Androgen-Related Effects on Peripheral Glucose Metabolism in Women with Congenital Adrenal Hyperplasia

Paula, Francisco José Albuquerque de; Gouveia, L. M. F. B.; Paccola, G M G F; Piccinato, Carlos Eli; Moreira, Ayrton Custódio; Foss, Milton César

doi:10.1055/s-2007-1001755

Cited by 27 publications

(10 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A positive correlation was shown between androgens and insulin levels in the NC-CAH group. This correlation has also been demonstrated in many studies with PCOS patients [30,31,32] with or without body mass excess. Not many studies were found in the literature investigating NC-CAH patients on this aspect.…”

Section: Discussionsupporting

confidence: 70%

See 1 more Smart Citation

Hyperinsulinemia and Insulin Insensitivity in Women with Nonclassical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: The Relationship between Serum Leptin Levels and Chronic Hyperinsulinemia

2005

View full text Add to dashboard Cite

Background/Aim: Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NC-CAH) is associated with hyperandrogenemia, chronic anovulation, hirsutism, acne and adrenal hyperplasia. A few studies have shown hyperinsulinemia and insulin insensitivity in NC-CAH. Hyperinsulinemia can stimulate leptin secretion, and androgens can inhibit leptin secretion. Thus, we designed a study to investigate the insulin levels and insulin sensitivity and the effect of chronic endogenous hyperinsulinemia and androgens on leptin in patients with NC-CAH. Methods: Eighteen women with untreated NC-CAH and 26 normally cycling control women with a similar body mass index (BMI) were studied. Basal hormones, fasted and fed insulin levels, leptin and stimulated 17-hydroxyprogesterone (17-OHP) concentrations were studied. Homeostasis model assessment was used to assess insulin sensitivity. Results: The basal 17-OHP, the free testosterone (fT) and dehydroepiandrosterone sulfate (DHEA-S) were significantly different in the 2 groups (p < 0.05). Fasting and fed insulin levels of the NC-CAH group were higher than those of the control group (p < 0.05) and insulin sensitivity was lower in NC-CAH than in controls (p < 0.05). Insulin levels were correlated with fT and 17-OHP (p < 0.05). Serum leptin levels for NC-CAH (25.9 ± 12.5 µg/l) did not differ from the controls (25.4 ± 12.06 µg/l) and were positively correlated with BMI (r = 0.725) and percent body fat (r = 0.710) for both groups (both p < 0.001). Leptin levels were not correlated with estrogen or androgens, gonadotropins or insulin levels. Conclusion: Hyperinsulinemia and insulin insensitivity associated with hyperandrogenism were detected in untreated NC-CAH patients as in previous reports, whereas serum leptin levels did not differ from those of controls.

show abstract

Section: Discussionsupporting

confidence: 70%

“…Not many studies were found in the literature investigating NC-CAH patients on this aspect. A few studies [8, 9, 30] found that patients with NC-CAH had lower insulin sensitivity than controls. They concluded that this inborn error of metabolism can induce a reduction in insulin sensitivity [8].…”

Section: Discussionmentioning

confidence: 99%

Hyperinsulinemia and Insulin Insensitivity in Women with Nonclassical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: The Relationship between Serum Leptin Levels and Chronic Hyperinsulinemia

2005

View full text Add to dashboard Cite

show abstract

“…However, there are no obvious pathophysiological consequences of androgen excess, only a trend toward increased testicular mass. It seems unlikely that androgen excess contributes to abnormalities in glucose metabolism as has been noted in female CAH patients (49). First, glucose metabolism in female null mice was unaffected, and second, glucose intolerance has been noted in androgen receptor knock-out mice (50).…”

