To test the hypothesis that the triad of hyperandrogenism, insulin resistance and acanthosis nigricans (HAIRAN syndrome) in the presence of obesity, also known as type C insulin resistance, is caused by mutations in the gene for peroxisome proliferator activated receptor gamma (PPARgamma), a receptor for the thiazolidinedione drugs that enhance sensitivity to insulin.
Two hypermethylated CpG sites in the PPARG1 promoter and five hypomethylated CpG sites in the NCOR1 promoter were observed only in HA PCOS women (P < 0.01 to P < 0.0005).
In addition, the results support previous findings in which heterozygous CYP21 mutations are associated with symptoms of hyperandrogenism in susceptible individuals.
The heterozygous carriers of CYP21 mutations are at increased risk of developing clinically evident hyperandrogenism, even though clinical and laboratory characteristics are still underestimated.
Depending on CYP21A2 genotype, congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to biochemical alterations (including hyperandrogenism, hypocortisolism, and hypoaldosteronism) and a wide spectrum of phenotypic disease manifestation.
Four patients (three with idiopathic hirsutism, one with ovarian hyperandrogenism) and one control were carriers of CYP21 mutations typically associated with classic congenital adrenal hyperplasia but had normal basal and ACTH-stimulated 17-hydroxyprogesterone levels.
Biological hyperandrogenism was found in the prepubertal CYP21A2 mutation carriers, whereas the four heterozygous girls who were followed long enough to have reached pubertal age presented biological and clinical hyperandrogenism.
We have hypothesized that heterozygosity for CYP21 mutations in women increases their risk of developing clinically evident hyperandrogenism, and that this risk is related to the severity of the mutation of CYP21 and/or the 17-hydroxyprogesterone (17-OHP) response to ACTH stimulation.
The frequency of heterozygosity for CYP21 mutations was increased in women with symptomatic hyperandrogenism (10/30) compared to healthy controls (1/14).
In addition, we found that the other genotypes for non-obese PCOS group, AG/GG for rs12970134 and CT/TT for rs17782313, are associated with hirsutism, loss of hair, hyperandrogenism and anti-Müllerian hormone in PCOS.
After adjustment for age and BMI, variants in luteinizing hormone/choriogonadotropin receptor (LHCGR) (rs13405728), C9orf3 (rs4385527) and insulin receptor gene (INSR) (rs2059807) were strongly associated with OA (Padjust < 0.01, <0.001 and <0.05, respectively); rs4385527 in C9orf3 was strongly associated with HA (Padjust< 0.001); variants in the thyroid adenoma associated gene (THADA) (rs13429458 and rs12478601), DENN/MADD domain containing 1A (DENND1A)(rs10818854), and C9orf3 (rs4385527) were significantly associated with PCOM (Padjust < 0.01, <0.001, <0.05 and <0.001, respectively).
Mutations have recently been identified in the insulin receptor gene of patients with extreme forms of insulin resistance associated with hyperandrogenism (eg, type A insulin resistance), and these mutations account for the insulin resistance in such patients.
Mutations in the genes for the insulin receptor, 21-hydroxylase, 11 beta-hydroxylase, and 3 beta-hydroxysteroid dehydrogenase isomerase enzymes are associated with hyperandrogenism.
The main goal of the present study was to assess the influence of the androgen receptor gene CAG repeat polymorphism on hyperandrogenism and its phenotypical features in patients with polycystic ovary syndrome (PCOS).
We have used DGGE to screen for mutations in the insulin receptor gene in a family in which four of five daughters were affected by type A insulin resistance in association with acanthosis nigricans and hyperandrogenism.
Another patient with adrenal hyperandrogenism carried the V281L mutation, and her ACTH-stimulated 17-hydroxyprogesterone level was elevated only during gonadal suppression.
In conclusion, our present results suggest that the TNF-α system might contribute to the pathogenesis of HA, Ob, and IR in PCOS independent of a polymorphism of the TNF-α C850T (rs1799724) in our population.
Only the Wnt4 gene has been clearly implicated in MRKH syndrome and found to be associated with clinical and/or biological signs of hyperandrogenism in three different works.