that can cause increased estrogen receptor stimulation?

1. combined hormonal contraceptives

2. pregnancy

How do oral contraceptives & pregnancy contribute to increased PRL?

increased levels of estrogen = increased estrogen receptor stimulation and PRL secretion

What is the name of the disease state that causes increased TRH receptor stimulation and how?

1 hypothyroidism

leads to decreased T3/T4 = decreased (-) feedback to TRH = increased TRH (+) of lactotrophs

What are the 2 primary affects we see in hyperprolactinemia?

1. galactorrhea

2. decreased sex steroids (hypogonadism)

Describe how we get galactorrhea from PRL secretion?

PRL acts on breast tissue → milk production → galactorrhea

Describe how we get decreased sex steroids from PRL secretion?

PRL leads to decreased GnRH release → decreased LH/FSH (gonadotropins) → decreased sex steroids and gonad function

What does hyperprolactinemia present as in premenopausal women? (3 main presentations)

1. infertility (no ovulation)

2. amenorrhea (no menses)

3. galactorrhea

What are the 3 typical symptoms seen in women due to decreased estrogens?

1. hot flashes

2. vaginal dryness

3. decreased bone mineral density

Why is it harder to decreased ovarian estrogen symptoms in post-menopausal women?

they usually already exhibit these symptoms because they are menopausal symptoms

What does hyperprolactinemia present as in men? (3 presentations)

1. infertility

2. gynecomastia

3. galactorrhea

What are the 4 typical symptoms decreased testicular androgens?

1. decreased libido

2. decreased muscle mass

3. erectile dysfunction

4. decreased bone mineral density

What is the extra clinical finding that can occur if hyperprolactinemia is caused by a lactotroph adenoma (ant pit tumor)?

Bitemporal Hemianopia

What is Bitemporal Hemianopia?

loss of half of the peripheral field vision of BOTH eyes

How does bitemporal hemianopia happen?

as the ant pit tumor grows, it compresses the OPTIC CHIASM

the optic chiasm carries peripheral visual field information from both eyes → compression leads to loss of peripheral vision

What does the peripheral vision loss initially look like when the tumor first begins to grow?

initially impacts the upper vision fields first

the upper vision fields travel through the bottom of the optic chiasm

What are the 2 additional symptoms we can get due to the lactotroph adenoma in the ant pit?

1. headaches

2. mass effect of decreased ant/pit hormones

Why do we see a mass effect of other hormones being decreased with an ant pit tumor?

as the tumor grows, the other cell types by the tumor become crowded out and can become damaged

What are the 2 main methods of treating hyperprolactinemia caused by prolactinoma?

1. Pharmacological treatment

2. surgical treatment

What are the 2 classes of pharmacological drugs used for treatment?

1. DA receptor agonists

2. hormone replacement

What are the names of the 2 DA receptor agonists?

1. Cabergoline

2. Bromocriptine

What is the MOA of Cabergoline/Bromocriptine?

inhibit PRL secretion and decrease the size of the tumor

What are the 3 main AEs of DA-R agonists?

1. nausea/vomiting

2. orthostatic/postdural hypotension

3. impulse control symptoms

Why do we get impulse control symptoms with DARAs?

DA is involved in the reward system → when stimulated it could cause these issues

What are the 2 impulse control symptoms we would see with DARAs?

1. hypersexuality

2. pathological gambling/shopping

How do we prevent development of these behavioral changes?

take DARA at a lower dose

What is an additional AE of Cabergoline?

VALVULAR HEART DISEASE (regurgitation/stenosis)

What is the name of the receptor involved in cardiac valvulopathy as an AE of Cabergoline? Where is it located?

5HT2B receptor located on heart valves

What are the 2 different hormones that can be given to a man or woman as treatment of prolactinoma? Why are they given?

estradiol + progestin → women

testosterone → men

given to REPLACE the hormones that are low due to high PRL supressing them

If the patient were worried about their fertility, what additional thing should we do to preserve that?

have to suppress PRL in addition to replacing the missing hormones to get the gonads to work again

What is the name of the surgery that is done as treatment for prolactinoma?

transsphenoidal surgery → removal of tumor

What is Acromegaly/Gigantism?

disorder caused by the pituitary gland production of too much growth hormone

What are 4 causes acromegaly/gigantism?

