Contribution of allelic variability in prostate specific antigen (PSA) & androgen receptor (AR) genes to serum PSA levels in men with prostate cancer.

Background & objectives: Wide variability in serum prostate specific antigen (PSA) levels exists in malignant conditions of the prostate. PSA is expressed in normal range in 20 to 25 per cent of prostate cancer cases even in presence of high grade Gleason score. This study was aimed to assess the influence of genetic variants exhibited by PSA and androgen receptor (AR) genes towards the variable expression of PSA in prostate cancer. Methods: Pre-treatment serum PSA levels from 101 prostate cancer cases were retrieved from medical record. PSA genotype analysis in promoter region and AR gene microsatellite Cytosine/Adenine/Guanine (CAG) repeat analysis in exon 1 region was performed using DNA sequencing and fragment analysis techniques. Results: A total of seven single nucleotide polymorphisms (SNPs) in the PSA promoter region were noted. Only two SNPs viz., 158G/A (P<0.001) in the proximal promoter region and -3845G/A (P<0.001) in enhancer region showed significant association with serum PSA levels. The carriers of homozygous GG genotype (P<0.001) at both of these polymorphic sites showed higher expression of PSA whereas homozygous AA genotype (P<0.001) carriers demonstrated lower PSA levels. The combination effect of PSA genotypes along with stratified AR CAG repeats lengths (long, intermediate and short) was also studied. The homozygous GG genotype along with AR long CAG repeats and homozygous AA genotype along with AR short CAG repeats at position -3845 and -158 showed strong interaction and thus influenced serum PSA levels. Interpretation & conclusions: The genetic variants exhibited by PSA gene at positions -3845G/A and -158G/A may be accountable towards wide variability of serum PSA levels in prostate cancer. Also the preferential binding of G and A alleles at these polymorphic sites along with AR long and short CAG repeats may contribute towards PSA expression.

Molecular & genetic factors contributing to insulin resistance in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of unknown etiology. Insulin resistance is very common and plays a central pathogenic role in PCOS. During last decade several studies have been conducted to understand the mechanisms contributing to the state of insulin resistance and insulin-induced hyperandrogenemia in PCOS. Insulin signaling pathways have been dissected in different insulin responsive tissues such as skeletal muscles, adipose tissues, fibroblasts as well as ovaries to elucidate the mechanism. These studies suggest a post receptor signaling defect where metabolic action of insulin is affected but not the steroidogenic and mitogenic actions. Despite advancement in these studies gaps exist in our understanding of the mechanism of insulin resistance as well as insulin-induced steroidogenesis in PCOS. The syndrome is now considered as a complex multigenic disorder. Efforts are ongoing to dissect the variants of genes from multiple logical pathways which are involved in pathophysiology of the syndrome. But still today no gene has been emerged as universally accepted susceptibility gene for PCOS. This review briefly describes the lacunae along with the current status of molecular events underlying insulin resistance and the contribution of insulin signaling pathway genes in pathogenesis of PCOS along with future researchable areas.

Congenital adrenal hyperplasia: biochemical and molecular perspectives.

Congenital adrenal hyperplasia is a disorder occurring in both sexes and is the commonest cause of ambiguous genitalia. It is a group of autosomal recessive disorders in which, on the basis of an enzyme defect the bulk of steroid hormone production by adrenal cortex shifts from corticosteroids to androgens. Autosomal recessive mutations in the CYP21, CYP17, CYP11B1 and 3betaHSD genes that encode steroidogenic enzymes, in addition to mutations in the gene encoding the intracellular cholesterol transport protein steroidogenic acute regulatory protein StAR can cause CAH. Each of the defects causes different biochemical consequences and clinical features. Deficiencies in 21 hydroxylase (21-OH) and 11beta-Hydroxylase (11beta-OH) are the two most frequent causes of CAH. All the biochemical defects impair cortisol secretion, resulting into compensatory hypersecretion of ACTH and consequent hyperplasia of the adrenal cortex. Research in recent years has clarified clinical, biochemical and genetic problems in diagnosis and treatment of the disorders. Expanding knowledge of the gene mutations associated with each of these disorders is providing valuable diagnostic tools in addition to the biochemical profile and phenotype. Genotyping is useful in selecting instances to provide genetic counseling and to clarify ambiguous cases.