Endocrine block:

Feedback loop: CNS controls release of hypothalamic and anterior pituitary hormones which act as
tropic hormones on target organ which in turn releases target hormone that works on specific organs as
well as provide a negative feedback on the CNS.

Embryology: thyroid is first to develop (24th day gestation) from the floor of primitive pharynx then
descends to the neck (remains connected to tongue by thyroglossal duct). The foramen cecum and
pyramidal lobe are normal remnant of the thyroglossal duct. When an additional thyroglossal duct
remains, the formation of a cyst is possible.

The most common ectopic site of cyst is the tongue. We differentiate a thyroglossal duct cyst from a
branchial cleft cyst (from persistent cervical sinus) by location (branchial is not midline and doesn’t move
with swallowing unlike the other).

The fetal adrenal has an inner fetal zone and dormant outer adult zone. Late in gestation, adult zone
starts to secrete cortisol due to ACTH and CRH released from pituitary and placenta. Cortisol is
important for lung maturation and surfactant production.

Anatomy:

Adrenal: consists of outer cortex (mesoderm) composed of zona glomerulosa (mineralocorticoids:

aldosterone), fasciculata (glucocorticoids: cortisol, sex hormones), reticularis (sex hormones) and inner
medulla (neural crest) is made up of chromaffin cells that secretes catecholamines directly into blood
(unlike other organs which releases catecholamines into target organs only) thus has a universal affect.

Zona glomerulosa is controlled via RAS, fasciculata/reticularis by ACTH and CRH, medulla by
preganglionic sympathetic fibers.

Pheochromocytoma (adults; characterized by episodic HTN) and neuroblastoma (children) are

the most common adrenal tumors.
Venous drainage: similar to that of gonad, left adrenal vein > left renal > IVC. Right > IVC.
Pituitary: in sella turcica (sphenoid depression).
Neurohypophysis (neuroectoderm, an extension of hypothalamus) secretes ADH (increases
water resorption, pituitary lacks a BBB and can sense osmolarity and blood volume changes)
and oxytocin (uterine contraction and milk letdown) that was made in the hypothalamus (from
neuronal cells not gland cells) and down the axons into the pituitary by neurophysins
(carrier/chaperone protein).
Adenohypophysis (oral ectoderm: Rathke’s pouch): has its own portal circulation; secretes FSH,
LH, ACTH, TSH, prolactin, GH, MSH. Only GH and prolactin are released by acidophils instead of
basophils. MSH is a derivative of POMC, the parent molecule of ACTH. Failure of adrenal to
respond to ACTH (Addison’s) causes an increase of POMC, ACTH and melanotropin (skin
darkening).
HPA: hypothalamus > releasing hormones that enters pituitary via portal system > pituitary
releases respective hormones that upon reaching target glands makes products that negatively
feedbacks the pituitary and hypothalamus.
Hormones are made up of an a subunit and a b subunit. TSH, FSH, LH and hCG have a common
a subunit, so it is the b subunit that determines its specificity.
Endocrine pancreas: islet of Langerhans seen most at the tail; a cell at the periphery (glucagon),
b cell (insulin) centrally and d cells (somatostatin) scattered.
Insulin: proinsulin is made of c peptide, a chain, b chain; the latter of two that makes up insulin
once c peptide is cleaved. Exogenous insulin has no c peptide; thus, c peptide can be used to
measure endogenous insulin production (should be directly proportional to insulin level). When
b cells takes up glucose, it undergoes aerobic respiration to produce ATP, rising ATP closes ATP
dependent K channels, depolarizing the cell and inducing voltage gated Ca channels to open,
the influx of Ca causes the exocytosis of insulin containing granules. Insulin’s effect includes:
energy storage (increase glucose transport, glycogen & triglyceride synthesis and storage,
protein synthesis in muscles), Na retention (kidney), cell uptake of K and aa (in all cells). Insulin
is inversely proportional to glucagon, cortisol, catecholamines and GH. When insulin is released
from b cells, it blocks neighboring a cells. Hypoglycemia is more dangerous than hyperglycemia
thus there are more regulatory hormones geared to increasing glucose levels rather than
decreasing. Insulin is regulated by hyperglycemia, GH, b2 antagonist and cortisol which
increases insulin while hypoglycemia, somatostatin, a2 agonists decrease insulin. Only GLUT 4 is
insulin dependent (adipose, skeletal muscle), while GLUT 1 (RBC, brain) are insulin independent,
2 (b cell, liver, kidney, cornea, small intestine) are bidirectional. Brain uses glucose for
metabolism and ketones during starvation but RBC always uses glucose since it lacks
mitochondria for aerobic metabolism. Insulin doesn’t cross placenta.
Glucagon: from a cells, secreted in response to hypoglycemia; inhibited by insulin,
hyperglycemia and somatostatin. Function: increases glycogenolysis, gluconeogenesis, lipolysis,
ketone production and inhibits release of insulin and further glucagon release.
Physiology:
HPA concept:
CRH stimulates release of ACTH
GHRH stimulates release of GH
GnRH stimulates release of FSH and LH
TRH acts on TSH and also promotes prolactin release. The negative regulator of
prolactin is dopamine which is constitutively released and prolactin itself is a negative
regulator of GnRH. This blockade of GnRH is the reason why women who are
breastfeeding do not ovulate.
Finally we note here the effect of somatostatin which as we mentioned comes from the
delta cells in the pancreas. Somatostatin blocks the release of GH and TSH from the
anterior pituitary.
Prolactin regulation to make sure we understand all of its intricacies as you can see
there is both negative regulation from dopamine and positive regulation from TRH.
Prolactin once secreted actually feeds back to upregulate dopamine production which
inhibits prolactin secretion thereby maintaining homeostasis. Prolactin inhibits GnRH
and is also responsible for stimulating milk production in the breasts.

