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.
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.