Section: Discussionmentioning

confidence: 93%

Cyp11b1 Null Mouse, a Model of Congenital Adrenal Hyperplasia

Mullins

Peter

Wrobel

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Patients with congenital adrenal hyperplasia arising from mutations of 11␤-hydroxylase, the final enzyme in the glucocorticoid biosynthetic pathway, exhibit glucocorticoid deficiency, adrenal hyperplasia driven by unsuppressed hypothalamo-pituitary-adrenal activity, and excess mineralocorticoid activity caused by the accumulation of deoxycorticosterone. A mouse model, in which exons 3-7 of Cyp11b1 (the gene encoding 11␤-hydroxylase) were replaced with cDNA encoding enhanced cyan fluorescent protein, was generated to investigate the underlying disease mechanisms. Enhanced cyan fluorescent protein was expressed appropriately in the zona fasciculata of the adrenal gland, and targeted knock-out was confirmed by urinary steroid profiles and, immunocytochemically, by the absence of 11␤-hydroxylase. The null mice exhibited glucocorticoid deficiency, mineralocorticoid excess, adrenal hyperplasia, mild hypertension, and hypokalemia. They also displayed glucose intolerance. Because rodents do not synthesize adrenal androgens, changes in reproductive function such as genital virilization of females were not anticipated. However, adult homozygote females were infertile, their ovaries showing an absence of corpora lutea and a central proliferation of disorganized steroidogenic tissue. Null females responded normally to superovulation, suggesting that raised systemic progesterone levels also contribute to infertility problems. The model reveals previously unrecognized phenotypic subtleties of congenital adrenal hyperplasia.The final steps leading to the production of glucocorticoids and mineralocorticoids are undertaken by 11␤-hydroxylase and aldosterone synthase, encoded by two closely linked genes, Cyp11b1 and Cyp11b2, respectively, that share 95% sequence homology. In rodents, the common substrate, deoxycorticosterone, is converted into the mineralocorticoid, aldosterone, in the adrenal zona glomerulosa by aldosterone synthase and into corticosterone, the main glucocorticoid, by 11␤-hydroxylase in the zona fasiculata. Cortisol rather than corticosterone is the main glucocorticoid in humans because Cyp17 is expressed in the zona fasciculata. Unlike rodents, human adrenals produce significant amounts of the androgen dehydroepiandrosterone (DHEA). 2 Patients with congenital adrenal hyperplasia (CAH) have a markedly reduced capacity to produce glucocorticoids. In ϳ90% of cases CAH is caused by deficiency of 21-hydroxylase, the penultimate enzyme in the pathways of both aldosterone and cortisol synthesis (1). In 8% of CAH cases, point mutations in or deletion of Cyp11b1 drastically reduce or completely destroy 11␤-hydroxylase activity (2-4).Adrenal hyperplasia is a consequence of increased ACTH secretion in the absence of normal negative feedback control by glucocorticoids of the hypothalamo-pituitary-adrenal axis. In 21-hydroxylase-deficient patients, ACTH drives the production of progesterone and 17-hydroxyprogesterone and channels earlier 17-hydroxylated intermediates in the glucocorticoid pathway toward the synthesis of adr...

show abstract

“…Our patients had increased insulin release during the OGTT and older patients tended to have higher HbA1c than younger ones, suggesting an increased risk of T2DM in the older CAH males. Insulin resistance has been found in adult CAH by all investigators (6,8,9,12,13,18,(20)(21)(22)(23), but one (18) and has most commonly been expressed as homeostasis model assessment (HOMA) index. We did not calculate this index because fasting glucose was low in our patients, which may lead to a falsely low estimation of insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Inadequate mineralocorticoid therapy for aldosterone deficiency may also have negative impact on the vascular system (11). Previous reports on cardiovascular and metabolic profiles in CAH adults have mainly included young females, in spite of the fact that males in general have a higher cardiovascular risk, and the results have been contradictory (6,8,9,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). A very recent publication described however a cohort of 203 individuals with CAH including 62 males reporting adverse metabolic profiles (23).…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular risk, metabolic profile, and body composition in adult males with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Falhammar¹,

Nyström²,

Wedell³

et al. 2011

European Journal of Endocrinology

101

View full text Add to dashboard Cite

Objective: Lifelong glucocorticoid therapy in patients with congenital adrenal hyperplasia (CAH) or the disease per se may result in increased cardiovascular risk. We therefore investigated cardiovascular and metabolic risk profiles in adult CAH males. Subjects and methods: We compared CAH males (nZ30), 19-67 years old, with age-and sex-matched controls (nZ32). Subgroups of different ages (!30 years or older) and CYP21A2 genotypes (null, I2splice, and I172N as the mildest mutation) were studied. Anthropometry, fat and lean mass measured by dual-energy X-ray absorptiometry, lipids, liver function tests, homocysteine, lipoprotein-(a), glucose and insulin during an oral glucose tolerance test (OGTT), urine albumin, adrenal hormones, and 24 h ambulatory blood pressure measurements were studied. Results: CAH males were shorter. Waist/hip ratio and fat mass were higher in older patients and the I172N group. Heart rate was faster in older patients, the I2splice, and I172N groups. Insulin levels were increased during OGTT in all patients and in the I172N group. g-glutamyl transpeptidase was increased in older patients and in the I172N group. Testosterone was lower in older patients. Homocysteine was lower in younger patients, which may be cardioprotective. The cardiovascular risk seemed higher with hydrocortisone/cortisone acetate than prednisolone. Urinary epinephrine was lower in all groups of patients except in I172N. Conclusions: Indications of increased risk were found in CAH males R30 years old and in the I172N group. In contrast, younger CAH males did not differ from age-matched controls. This is likely to reflect a better management in recent years.

show abstract

Androgen-Related Effects on Peripheral Glucose Metabolism in Women with Congenital Adrenal Hyperplasia

Cited by 27 publications

References 14 publications

Hyperinsulinemia and Insulin Insensitivity in Women with Nonclassical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: The Relationship between Serum Leptin Levels and Chronic Hyperinsulinemia

Hyperinsulinemia and Insulin Insensitivity in Women with Nonclassical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: The Relationship between Serum Leptin Levels and Chronic Hyperinsulinemia

Cyp11b1 Null Mouse, a Model of Congenital Adrenal Hyperplasia

Cardiovascular risk, metabolic profile, and body composition in adult males with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Contact Info

Product

Resources

About