Before you start thinking that everything in endocrinology involves a negative feedback
loop I should say that there are some important positive feedback loops to be aware of.
Prior to ovulation the release of LH from the pituitary stimulates the ovary to secrete
estrogen and the estrogen feeds back to stimulate the pituitary to produce more LH, this
positive feedback loop creates a dramatic increase in both LH and estrogen levels that
triggers ovulation.

There are some drugs that interact with prolactin that you should be familiar with.
Bromocriptine is a dopamine agonist and therefore it inhibits prolactin, this drug can be
used for treatment of prolactinoma which is the most common type of pituitary tumor.
On the other hand dopamine antagonists including most antipsychotics and estrogens
such as oral contraceptive pills stimulate prolactin release.

Growth hormone is released in a pulsatile fashion in response to GHRH, secretion is

higher during exercise and sleep and is inhibited by glucose and somatostatin. Growth
hormone promotes linear growth and increase in muscle mass via IGF-1 or
somatomedin secretion. As one of the counter regulatory hormones, GH is diabetogenic
because it increases insulin resistance. Pituitary adenomas that secrete excess
amounts of GH can cause acromegaly and adults whose growth plates have fused or
gigantism and children whose growth plates have yet to fuse.
Adrenals: lets familiarize ourselves with the diagram, look at the starting and ending
Products. We begin at the top left with cholesterol (these are all steroid
hormones and cholesterol is the building block), now let's look at our products:
aldosterone from the zona glomerulosa, cortisol from the zona fasciculata and
testosterone from the zona reticularis. You can see here at the far right that
testosterone in its precursor androstenedione can be peripherally converted to the other
sex hormones including estrone, estradiol and DHT or dihydrotestosterone which is a
more potent androgen than testosterone. Now that we have a sense for where we are
starting and finishing let's take a closer look at how we get from one molecule to the
next. If cholesterol is just sitting in the adrenal cortex it doesn't have any motivation to
change, what it needs is an enzyme to catalyze the process: desmolase and that
enzyme must in turn be activated by an external signal in this case it is circulating
ACTH. There's a clinical correlation here as well, ketoconazole an antifungal agent
can actually inhibit the enzyme desmolase and prevent the entire process we were
about to discuss from starting. When desmolase acts on cholesterol the molecule is
converted to pregnenolone, at this point the molecule can either gain a hydroxy group
and become 17 hydroxy pregnenolone or it can be oxidized to progesterone by
3 beta hydroxysteroid dehydrogenase. You can follow the other steps and see the
relevant conversions a few other points to be made about the reactions here stop
looking at the screen for a moment and ask yourself what stimulates the production of
aldosterone if you don't know it immediately here's a hint it's part of RAA system got it
the answer is angiotensin 2 and if you look back at the screen now you'll see that
angiotensin 2 stimulates aldosterone synthase which is responsible for
catalyzing the final step in the aldosterone synthesis pathway. Over on
the right side you'll see the peripheral conversions of testosterone into estrogen or DHT,
the relevant enzymes are absolutely critical for you to know because they are the target
of several drugs and the boards love them. Testosterone is converted to estradiol by the
action of aromatase and aromatase inhibitors such as anastrozole are important drugs
in the treatment of some types of breast cancer. The enzyme 5 alpha reductase
converts testosterone to DHT which binds to androgen receptors with a hundredfold
greater affinity than testosterone, inhibitors of 5 alpha reductase such as finasteride are
used in the treatment of benign prostatic hyperplasia or BPH.

