section 31.2
Pituitary Gland (Hypophysis)
743
S>
<
s>
<
E>
<
Pro-opiomelanocortin (PMOC)
----------- f
E?
<
2 3 0 +
Human N-terminal (hNT)
---------------- >—
r
7 6
%-MSH
2 7
ACTH
— f-----
3 9
<
ß-Lipotropin ( ß-LPH)
91
I
ß-Endorphinl *
5 8
31
Intermediate lobe of subhuman species
a-MSH
CLIP
ß-MSH |
1 3
22
22
FIGURE 31-7
Posttranslational processing of pituitary pro-opiomelanocortin (pmoc). * , Released into blood.
and/or brain may be capable of forming
a-
and /1-MSH
from POMC, since these peptides appear to exert central
effects.
Inherited defects in POMC production result in defi-
ciency or a complete lack of secretion of ACTH, MSH (a -,
fi-, y-),
and /1-endorphin. These patients exhibit adrenal
insufficiency, red hair pigmentation, and early-onset obe-
sity that has been related to deficiency of a-MSH pro-
duction. Animal studies have shown that a-MSH regu-
lates food intake by activation of melanocortin receptor-4
(Chapters 5 and 22). In mioe, a
POMC
gene defect also
leads to adrenal deficiency, altered pigmentation, and obe-
sity with loss of a significant portion of the patient’s ex-
cess weight when he or she is treated with a stable a-MSH
preparation. Other genetic causes of obesity include de-
fects in genes encoding prohormone convertase
- 1
(i.e., in-
ability to convert POMC to various peptides), leptin, and
leptin receptor (Chapters 5 and 22).
ACTH
(Table 31 -
6
) is a polypeptide of 39 residues, the
first 24 of which are required for corticotropic activity and
do not vary among species. ACTH]
2 4
has been synthe-
sized and is used for diagnostic purposes. Because it con-
tains the MSH sequence in residues 6-9 (His-Phe-Arg-
Trp), ACTH has intrinsic melanocyte-stimulating activity;
it can thus cause skin darkening if present in high con-
centrations. In normal adults, the pituitary contains about
0.25 mg of ACTH, and the basal level of ACTH in blood
is about 50 pg/mL.
ACTH acts mainly on the cells of the zona fasciculata
of the adrenal cortex to stimulate the synthesis and release
of cortisol (Chapter 32). It also stimulates the secretion of
adrenal androgens from the zona reticularis. Binding of
ACTH to receptors activates formation of cAMP, which
mediates cortisol formation and secretion and protein syn-
thesis. Deficiency of ACTH leads to reduction in size and
activity of adrenocortical cells in the inner two zones.
ACTH secretion is regulated so as to ensure constant,
adequate levels of cortisol in blood. Corticotrophs in
the pituitary are under tonic stimulation by CRH and
are modulated by the negative feedback effect of blood
cortisol, which inhibits POMC synthesis by repression
of the
POMC
gene. Although cortisol also exerts an
effect on the hypothalamus and related areas in the
brain (limbic system, reticular formation), this activity
may involve the regulation of emotion and behavior and
not of CRH release. The regulation of the ACTH and
cortisol is illustrated in Figure 31-8. Secretion of POMC
in the intermediate lobe is not regulated by CRH and
glucocorticoids, since the intermediate lobe is poorly
vascularized and contains no glucocorticoid receptors.
However, the intermediate lobe is rich in dopaminergic
fibers, so that dopamine agonists (ergocryptine) decrease,
