Chapter 8 (Continued) Physiology 1:

Return to HPA Concept: Note that relationships can be simple (CRH, GHRH, and
GnRH) or complicated (TRH (releases 2), dopamine (constitutively released) and
prolactin (negative regulator of GnRH), and somatostatin (blocks 2)).
Application: Prolactin -> inhibiting GnRH, is the reason why women who are
breastfeeding, dont ovulate.

Prolactin has -> negative regulation from dopamine, and positive regulation from TRH.
When secreted, prolactin feeds back to up-regulate dopamine production, which in turn,
inhibits prolactin secretion, thereby maintaining homeostasis.
Prolactin inhibits GnRH and stimulates milk production (in the breasts).
-Despite majority negative feedback loops, there are some important positive feedbackloops to be aware of:
-> Prior to ovulation, the release of LH from the pituitary stimulates the ovary to secrete
estrogen, which in turn, 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.
Drugs that interact with prolactin: bromocriptine (dopamine agonist) -> can be used to
treat prolactinoma (most common type of pituitary tumor).

GH is released in a pulsatile fashion in response to GHRH. As one of the counterregulatory hormones, GH is diabetogenic b/c it increases insulin resistance.
Acromegaly in adults -> whos growth plates have fused.
Gigantism in children -> whos growth plates have yet to fuse.

Chemical reactions in the different zones:

-> Layers of adrenal cortex -> GFR.
Cholesterol is the building block of steroid hormones (all end products listed).
End Products:
ZG -> Aldosterone
ZF -> Cortisol
ZR -> Testosterone
Look to far right (of image above). -> Testosterone and its precursor Androstenedione,
can be peripherally converted to the other sex hormones including -> estrone, estradiol
and DHT (more potent than TST).

- circulating ACTH stimulates desmolase.

Clinical Correlate: ketoconazole -> antifungal agent can inhibit desmolase.
What stimulates aldo production? Hint: Part of R-A-A system. Ans: Angiotensin II, which
stimulates aldo synthase (responsible for catalyzing the final step in the aldo synthesis
pathway).
-> On the right side of the flow chart: note the peripheral conversions of TST into
Estradiol or DHT.
-> Relevant enzymes are critical -> b/c they are the targets of several drugs.
TST ----(aromatase)----> Estradiol => Aromatase inhibitors (ie: anastrazole is an
important drug in some breast cancer treatments)
TST ----(5-alpha-reductase)-- DHT => 5-alpha-reductase inhibitors (ie: finasteride, are
used in Rx of BPH) bind to androgen receptors with 100x more affinity than TST.

Consideration of enzyme deficiency diseases:

-> 3 major forms of CAH are highly testable concepts.
Why do the CAH deficiencies lead to bilateral hyperplasia?
B/c all of these conditions lead to decreased cortisol production. -> Therefore less
cortisol is available to negatively feedback and inhibit further release of ACTH.

End result is that the body tries to increase cortisol production by releasing more ACTH
to stimulate the adrenal cortex (although elevated ACTH cant overcome an enzyme
deficiency -> so ACTHs main effect -> is trophic).
ACTH stimulates tissue growth and hyperplasia, NOT HYPERTROPHY!
17-alpha-hydroxylase deficiency (enzyme A in diagram above) => the only product that
the adrenals glands can make, is aldosterone. Hence, 17-alpha-hydroxylase deficiency
is associated with increased aldo levels -> resulting in hypertension and hypokalemia,
while cortisol and sex hormone levels are too low.
In XY patients -> the lack of DHT results in pseudohermaphroditism -> people with
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 hormones -> prevent the development of normal sex characteristics.
21-hydroxylase deficiency (most common of 3 forms) -> steroid precursors cannot make
mineralocorticoids or glucocorticoids. Only option is -> conversion to sex hormone
conversion. -> these patients have overmasculinized phenotypes
(pseudohermaphroditism for genetic females). B/c there is limited aldo production =>
these patients also suffer from hypotension and hyperkalemia. In the newborn setting ->
pts present with hypovolemic shock.
11--hydroxylase deficiency (noted as C on diagram above) -> abnormally low cortisol
and aldo levels (similar to 21-deficiency). Both of these latter forms feature
masculinization, however an important difference between them arises from notion that
-> 11-deoxycorticosterone (has similar but NOT equiv. mineralocorticoid activity to aldo).
Excess 11-deoxycorticosterone leads to hypertension (as opposed to hypotension, seen
in 21-hydroxylase deficiency)