Now let's consider the issue of enzyme deficiency diseases the three major
forms of congenital adrenal hyperplasia or CAH are highly tested concepts. Let's
start by asking why do the CAH enzyme deficiencies lead to bilateral hyperplasia? Well
all these conditions results in decreased cortisol production therefore less cortisol is
available to negatively feedback and inhibit further release of ACTH, the end result is
that the body tries to increase cortisol production by releasing more ACTH to stimulate
the adrenal cortex, however elevated ACTH cannot overcome an enzyme deficiency so
the main effect of ACTH is trophic. ACTH stimulates tissue growth and hyperplasia not
hypertrophy. The first deficiency is that of 17 alpha hydroxylase which is enzyme a in
the diagram. You can see how if the rightward pointing arrow is depicting the role of
this enzyme are blocked the only product the adrenal gland can make is aldosterone
hence patients with 17 alpha hydroxylase deficiency have high aldosterone levels
resulting in hypertension and hypokalemia while the cortisol and sex hormone levels are
too low. In XY patients the lack of DHT results in pseudohermaphroditism, people who
have ambiguous external genitalia and male internal reproductive structures including
undescended testes. In XX patients the external genitalia and internal reproductive
structures are female but low sex hormone levels prevent development of secondary
sex characteristics.

Let's move on to the second form of CAH 21 hydroxylase deficiency this is actually
the most common of the three forms of CAH. As you can see from the diagram if there
is a deficiency in 21 hydroxylase noted as B then the steroid precursors cannot move
down the pathway to become mineralocorticoids or glucocorticoids. The only option is to
convert to sex hormones so these patients end up with over masculinized phenotypes,
pseudohermaphroditism for genetic females. Because there is limited aldosterone
production these patients also suffer from hypotension and hyperkalemia in the
newborn setting patients often present with hypovolemic shock.

Lastly we have 11 beta hydroxylase deficiency this enzyme is noted as see on the
diagram. Similar to 21 hydroxylase deficiency there are abnormally low levels of
aldosterone and cortisol. Both forms of CAH feature masculinization however an
important difference between these two forms of CAH arises from the fact that eleven
deoxycorticosterone shown here has mineralocorticoid activity that is similar though not
equivalent to aldosterone. Excess 11 deoxycorticosterone leads to hypertension as
opposed to hypotension seen in 21 hydroxylase deficiency.

We've now talked quite a bit about the synthetic pathways that produce cortisol in the
adrenal cortex now let's discuss the functions of cortisol in the body. One of the most
important functions for cortisol is to maintain blood pressure. Cortisol up regulates
alpha-1 receptors on arterioles which biases them towards vasoconstriction. Cortisol is
also one of the counter regulatory hormones along with glucagon, catecholamines and
growth hormone which opposed the actions of insulin by up regulating gluconeogenesis,
lipolysis and proteolysis, cortisol is therefore diabetogenic. There are two other
functions of cortisol we will mention here. The hormone antagonizes bone formation and
immune cells the latter gives it an overall anti-inflammatory effect. Cortisol is carried
through the blood stream by corticosteroid binding globulin also known as transcortin
which is produced in the liver like many other carrier proteins. Additionally studies have
shown that chronic stress induces prolonged secretion of cortisol. Since you already
know that cortisol depresses immune function it makes sense that chronic stress may
result in higher susceptibility to infection and cancer.