1. somatotroph tumor

2. GHRH tumor

3. IGF-1 tumor

4. exogenous GH

What does a somatotroph tumor lead to (in terms of hormone production)?

increased GH = increased IGF-1

What is the feedback control for growth hormone?

hypothalamus → SST and GHRH → SST (-) anterior pituitary somatotrophs / GHRH (+) ant pit somatotrophs → (+) GH → liver → IGF-1 and glucose

IGF-1 → (-) ant pit & hypothalamus (release of GHRH)

IGF-1 → (+) hypothalamus (release of SST)

glucose → (-) ant pit somatotrophs

What is a common cause of a somatotroph tumor?

a mutation in the GTPase enzyme that keeps GHRH signaling ON → causes lots of growth and GRH release

What type of GPCR is GHRH-R coupled to?

Gs

What type of GPCR is SST-R coupled to?

Gi

Describe the normal function of GHRH-R stimulation

GHRH binds its receptor on somatotroph → Gs-GTP active stimulates AC → increases cAMP/PKA → PKA stimulates GRH release and growth of somatrophs

GTPase typically makes Gs-GTP inactive to Gs-GDP

What does a GHRH tumor cause (in terms of hormone levels)?

increased GHRH = increased GH = increased IGF-1

What does an IGF-1 tumor cause (in terms of hormone levels)?

increased IGF-1 = negative feedback to decrease GHRH = decreased GH

What does exogenous GH cause (in terms of hormone levels)?

increased IGF-1

What are the 5 categories of clinical findings we’d see in someone with acromegaly/gigantism?

1. skin/soft tissue proliferation

2. bones/joints stimulated to grow

3. other places enlarge

4. metabolic

5. CV disease

What are the 3 clinical findings we see due to skin/soft tissue proliferation?

1. increased sweating/oily skin

2. heat intolerance

3. fatigue

What are the 5 clinical findings we see due to bones/joints being stimulated to grow?

1. degenerative arthritis

2. thickening skull

3. enlargement of jaw

4. increased hand/feet size

5. carpel tunnel syndrome

What is the term for thickening skull called?

frontal bossing → frontal bones enlarged

What is the term for enlargement of the jaw called?

macrognathia

Why do we get carpel tunnel syndrome?

when the bones grow, they entrap the median nerve in the wrist and cause damage

What are the the 2 other places that can enlarge?

1. increased tongue size

2. increased organ size

What is the term for enlarged heart?

visceromegaly

What are the 3 clinical findings we can see due to CV disease/visceromegaly?

1. hypertension

2. cardiac hypertrophy (muscle thickening)

3. HF

What is the most common cause of death in patients with acromegaly?

HF due to enlarged heart valves

What is the metabolic associated clinical finding we see?

increased blood glucose (due to high GH)

Which type of cancer is at increased risk with high GH levels?

colorectal cancer

What clinical finding would we see in someone with increased GH/IGF-1 secretion before the epiphyseal/growth plates close?

GIGANTISM → dramatic increase in linear height

Describe the 3 extra clinical findings that could occur if a patient has a somatotroph tumor

1. bitemporal hemianopia

2. headaches

3. mass effect of decreased ant pit hormones

Describe the roles of SST and GHRH on somatotrophs

somatotroph has SST and GHRH receptors

GHRH (Gs) → release of GH → increases IGF-1 → effects

SST (Gi) → inhibits GH → no IGF-1

What are the 2 medications used for treating the somatotroph GH secreting tumor?

1. Octreotide

2. Peguisomant

What is the MOA of Octreotide?

somatostatin receptor agonist

What are the 2 beneficial effects of Octreotide?

1. shrink somatotroph tumor

2. decrease GH release

What are the 4 AEs of Octreotide?

1. nausea

2. abdominal bloating

3. fat malabsorption

4. gallstones

Why do we see GI related effects with Octreotide?

