Clinics in Endocrinology and Metabolism最新文献

The precursor of ACTH and β-LPH is a glycoprotein with a molecular weight of more than 30000. Its gene consists of three exons with two intervening sequences and most of the protein coding sequence is in exon 3. The gene is expressed not only in the pituitary gland but also in extrapituitary tissues. The gene expression in the anterior pituitary gland is regulated by CRF and glucocorticoids, but it is regulated differently in other tissues. The processing of the ACTH/β-LPH precursor yields several peptides, but final products vary in tissues due to differential processing. The processing is abnormal in ACTH-producing tumours, especially in ectopic ACTH-producing tumours. Some abnormalities may also occur at the transcriptional or post-transcriptional level as well.

Peptides derived from the same precursor are secreted concomitantly from the pituitary gland. CRF is the major stimulating factor, but vasopressin and some other factors are also involved in stimulating ACTH release. On the other hand, glucocorticoids inhibit ACTH release by acting at the hypothalamic and pituitary levels. In the pituitary ACTH-producing adenomas of Cushing's disease, CRF, vasopressin as well as other non-physiological factors stimulate ACTH secretion. Such abnormal receptor mechanisms are also seen in ectopic ACTH-producing tumours.

The biosynthesis of adrenocortical steroids is now a reasonably well understood process, which proceeds by discrete, enzyme directed steps from cholesterol to the various hormonal steroids. However, much of our knowledge derives from studies of animal tissues and there is a need for further studies of human glands. In particular, the details of individual enzyme systems, and the extent and significance of compartmentalization of steroid intermediates requires further exploration. The adrenal metabolic errors also merit further study, to clarify some aspects of congenital adrenal hyperplasia and to explain the relationship between biochemical and clinical observations.

The advent of immunoassay methods for the measurement of steroid hormone levels in plasma has changed the approach to diagnostic steroid endocrinology, with less emphasis now on the measurement of urinary steroid metabolites, particularly in regard to androgens. The newer and sensitive methods available also allow the assay of steroid hormones in saliva, and the ready availability of this fluid, and the fact that sampling is a non-invasive technique makes salivary steroid assay an attractive alternative to other, traditional methods of investigation requiring blood or urine collection.

Inhibitors of steroid biosynthesis and of steroid action have been used with considerable success in diagnostic techniques and to a limited extent in the treatment of steroid disorders. As our understanding of the details of steroid biosynthesis, mechanism of steroid action, and control of steroid secretion improve, further progress in designing clinically useful inhibitors should be possible.

Recent findings indicate that interactions between the pituitaryadrenocortical axis and the immune system involve more than simply the effects of glucocorticoid hormones. This altered view has resulted from the observations that: 1) cells of the immune system have receptors for and are directly acted upon by ACTH and endorphins, and 2) the immune system is an important non-pituitary source of these peptide hormones. In this chapter, while we review in a cursory way the older findings with glucocorticoid hormones, we concentrate on the newer developments which suggest that leukocyte- and pituitary-derived ACTH and endorphins perform regulatory functions within and between the immune system and the pituitary-adrenocortical axis.

The physiological control of adrenal androgen secretion has not been definitively established. However, there is evidence to suggest that a dexamethasone-suppressible factor other than ACTH may have a specific role to play. The majority of patients with idiopathic hirsutism (hirsutism associated with regular menstruation) have findings suggestive of adrenal androgen excess, including enhanced androgen responsiveness following administration of metyrapone, and respond to treatment with dexamethasone, 0.5 mg given each night. Patients with idiopathic hirsutism have elevated androgens but normal oestrogen and gonadotrophin levels. In contrast, while patients with polycystic ovary syndrome (PCOS) also demonstrate evidence of adrenal androgen excess, these patients have elevated oestrone levels and gonadotrophin secretion is abnormal. Approximately 50% of patients with PCOS treated with dexamethasone resume regular menstruation. Oestrone excess appears to be primary to the abnormal gonadotrophin secretion and to the development of PCOS. In non-obese patients with PCOS elevated oestrone appears to occur as a consequence of the availability of the excessive amounts of its immediate precursor, androstenedione, an androgen mainly of adrenal origin. Androstenedione is converted to oestrone in fat. Obese amenorrhoeic subjects have normal androstenedione values but elevated oestrone levels with abnormal gonadotrophin secretion as seen in PCOS. These findings indicate that abnormal gonadotrophin secretion is associated with elevated oestrone levels whether these occur as a consequence of excessive adrenal androgen secretion, or the excessive conversion of normal amounts of available androstenedione. Patients with idiopathic hirsutism and elevated androstenedione levels but normal oestrone values appeared to be protected against the development of PCOS by relatively poor conversion of androstenedione to oestrone. It is likely, therefore, that if patients with idiopathic hirsutism gain additional adipose tissue, elevated oestrone levels will result and PCOS will develop. These observations explain the frequent association of PCOS and obesity. There is a close clinical association between elevated androgen levels and hirsutism and between elevated oestrone levels and menstrual disturbances. However, some patients with amenorrhoea but without hirsutism may demonstrate marked elevations of androgens and oestrone, the correction of which leads to the resumption of regular ovulation. This presentation, ‘amenorrhoea with cryptic hyperandrogenaemia’, is probably explained by diminished sensitivity of androgen receptors. While adrenal androgen excess may be associated with hirsutism and menstrual disturbances in patients with Cushing's syndrome, the features of glucocorticoid excess usually predominate. When frank virilization develops, the presence of an androgen-secreting adrenal or ovarian tumour should be suspected. Ultrasonography, CT scanning, adrenal rad