We're going to shift gears now and discuss parathyroid hormone and the regulation of
calcium and phosphate. The key things to know about PTH are that it increases serum
levels of calcium and decreases serum levels of phosphate a helpful way to remember
this is to treat PTH as an acronym for phosphate thrashing hormone. Let's take a closer
look at the ways it accomplishes this task. PTH is produced by the chief cells of the
parathyroid gland, when ionized calcium levels in the blood are low the parathyroid
gland releases PTH to increase calcium. One function of PTH is to increase bone
resorption of both calcium and phosphate, interestingly PTH directly stimulates
osteoblasts rather than osteoclasts because the latter have no PTH receptors. PTH
binding to osteoblasts increases their expression of rank L and decreases their
expression of OPG the latter of which is an inhibitor of rank L. Rank L on osteoblasts
bind to rank on osteoclast precursors stimulating them to fuse forming new osteoclasts
that are capable of resorbing bone. The other action of PTH occurs in the kidney: first
PTH directly causes increased reabsorption of calcium in the distal convoluted tubule
simultaneously it causes decreased reabsorption of phosphate in the proximal
convoluted tubule. Lastly PTH stimulates 1-alpha hydroxylase in the proximal tubule of
the kidney which increases the production of active vitamin d the 125 dihydroxy form
also known as calcitriol and this goes on to increase intestinal calcium and phosphate
absorption. Once again the overall effect of PTH is to increase calcium and decrease
serum phosphate. A final aspect of the hormone that is important to know is that it can
be affected by serum magnesium concentration, when the magnesium concentration is
low PTH secretion is increased but this effect is reversed if the serum magnesium is
extremely low. This low magnesium state is seen in patients with diarrhea and alcohol
abuse as well as those taking amino glycosides or certain diuretics.

Now we already started to discuss vitamin D above in relation to PTH but let's
concentrate on just vitamin D for the moment. This is a critical vitamin with important
functions in mineral homeostasis. The d3 version comes from sun exposure and the d2
version is ingested from plants. Liver is responsible for hydroxylated each version at the
number 25 position and the kidney is responsible for hydroxylating at the number one
position, hence generating the active form of vitamin D known as 125 dihydroxy vitamin
D requires both a functional liver and kidney. You might see a question on the boards
where you need to make the connection between vitamin D deficiency and some forms
of kidney disease. We now know where vitamin D is coming from and how it is modified
in the body but what exactly does it do? Its main function is to increase the absorption of
calcium and phosphate from the GI tract and additionally vitamin D acts to increase
bone resorption of calcium and phosphate. Like PTH it increases serum calcium levels
but in contrast to PTH it increases phosphate levels as well. There are two forms of
vitamin D deficiency in children it is known as rickets in adults it is called osteomalacia
more on that in the musculoskeletal lectures. Vitamin D production is stimulated by
increased PTH, decreased serum calcium and decreased serum phosphate. Not
surprisingly vitamin D also exhibits feedback inhibition on its own production. Another
aspect of the calcium story comes from the hormone calcitonin, this molecule is usually
not relevant to normal calcium homeostasis but it is sometimes used as a drug to
combat hypercalcemia. The function of calcitonin is to decrease bone resorption of
calcium. We like to say that calcitonin tones down serum calcium levels though
repeated studies in humans show that its effects are minimal at best. The endogenous
source of calcitonin is the pair of follicular or c cells of the thyroid gland and secretion is
increased by high serum levels of calcium.

