Clinical scenario
A 28-year-old interior designer, ZL,
presented to her GP with a 12-month history of change in her appearance, excess
facial hair growth and irregular, scanty periods. She had noticed that her
cheeks were becoming fatter and that she was always red in the face, with the
onset of greasy skin and acne more latterly. She had marked hair growth over
her chin and upper lip. On questioning, she had gained weight ‘round the middle’
and noticed the development of red stretch marks on her abdomen. She generally
felt very low about things. Physical examination suggested that she had
Cushing’s syndrome and she was referred to the local endocrine clinic. When she
arrived there, the above features were noted plus a marked proximal myopathy.
Investigations revealed elevated urinary free cortisol levels, plasma cortisol
concentrations of 1059 nmol/L at 0900 h and 1003 nmol/L at midnight. The ACTH
concentration at 0900 h was 230 ng/L. Pituitary MRI scanning suggested an
abnormality in the left side of the gland, and this was supported by bilateral
catheterization of the petrosal sinuses with multiple ACTH measurements. She
underwent trans-sphenoidal surgery with removal of a pituitary adenoma which
stained strongly for ACTH on immunohistochemical testing. Postoperatively her
symptoms resolved associated with normalization of her pituitary function.
Adrenocorticotrophic hormone
Control of adrenocorticotrophic
hormone (ACTH) secretion. ACTH is
synthesized in the anterior pituitary corticotroph cells and is released on
stimulation of the corticotroph cell by the hypothalamic peptide
corticotrophin-releasing hormone (CRH; Fig. 18a). Human CRH is a peptide
containing 41 amino acids and is sometimes referred to as CRH-41. It is a
potent releaser of ACTH, both in vivo and in vitro. CRH-41 is
widely distributed throughout the brain but the greatest concentration is in
the hypothalamus, within the parvocellular neurones of the paraventricular
nucleus (see Chapter 5). These neurones project many fibres to the median
eminence, where they release CRH into the portal circulation. Other peptides,
notably vaso- pressin, may physiologically potentiate the ACTH-releasing action
of CRH. The interaction between CRH and vasopressin (here abbreviated to AVP,
because it is structurally arginine– vasopressin) involves their interaction
with receptors on the membrane of the anterior corticotroph cell (Fig. 18b).
AVP activates the IP3 second messenger
system, which opens receptor-gated calcium channels. CRH acts through the
adenylate cyclase–cAMP second messenger system, and opens voltage-gated calcium
channels. The increased free intracellular Ca2+ stimulates ACTH
release. ACTH synthesis is stimulated through CRH-mediated increased expression
of the proopiomelanocortin (POMC) gene, which contains the genetic information
required for synthesis of ACTH, and the hormone melanocyte-stimulating hormone.
CRH release from the hypothalamus is
stimulated by the neurotransmitters acetylcholine and serotonin (5HT). It is
inhibited by gamma-aminobutyric acid (GABA) and norepine- phrine (NE). CRH and
ACTH release are inhibited by the glucocorticoids in a negative-feedback
loop; this loop is useful in testing the integrity of the hypothalamic–hypophyseal–adrenal
axis (Chapter 17).
The pro-opiomelanocortin (POMC)
system. Anterior pituitary
corticotrophs synthesize a glycoprotein which contains the complete amino acid
sequences of ACTH, β-lipotrophin (β-LPH), melanocyte-stimulating hormone (MSH),
met- enkephalin and a number of other peptides (Fig. 18c). POMC has a 26 amino
acid signal sequence, followed by three main structural domains, namely: (i)
ACTH; (ii) β-LPH at the C-terminal; and (iii) the N-terminal sequence pro-
γ-MSH (for which no biological role has yet been found). POMC is first cleaved
to give β-LPH and ACTH, which is still attached to the N-terminal fragment. In
anterior pituitary corticotrophs, ACTH is released at the second cleavage. A
number of molecules of β-LPH are cleaved to give β-endorphin and γ-LPH. It
appears that on stimulation of the corticotroph with CRH, all the POMC-derived
peptides are secreted together, suggesting that they are held together in the
same secretory granule, and sup-porting the idea that they all derive from
POMC. In species which possess a functional pituitary intermediate lobe (e.g.
the rat, but not the adult human), further cleavage of many of the peptides
occurs; for example the cleavage of ACTH into ACTH1–13, which is α-N acetylated
to yield α-MSH and ACTH18–39.
Mechanism of adrenocorticotrophic
hormone action.
ACTH binds to high affinity membrane
receptors on the adrenal cell, activating the adenylate cyclase system
(Fig.18d). Maximum stimulation of steroidogenesis can be achieved with a plasma
concentration of around 3 ng/L of ACTH. Increased intracellular concentrations
of cAMP enhance the transport of cholesterol to a mitochondrial side chain
cleavage enzyme, and they activate cholesterol ester hydroxylase. In addition,
RNA and protein synthesis in the cell are stimulated, and there is a net
increase in adrenal protein phosphorylation.
ACTH and calcium channels. ACTH promotes cortisol secretion partly through
stimulation of Ca2+ channel production on cortisol-releasing cells,
and this finding may have important implications for future modification of
cortisol release.
ACTH, CRH and the immune system. CRH stimulates B cell proliferation and NK
activity. It also stimulates IL-1, IL-2 and IL-6 production. CRH receptors have
been found on immune cells. Injection of CRH directly into the cerebral
ventricles inhibits immune function. CRH injected intracerebrov- entricularly
has largely inhibitory effects on immune function. ACTH has been shown to
inhibit antibody production to some extent and it modulates B cell function.
