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

Abstract

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.

Association of Vitamin D Repletion with Normalization of Elevated Serum 17-OH-Progesterone

“…The present report adds further support to the notion that vitamin D repletion/supplementation may be a valid treatment for insulin resistance and its associated comorbidities in the context of vitamin D deficiency/ insufficiency. It reinforces several emerging concepts: (1) Insulin resistance is associated with a number of conditions, such as non-classic 21-hydroxylase deficiency [7,8]; (2) interventions likely to improve insulin sensitivity often ameliorate co-morbidities associated with insulin resistance; (3) serum vitamin D is often deficient/insufficient in insulin resistant individuals; (4) disorders associated with insulin resistance may be mitigated in association with vitamin D repletion.…”

“…Although his infection certainly improved he remained under a great deal of stress as a result of postsurgical pain and phantom pain associated with his amputation as well as the prospect of lengthy rehabilitation and considerable loss of income and mounting hospital bills during this period, thus his HPA axis likely remained very active. Beyond these considerations, as discussed in references [3,4,8]. We have reported these types of rapid responses to a number of insulin-sensitizing interventions.…”

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

“…Glucocorticoids, the foundation of CAH treatment, is often given in supraphysiological doses to normalize the adrenal androgens, which may lead to unfavorable metabolic consequences: obesity, insulin resistance with type 2 diabetes (T2DM), and hypertension. Longstanding undertreatment with elevation of adrenal androgens may also reduce insulin sensitivity (8,9) and induce hypogonadism with low testosterone values by gonadotropin suppression. Hypogonadotropic hypogonadism has been shown to be a risk factor for the metabolic syndrome and T2DM and to increase cardiovascular mortality (10).…”

“…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).…”

Pioglitazone improves insulin resistance and decreases blood pressure in adult patients with congenital adrenal hyperplasia

“…Of the few studies that have explored insulin sensitivity in CAH, most have concluded that CAH patients are indeed characterized by insulin resistance (5)(6)(7)(8)(9)(10)(11). Many different methods have been used to assess insulin sensitivity, but studies using the euglycemic hyperinsulinemic clamp method, the gold standard to assess insulin sensitivity, are lacking.…”