Essentially all hormones are variations of one of two chemical types: peptides
and steroids. The mechanisms of action are quite different for these two classes of
hormones. The peptide group binds to their target receptors on the plasma membrane,
receptor ligand interaction initiates an intracellular signal transduction cascade that may
involve second messengers such as cyclic AMP, cyclic GMP and ip3 or tyrosine
kinase activity either intrinsic to or associated with the target receptor. On the other
hand the typical site of action for the steroid group as well as thyroid hormone is the cell
nucleus.

The key thing to remember is that steroid hormones such as testosterone are lipophilic.
There are two important consequences of this chemical feature first steroid hormones
can pass freely through cell membranes and into the nucleus and second they are
insoluble in plasma and are carried by specific molecules called binding globulin.
Steroid hormones pass through the lipid bilayers that compose cell membranes and
interact with receptors either in the cytoplasm or nucleus which then adopt a
conformation able to bind DNA to alter gene expression. Thyroid hormone has a similar
mechanism of action as steroid hormones and indeed there is a shared family of steroid
and thyroid receptor molecules. As you can imagine since these hormones act by
altering gene expression their effects take time to manifest, contrast this to the rapid
effects of a peptide hormones such as insulin which causes an immediate increase in
glucose uptake by cells enabling cellular respiration and ATP production.

Binding globulin increase the solubility of the steroid hormones they carry and improves
delivery to target tissues. The serum level of binding globulin often has clinical
relevance for example sex hormone binding globulin or SHBG is the specific carrier for
sex hormones such as testosterone. Increased levels of SHBG lower the amount of free
testosterone, in men decreased free testosterone manifests as gynecomastia when the
levels of shbg drop in women there is more free testosterone in the bloodstream which
manifests as hirsutism which is male pattern hair growth.

Move on to discussing thyroid hormone the pathological conditions of hypo and hyper
thyroidism are absolutely critical to know for the USMLE. Thyroid hormone is produced
in follicular cells also known as thyrocytes of the thyroid gland it contains iodine and
controls the body's basal metabolic rate. You can see in this diagram of a follicular cell
that thyroglobulin protein tgb is produced in the cytoplasm and secreted into the lumen.
In parallel iodide ions are taken up by follicular cells via a sodium iodine co-transporter,
oxidize the diatomic iodine and then secreted into the lumen. In the lumen thyroid
peroxidase is responsible for adding iodine onto tyrosine residues of thyroid globulin.
Upon stimulation by TSH iodinated thyroglobulin is endocytosed from the lumen back
into follicular cells where it is digested by lysosomal proteases to release
monoiodotyrosine MIT and diodotyrosine DIT into the cytoplasm. Combining MIT with
DIT results in triiodothyronine known as T3 whereas combining two DIT molecules
results in thyroxine known as T4, these two forms of thyroid hormone are then
transported across the basolateral membrane of thyrocytes and into the bloodstream in
a TSH mediated process. Thyroid peroxidase is a versatile enzyme not only does it
incorporate iodine into thyroidglobulin a process known as organification it is also
responsible for oxidation of iodide ions and coupling MIT and DIT to form thyroid
hormone. It's worth pointing out that t4 is the major product of follicular cells. Though
some t3 is produced in the thyroid gland itself the majority of t3 in the body is derived
from peripheral deiodination of t4, specifically a removal of the 5-prime iodine by five
prime deiodinases. You can consider t4 to be a prohormone for T3 since t3 is much
more active than t4.

Okay let's turn now to the functions of thyroid hormone, as we already noted the major
role of thyroid hormone is to control the body's basal metabolic rate, how does it do
that? In brief thyroid hormone increases sodium potassium ATPase activity and
expression which increases oxygen consumption, the respiratory rate and body
temperature it also up regulates glycogenolysis, gluconeogenesis and lipolysis to
increase ATP production. Additionally thyroid hormone up regulates the number of beta
1 receptors in the heart which leads to an increase in heart rate, stroke volume
contractility and therefore cardiac output as well. This is the reason why hyperthyroidism
is associated with palpitations. There are two other critical functions of thyroid hormone
in the developing body it promotes bone growth along with growth hormone in a
synergistic fashion and it promotes maturation of the central nervous system. Patients
with thyroid deficiency early in life develop neonatal hypothyroidism or cretinism which
is characterized by severely stunted physical and mental growth. For example short
stature and low IQ you may find it helpful to think of thyroid hormone in terms of the four
B's: brain maturation, bone growth, beta adrenergic affects and increased basal
metabolic rate.

