Bone mineral density analysis in patients with congenital adrenal hyperplasia by 21-hidroxylase enzyme deficiency: correlation with cumulative dose of glucocorticoid and with polymorphisms in glucocorticoid receptor gene

Abstract

Ninety percent of the Congenital Adrenal Hyperplasia (CAH) cases present the 21-hydroxylase deficiency resulting in an impaired Cortisol secretion and, in some cases an impaired aldosterone secretion. Then, an increased production of steroid precursors occurs secondary to ACTH accumulation by missing negative feedback in the Pituitary gland. In the Adrenal, these precursors are deviated to androgens synthesis pathway, and then, patients present hyperandrogenism signs. This disease presents itself in three different clinical forms, which represent different degrees of enzymatic impairment activity. The diagnosis is made clinically and by increased 17OH-progesterone levels. The treatment is based on glucocorticoid (GC) and/or mineralocorticoid replacements, which aim to replace the daily hormonal necessities, as well as to suppress the androgens levels according to sex and age. The GC are known stimulants of bone resorption; therefore, excessive administration can be a risk to osteopenia development. CAH patients are living more and it is still controversial whether they could have a higher frequency of low bone mineral density (BMD) due to GC treatment. The CAH therapy does not mimic accurately the physiologic cortisol secretion of a health organism. Then, it becomes an important aspect the knowledge of predictive risk factors of low BMD in CAH patients. The current literature disposes conflicting data about this topic. There are researches showing significant and discreet alteration in BMD. However, those data were obtained from heterogeneous cohorts and desconsider important factors, in a way that do not reach satisfactory conclusions regarding the predisposing factors. Thus it is required a reassessment of this topic, now using a broad and adequate sample. In addition, genetic factors that define the individual sensitivity to GC treatment have not been evaluated in previous works. The NR3C1 allelic variants have been associated with high transactivation activity and will be investigated as potential contributors to low BMD in these CAH patients, for whom a standardized physiological therapeutic dose could be acting as an excessive dose. Parameters of bone metabolism and contraceptive use will be also evaluated, in order to avoid the omission of influence factors on BMD. This study aims to evaluate the BMD of CAH patients receiving a homogeneous therapeutic GC regimen, followed at a single center, from childhood to adulthood. This study will involve 68 patients (48F, 20M), with an average age of 28.4 (+ -9) years, being 34 patients with the salt wasting form and 34 with simple virilizing one. The BMD data will be achieved by bone densitometry, and NR3C1 gene will be amplified by PCR with specific primers, and the products subjected to automatic direct sequencing to scream the allelic variants. The cumulative dose of GC will then be converted into hydrocortisone equivalence and correlated with BMD data according to age and sex. BMD values will also be correlated with the NR3C1 allelic variants as well as with the various laboratorial bone metabolism parameters. We hope to identify predictive factors for low BMD, which could be useful in the clinical practice to early identification of risk patients. (AU)