Abstract
Within potential target cells, the actions of physiological glucocorticoids (cortisol and corticosterone) are modulated by isoforms of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). To date, two isoforms of 11 beta HSD have been cloned: 11 beta HSD1 acts predominantly as an NADP(H)-dependent reductase to generate active cortisol or corticosterone, and 11 beta HSD2 is a high affinity NAD(+)-dependent enzyme that catalyses the enzymatic inactivation of glucocorticoids. Whereas the regeneration of active glucocorticoids by 11 beta HSD1 has been implicated in the cellular mechanisms of pituitary function, ovulation and parturition, the enzymatic inactivation of cortisol and corticosterone by 11 beta HSD enzymes appears to be central to the protection of gonadal steroidogenesis, prevention of intra-uterine growth retardation, and lactation. Recent evidence indicates that follicular fluid contains endogenous modulators of cortisol metabolism by 11 beta HSD1, the concentrations of which are associated with the clinical outcome of assisted conception cycles and are altered in cystic ovarian disease. In conclusion, the two cloned isoforms of 11 beta HSD fulfil diverse roles in a wide range of reproductive processes from conception to lactation.
Highlights
The definitive role of glucocorticoids, synthesized in the zona fasciculata of the adrenal cortex in response to adrenocorticotrophic hormone (ACTH), is to increase plasma glucose concentrations
Before excretion in the urine or faeces, glucocorticoids must be rendered water soluble by the sequential actions of hepatic 5␣or 5-reductase and 3␣- or 3-hydroxysteroid dehydrogenase (3␣HSD or 3HSD) which reduce C=C double bonds and ketones, respectively, to generate hydrophilic dihydro- and tetrahydro-steroid metabolites. It was recognized in the late 1950s that within potential target cells, the actions of glucocorticoids are modulated by 11-hydroxysteroid dehydrogenases (11HSD) (EC 1.1.1.146) which catalyse the reversible inactivation of cortisol and corticosterone to their inert 11-ketosteroid metabolites, cortisone and 11-dehydrocorticosterone, respectively (Bush et al, 1968) (Fig. 1)
As this field of reproductive biology is comparatively new, this review summarizes the current understanding of the physiological roles played by 11HSD in diverse processes including reproductive suppression, ovulation, luteinization, cystic ovarian disease, the developmental potential of oocytes, intra-uterine growth retardation (IUGR), parturition and lactation
Summary
The definitive role of glucocorticoids, synthesized in the zona fasciculata of the adrenal cortex in response to adrenocorticotrophic hormone (ACTH), is to increase plasma glucose concentrations. In attempting to resolve disputes over the preferred direction of action of 11HSD1 in Leydig cells in rats, evidence has accumulated to indicate the existence of an enzyme activity that is biochemically distinct from either of the cloned isoforms of 11HSD.
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