Like steroid hormones thyroid hormone is transported in the blood by a binding globulin:
thyroxine binding globulin. Tbg binds most of the t3 and t4 and the only thyroid hormone
that actually acts on the tissue is a fraction of free unbound thyroid hormone. Lab tests
are available to measure the total amount of hormone as well as the free portion of the
hormone to allow clinicians to understand the source of change hormone levels. Two
situations in which this is relevant are in hepatic failure when the TBG level is low and in
pregnancy when the tbg level goes up. So in pregnancy for example the TBG is high
and the total amount of thyroid hormone is high but the amount of free hormone should
stay constant and therefore the patient is considered to be euthyroid. Make sure you
don't confuse tbg or thyroxine binding globulin a carrier thyroid hormone in the blood
and TGB or thyroglobulin the precursor of thyroid hormone.

Graves disease is an autoimmune condition in which production of thyroid stimulating

immunoglobulin or tsi in large quantities stimulates follicular cells in a similar manner to
TSH resulting in hyperthyroidism. Two common anti-thyroid drugs used to treat
hyperthyroidism are propylthiouracil or PTU and methimazole. While PTU inhibits both
thyroid peroxidase and five-prime deiodinases, methimazole all only inhibits peroxidase.
Both drugs take time to have a clinical effect because they block synthesis of thyroid
hormone but do not deplete existing stores. Interestingly, excess ingestion of iodide can
lead to a transient decrease in thyroid hormone levels because of thyroid peroxidase
inhibition, this phenomena is known as the wolff chaikoff effect.
Okay before we leave endocrine physiology let's do a practice question a 17 year old
girl comes to see you with the chief complaint of primary amennorhea after physical
examination and additional testing you discover that she has a blinding vagin, no uterus
cervix or ovaries as well as undescended testes in the inguinal canal she also has a 46
XY genotype. What is the most likely diagnosis? The patient has a Y chromosome and
therefore produced sex-determining region Y or sry and mullerian inhibiting factor or
MIF in development which we'll learn more about in the reproductive lectures. Mif blocks
the development of female internal reproductive organs and sry stimulates
differentiation of the primitive gonads into testes this phenotype genotype combination
points to androgen insensitivity disorder a condition in which androgen receptors are
absent, what would you expect the patient's testosterone levels to be? Testosterone
would be very high because without androgen receptors to sense the circulating
testosterone there is no feedback inhibition on the production of LH and the body
stimulus testosterone production as that there is very little around. If there's one thing
you should take away from this lecture it is that endocrine physiology is all about
feedback loops usually negative feedback is involved to maintain homeostasis however
don't forget that there are some important exceptions in which positive feedback is
involved such as the LH estrogen loop that triggers ovulation.

