The fact, that obesity is a prominent feature of hypercortisolism (Cushing's syndrome) has stimulated investigation on the possible existence of the reverse relationship, namely that hypercortisolism is a feature of obesity. We have reviewed half a century of literature on this question, and have found out the following: (1) Hypercortisolism can exist in two forms: systemic hypercortisolism, in which there is an overall bodily excess of cortisol, and tissue, or intracellular, hypercortisolism, in which there is increased intracellular concentration of cortisol without an overall bodily excess. (2) There are two parameters of systemic hypercortisolism: CPR and plasma cortisol concentration. Proper evaluation of the first parameter requires correction for the active metabolic mass, which is best performed by expressing CPR per gram of urinary creatinine. The second parameter can be confounded by the marked moment-to-moment fluctuations in plasma cortisol concentrations due to cortisol's episodic secretion. Proper evaluation requires measuring the 24-hour mean concentration. Of these two parameters of systemic cortisol status, the plasma concentration is the more critical and accurate. (3) Corrected CPR is normal in obese individuals, and 24-hour mean plasma cortisol concentrations are slightly but definitely subnormal. This combination of findings indicates diminished stimulability of the hypothalamic-pituitary-adrenal (HPA) axis, which normally regulates bodily cortisol status. This deduction is supported by empirical studies on HPA reactivity. (4) Tissue hypercortisolism, due to increased intracellular activity of 11beta-HSD-1, which catalyzes reduction of cortisone to cortisol, has been reported in obese mice and humans. The findings of various studies are not consistent, and whether the enzymatic overactivity is a cause or a result of obesity is still unclear.

Objective: Congenital adrenal hyperplasia (CAH) shows a range of severity which is explained in part by the different mutations of the CYP21 gene. To better understand the incomplete concordance between genotype and phenotype in CAH the role of the sensitizing N363S polymorphism of the glucocorticoid receptor (GR) was examined in CAH patients. Design: CAH patients were screened for N363S. Laboratory findings and clinical characteristics of carriers and non-carriers were analyzed retrospectively. Methods: The CYP21 gene of 200 CAH patients was analyzed by allele-specific PCR. The GR gene was tested for N363S by PCR followed by restriction fragment length polymorphism. Antropometric data (height, weight), degree of intrauterine virilization, hormone concentrations (17-OH-progesterone, dehydroepiandrosterone (DHEA), aldosterone, testosterone, plasma renin activity), substitution doses and clinical course were analyzed. Results: The carrier frequency of N363S in CAH patients was equivalent to that of the general Hungarian population (6% vs 7.8%). Interestingly, none of the non-classical CAH (NC-CAH) patients were carriers of the polymorphism. Carrier girls had milder genital virilization than mutation-matched non-carrier controls. There was no significant difference between the carriers and non-carriers in either the substitution doses, the hormonal, or the auxiological parameters. Conclusions: The association of sensitizing the GR variant with impaired cortisol production in CAH might be compensatory in mild NC-CAH and may prevent severe intrauterine virilization in classical form. Although the exact role of N363S in extrauterine life should be further investigated, the consideration of certain genetic polymorphisms of CAH patients may lead to better, individualized therapeutic regimes.European Journal of Endocrinology 154 859-864

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders, causing impaired secretion of cortisol and aldosterone from the adrenal cortex, with subsequent overproduction of adrenal androgens. The most common enzyme defect causing CAH is steroid 21-hydroxylase deficiency. To determine the mutational spectrum in the Hungarian CAH population, the CYP21 active gene was analyzed using PCR. A total of 297 Hungarian patients with 21-hydroxylase deficiency are registered in the 2nd Department of Pediatrics, Budapest, Hungary, and their clinical status was evaluated. Blood samples for CYP21 genotype determination could be obtained from 167 patients (representing 306 unrelated chromosomes and 56.2% of the total group of patients). Eight of the most common mutations were screened [In2 (intron 2 splice mutation), I172N, Del (Del: apparents large gene conversion), Q318X, R356W, 1761Tins, ClusterE6, V281L] using allele-specific amplification. The most frequent mutation in the Hungarian CAH population was found to be In2. Our results have shown a good genotype/phenotype correlation in case of most mutations; the In2 mutation is associated mostly with the severe form of the disease, whereas I172N was expressed in a wide spectrum of phenotypes. 1999)

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