SST plays a role in the GI tract to inhibit some normal processes in the GI tract

Why do we get gallstones with Octreotide?

due to decreased CCK and decrease gallbladder contraction

What is the typical role of CCK and why does its downregulation lead to gallstones?

CCK = cholecystokinin

GI hormone that contracts bile bag to release bile acid for fat digestion

if decreased CCK = decreased contraction = gallstones bc decreased bile acid

What is the MOA of Peguisomant?

GH receptor antagonist

What are the 2 beneficial effects of Peguisomant?

1. blocks the effects of GH

2. decreases IGF-1 (which typically drives growth)

What is the AE of Peguisomant?

hepatotoxicity

Why can we sometimes use Cabergoline/Peguisomant as an add on with Octreotide?

octeotride = tried first

add on other drugs if octeotride doesn’t work bc sometimes DA receptor stimulation by a tumor could be the cause for increased GH

Which surgery could be done to remove the somatotroph tumor?

transsphenoidal tumor removal surgery

In someone with a somatotroph tumor, why is it not helpful to block GHRH?

GHRH is not typically driving the problem with a somatotroph tumor → GHRH is typically LOW due to (-) feedback

the problem is increased GH

What is the name of the posterior pituitary hormone that is synthesized in the hypothalamus?

ADH - antidiuretic hormone (acts on the kidney)

Which body system does ADH control? Through which receptors?

plasma osmolarity

V₂ (Gs coupled) receptor on the kidney for water reabsorption

V₁ (Gq coupled) on vascular smooth muscle for vasoconstriction

When P_osm increases, ADH ____ and H₂O reabsorption ___

ADH increases and H₂O reabsorption increases

Draw the feedback control system P_osm and BP

hypothalamus sends ADH down to the pituitary gland through the pituitary stalk → posterior pituitary releases ADH →

• (+) kidney (H₂O reabsorption) → (-) V (urinary flow rate) / (+) U_osm / (-) P_osm → (+) hypothalamus / (+) thirst → (+) water intake → (-) P_osm

• (+) kidney (H₂O reabsorption) → (+) BP → (+) medulla → (-) hypothalamus

ADH also has (+) effects on BP through V₁

Describe what happens when ADH from the blood binds the V₂ receptor on the CD of the kidney

ADH binds V₂ on CD → V₂ (Gs) → increase cAMP/PKA → PKA stimulates insertion of AQII channels onto the apical membrane → H₂O from tubular fluid is REABSORBED

What is the role of ENaC in the CD? Which ions can enter?

it is responsible for Na⁺ gradient into the CD

Li⁺ can enter ENaC and cause disruption Gs signaling

What is SIADH?

syndrome of inappropriately HIGH ADH

Why do you have to be careful with drinking excess water with SIADH?

could get HYPONATREMIA

too much ADH = excess water reabsorption and dilution of plasma sodium

What are the 3 main causes of SIADH?

1. CNS disturbances

2. malignancies

3. drugs

How does a CNS disturbance contribute to SIADH?

something in the CNS could be damaged and cause excess ADH release

How do malignancies contribute to SIADH?

ECTOPIC ADH secretion from a tumor

What does ectopic secretion mean?

ADH production is happening from a source that doesn’t usually make ADH

What is an example of a malignancy that could secrete excess ADH?

lung tumor

What are examples of 2 drugs that could increase ADH release, even with low plasma osmolarity?

SSRIs and ecstasy

How do SSRIs and ecstasy cause excess ADH?

• SSRIs → block 5HT reuptake

• ecstasy → increase 5HT release

5HT stimulates SST → which leads to increased ADH release

What happens to plasma sodium with SIADH?

due to excess ADH → taking in extra water and unable to get rid of it = HYPONATREMIA

What are the effects of hyponatremia on the brain?

it causes neurological dysfunction from swelling neurons

with hyponatremia, we have low Na⁺ outside the cell but increased water going in to the cell to reach equilibrium→ causes swelling of the neuron

What is the severity of the neural swelling dependent on? (2 things)

MAGNITUDE and how QUICKLY we decrease P_Na+