To begin let's discuss Cushing syndrome which is a common set of clinical findings from
a variety of underlying causes. The one universal feature is that there is excess cortisol
and the clinicians main job is to figure out the source of the cortisol. The most common
cause by far is exogenous administration of steroids. Steroids are useful drugs that
doctors prescribe for a variety of conditions but unfortunately if used excessively they
can cause Cushing's syndrome. In the less common situations where the sources of
excess cortisol are endogenous, 70 percent of these cases can be traced to a pituitary
adenoma secreting adrenocorticotropic hormone or ACTH. When Cushing's syndrome
is caused by a pituitary tumor it is known as Cushing's disease the remainder of cases
can be attributed to either ectopic ACTH secretion from non pituitary tissue such as the
infamous small cell lung cancer or from adrenal adenoma, carcinomas or hyperplasia.
ACTH serum levels are useful in differentiating these different causes of Cushing's
syndrome. If exogenous steroids are being administered they will negatively feedback
on the hypothalamus and pituitary which is manifested by low levels of ACTH, similarly
if the adrenal is autonomously producing high steroid levels, negative feedback will
result in low serum ACTH; however if there is a high ACTH level and high cortisol you
know that the reason for high cortisol is the high ACTH either coming from its usual
source in the pituitary or from an ectopic location usually the lung. In order to
differentiate these last two options clinicians can perform what's known as a
dexamethasone suppression test. Dexamethasone is a synthetic glucocorticoid and
therefore will also cause negative feedback on ACTH levels. A patient's blood levels of
cortisol are measured before and after administration of low-dose dexamethasone in a
normalperson cortisol levels would be lower after dexamethasone administration
because the synthetic glucocorticoid suppresses endogenous acth production. Patients
with Cushing's syndrome however do not typically respond to the low doses and cortisol
levels remain high. Io differentiate the various etiologies of Cushing's syndrome the next
step is to give a high dose of dexamethasone and measure blood levels or cortisol for
athird time shortly after administration. Reduction in cortisol levels by high dose but not
low dose dexamethasone is indicative of Cushing's disease or an ACTH secreting
pituitary adenomas. If the cause of cushing's syndrome is an ectopic source of ACTH
or cortisol, cortisol levels will remain high after both low dose and high dose
dexamethasone; however ACTH will be high for an ectopic ACTH producing tumor but
low for a cortisol producing tumor due to negative feedback. So we've talked about
some of the lab testing for Cushing's syndrome but what exactly are the clinical features
of the disease? Some of the obvious external science include weight gain moon phases
truncal obesity Buffalo Hump and skin changes such as thinning and violaceous striae
worrisome cardiovascular issues include hypertension and hyperglycemia from insulin
resistance longer term effects which become important for patients on long term steroid
treatment include osteoporosis amenorrhea and immunosuppression we're going to
transition now to some diseases of the adrenal gland dosterone ism as the name
suggests is a disease with extremely high levels of aldosterone which you should recall
is produced in the zona glomerulosa of the adrenal cortex this can be either primary
meaning the adrenal is autonomously secreting more aldo than it should or secondary
meaning there is a signal causing the adrenal to produce too much aldo when it is
primary there is an aldosterone secreting tumor this is known as Conn's syndrome the
effects of having too much aldo in the circulation are hypertension hypokalemia and
metabolic alkalosis because the high blood pressure is detected by the kidneys there is
no stimulus to secrete renin and plasma levels are low a side note on this tumor is that it
can occur either unilaterally or bilaterally and it can be treated either surgically or
chemically with Sparano lactone and competitive aldosterone antagonist patients can
also have too much aldosterone as an effect of excessive adrenal stimulation you
should remember that angiotensin ii increases the production of aldosterone and that
angiotensin ii itself is formed after a stimulation by renin so there must be a high renin
level and the physicians job is to determine what process is causing the high renin level
some reasons for the kidneys to secrete excess renin include renal artery stenosis
chronic kidney disease congestive heart failure cirrhosis or nephrotic syndrome most of
these conditions cause the kidneys to perceive the intravascular volume as being
abnormally low and they respond by up regulating read and production you'll hear much
more about how these disease entities involve or interact with the kidney in the renal
lectures at the other end of the spectrum we have a disease entity where the adrenal
cortex is failing to function properly Addison's disease is defined as chronic primary
adrenal insufficiency and can be related to adrenal atrophy or destruction of the gland
by autoimmune diseases tuberculosis or metastatic cancer because the aldosterone
production is compromised patients develop hypotension hyperkalemia and metabolic
acidosis compromise cortisol production causes weakness anorexia GI disturbance and
weight loss a telling sign of the disease is increased skin pigmentation patients appear
