An Improved Method for the Detection of Heterozygosity of Congenital Virilizing Adrenal Hyperplasia

Abstract

S U M M A R YA modified short ACTH test for the detection of heterozygote carriers of 2 1-hydroxylase deficiency (2 1 -0HD) was applied to twenty-one controls and fourteen parents of children with 21-OHD. The following modifications were introduced: (1) Endogenous ACTH was suppressed by dexamethasone administration prior to the test, (2) Plasma 17-hydroxyprogesterone (1 7-OHP), cortisol (F), progesterone (P), corticosterone (B) and A4androstenedione (A) were measured, (3) Variables studied were the ratio of plasma increments (A) between precursors and end products, (4) Data were analysed by a step-wise discriminant analysis. Significant alterations in the metabolic pathway of F, B and A were demonstrated. The discriminant analysis showed that the addition of B pathway data did not improve the discrimination potency of the test performed on F pathway data. The combination of variates which provided the best discrimination was the logarithmic sum of A1 70HP/AF at 15 and 30 min. It led to a 94% correct classification for normals and carriers.Deficiency of 2 1-hydroxylase (21-OHD) is the commonest form of congenital adrenal hyperplasia (CAH). This autologous genetic disorder affects one child in about 5 000 (Prader et al., 1962). The frequency ofcarriers of the autologous recessive gene in a whole population has been estimated either at 1 : 125 (Childs et al., 1956) or at 1 : 28 (Prader et al., 1962). The prediction of 21-OHD is important since the disease is often accompanied by severe sodium depletion at birth, and by growth and endocrine disorders later on. In the basal state, it is not possible to distinguish between carriers and non-carriers. Several attempts were made to reveal the eventual latent metabolic block in the biosynthesis of cortisol by adrenal stimulation, which was induced either by exogenous ACTH injection (Childs et al., 1956) or by endogenous ACTH response to metyrapone administration

Metformin, naltrexone, or the combination of prednisolone and antiandrogenic oral contraceptives as first-line therapy in hyperinsulinemic women with polycystic ovary syndrome

“…However, the small number of patients in this study precludes any firm conclusions with respect to ovulation rates. Several previous studies have also shown that ovulation rates increase during M treatment independent of weight loss (7,16,17).…”

Polycystic ovarian disease unmasked by pulsatile GnRH therapy in a subgroup of women with hypothalamic amenorrhea

“…Thyroid disorders were excluded by documentation of normal values of TSH, fT3, and fT4. An ACTH test for detection of heterozygous C 21 -hydroxylase deficiency was performed according to Lejeune-Lenain et al (8) in four of six patients. Insulin resistance was evaluated by oral glucose tolerance test (OGTT).…”

Molecular Diagnosis of CYP21 Mutations in Congenital Adrenal Hyperplasia

“…[45] In one study, only 50% of obligate heterozygotes had 17-OHP measurements after ACTH stimulation, which differed significantly from those of genotypically normal individuals. [72] Heterozygotes can be more reliably identified hormonally by examining the ratio of 17-OHP to cortisol, [73] but genotyping is the gold standard for purposes of genetic counseling, especially when the proband's mutation is known. Heterozygotes for CAH alleles do not suffer from any significant symptoms or hormone imbalance, and are consequently not candidates for hormonal replacement therapy.…”