to have tan skin even without large amounts of sun exposure we'll go back to the
hypothalamic pituitary axis in order to understand the symptom when cortisol is
produced it feeds back to the hypothalamus and pituitary to decrease further production
of corticotropin-releasing hormone or CRH and ACTH since cortisol is not adequately
produced in Addison's disease there is no inhibition of the hypothalamic pituitary axis so
we get an increase in CRH and ACTH recall that ACTH is not the direct product of the
cortico troves in the anterior pituitary in fact ACTH is a sub product of propiomalonic
Orton or P o MC another sub product of P om c is melanocytes stimulating hormone or
MSH therefore if ACTH goes up then MSH also goes up which causes the
hyperpigmentation an important aspect of Addison's disease is that it affects all of the
layers of the adrenal cortex but spares the medulla also you can have similar clinical
findings in patients that is weakness anorexia GI disturbance weight loss hypotension
and acidosis but no skin color changes or hyperkalemia in this situation you are likely
dealing with secondary adrenal insufficiency in which the adrenal gland itself is
functionalbut there is reduced secretion of ACTH from the pituitary laboratory can easily
distinguish these based on this information what do you think tertiary adrenal
insufficiency is that's right reduced CRH secretion from the hypothalamus so far we've
discussed primary adrenal insufficiency in its chronic form that is Addison's disease but
patients can also present with acute adrenal crisis due to adrenal hemorrhage also
known as waterhouse Friedreich's in syndrome which is associated with the Syria
meningitis septicemia disseminated intravascular coagulation and ended toxic shock of
these three ideologies the link between the Syria septicemia and waterhouse
Friedreich's in syndrome is the most frequently tested this devastating syndrome
consists of shock coagulopathy and petechial rash about two tumors of the adrenal
medullathe first is the infamous pheochromocytoma this is a tumor that usually occurs in
the adrenal medulla though in ten percent of cases it is found in other sites of the body
such as the para ganglionic tissue near the abdominal aorta the tumor derives from
chromaffin cells of the neural crest the major products of pheochromocytoma are
epinephrine norepinephrine and dopamine the sporadic secretion of these
catecholamines causes episodic hypertension which is a cardinal feature of the disease
you should be familiar with the pathway on this page describing the metabolism of
catecholamines also recognized that the final conversion from norepinephrine to
epinephrine occurs only in the adrenal medulla because it requires the P n am T
enzyme that is only expressed there diagnostic testing includes checking levels of
plasma catecholamines as well as looking for breakdown products in the urine such as
hva nor meta nephron VMA and meta nephron definitive management of these tumors
is surgical but patients must get their hypertension under control for a period of months
before they can have a safe operation typically an irreversible alpha antagonist such as
phenoxy benjamine is given first to avoid a hypertensive crisis followed by beta blockers
to reduce the heart rate recall from the pharmacology lectures that epinephrine and
norepinephrine cause vasoconstriction by acting on alpha one adrenergic receptors so
an alpha blocker will prevent hypertension even when there are high levels of
catecholamines in the circulation so how would you recognize pheochromocytoma on
an exam there are five major signs and symptoms and they all start with the letter P so
it's easy to remember pressure as in high blood pressure pain and that's referring
specifically to a pounding headache perspiration palpitations which are associated with
an elevated heart rate and pallor patients won't present with a complaint of high blood
pressure but they may come in and say that they're having a headache perspiration and
palpitations the so called triad of pheochromocytoma you may have heard about the
rule of tens for pheochromocytoma pheochromocytoma is traditionally described as
being benign unilateral in the adrenal medulla and occurring sporadically in adults the
rule of tens gives you all the rare findings in 10% of cases the tumor is malignant ten
percent of the time it will occur bilaterally ten percent of tumors are not in the adrenal
ten percent of the tumors are calcified on imaging 10 percent of cases our current
children and ten percent of the time it occurs in families in the rare cases where
pheochromocytoma is familial it is usually associated with neurofibromatosis men2 a or
men2b where ma n stands for multiple endocrine neoplasia we'll discuss em en in detail
in a few minutes cancer and children is quite rare in general but neuroblastoma is one
of the more common solid tumors found in children this tumor occurs in the adrenal
medulla or anywhere along the sympathetic chain the tumor is typically discovered by
physical exam parents were physicians known an unusual growth in the abdomen
though there are many other clinical features lab testing includes elevated urine levels
of homel vanilla acid which is a breakdown product of dopamine these patients are less
likely to develop hypertension compared to patients with pheochromocytoma the key
Anki gene for this tumor is an Mik which has been associated with rapid tumor
progression histologically neuroblastoma is characterized by small round blue cells that
form home or right pseudo rosettes remember this important Association for the boards