cosyntropin and Oligomenorrhea

Our purpose was to establish the incidence of point mutations of the 21-hydroxylase gene (CYP21) in hyperandrogenic women with and without a 17-hydroxyprogesterone response to corticotropin stimulation above normal but below those levels associated with nonclassic adrenal hyperplasia.. We studied 22 patients with hirsutism or hyperandrogenic oligoovulation: eight with an exaggerated net increase in 17-hydroxyprogesterone (i.e., change in 17-hydroxyprogesterone between 8.8 and 36 nmol/L) and 14 with a normal change in 17-hydroxyprogesterone. Large deletions of the 21-hydroxylase gene were evaluated by laser densitometry. Point mutations were detected with the polymerase chain reaction and dot blot hybridization analysis and included 30 Leu, intron-2 (G), 8 bp deletion exon-3, 172 Asn, 236-237-239 exon-6, 281 Leu, 318 stop, 339 His, 341 Trp, 356 Trp, and 453 Ser.. Four patients with an increase in 17-hydroxyprogesterone carried a 281 Leu mutation, one patient had an intron-2 (G) mutation, and one had a complete deletion of CYP21. Only two of these patients demonstrated no obvious abnormality of CYP21. In contrast, only one of the control patients demonstrated a CYP21 abnormality, a significant difference (p < 0.001).. These findings suggest that the majority of hyperandrogenic women with an exaggerated 17-hydroxyprogesterone response to corticotropin stimulation are heterozygotes (carriers) for inherited defects of CYP21. Whether these mutations are incidental to the androgen excess or predispose to the development of this disorder remains to be determined.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Glands; Adult; Case-Control Studies; Cosyntropin; Female; Heterozygote; Hirsutism; Humans; Hydroxyprogesterones; Hyperandrogenism; Mutation; Oligomenorrhea; Peptide Fragments; Point Mutation; Steroid 21-Hydroxylase

One to 2% of hyperandrogenic women demonstrate a 17-hydroxyprogesterone (17-HP) level greater than 36.3 nmol/L (1200 ng/dL) after acute ACTH-(1-24) adrenal stimulation, consistent with 21-hydroxylase (21-OH) deficient late-onset adrenal hyperplasia (LOAH). The following study was undertaken to endocrinologically and genetically define hyperandrogenic patients with an exaggerated 17-HP response to ACTH stimulation, and which do not represent LOAH. Of 265 consecutive patients suffering from hirsutism and/or hyperandrogenic oligomenorrhea, 23 (8.7%) demonstrated a 17-HP level 30 min post stimulation greater than 9.6 nmol/L or 316 ng/dL (the upper 95th percentile in 41 eumenorrheic nonhirsute healthy control women). Seven patients or five separate families (1.8% of total) demonstrated poststimulation 17-HP levels consistent with LOAH. Of the remaining 16 patients, the net increment in 17-HP (delta 17-HP0-30) was within normal limits in seven (2.6%) and these women were assumed to have a normal 17-HP adrenocortical response superimposed on an elevated basal level of nonadrenal (e.g. ovarian) origin. In the remaining nine hyperandrogenic patients (3.4%) various abnormalities of adrenal response were noted in all but one patient, consistent with adrenal hyper-responsiveness. One patient demonstrated an 11-deoxycortisol poststimulation level greater than 3-fold the upper 95th percentile of normal, consistent with 11-hydroxylase LOAH and was excluded from further study. Six of these women were available for further genetic characterization, all Caucasian and unrelated. Three were heterozygotes for HLA-B14, three for B40, and one for B35 antigen, HLA-types associated with the inheritance of 21-OH deficiencies. Although, normally there are two 21-OH genes (a pseudogene and a functional gene) present in a 1:1 ratio, we have previously reported a high frequency of 21-OH gene ratio abnormalities in LOAH. All but one of our patients demonstrated an abnormal 21-OH gene ratio. In conclusion, 3.4% of our hyperandrogenic population demonstrated an exaggerated 17-HP increment after ACTH stimulation, not consistent with LOAH or increased extraadrenal 17-HP production. The increased prevalence of HLA alleles known to be linked to inherited defects of 21-OH function and the increased frequency in 21-OH gene ratio abnormalities suggest that a majority of these individuals may be carriers for these genetic disorders. However, the adrenocortical abnormalities noted were more consi

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Cortex Hormones; Adrenal Glands; Adult; Androgens; Cosyntropin; Female; Genes; Hirsutism; Humans; Hydroxyprogesterones; Hyperplasia; Oligomenorrhea; Steroid 21-Hydroxylase

The occurrence of uterine bleeding following administration of Metyrapone in cases of secondary amenorrhoea and oligomenorrhoea led the authors to measure pituitary, gonadal and adrenal hormone levels, before and after the oral administration of this drug in sixteen patients, in an attempt to provide an interpretation of this phenomenon. There were expected changes in plasma ACTH and urinary 17-hydroxycorticosteroids, but no variations were noted in serum FSH and LH, plasma oestradiol and urinary oestrogens; the most important alterations occurred in plasma progesterone and urinary pregnanetriol levels. It is suggested that bleeding occurs because of the changes which are induced in plasma progesterone levels.

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Adult; Amenorrhea; Cosyntropin; Estradiol; Estrogens; Female; Follicle Stimulating Hormone; Humans; Luteinizing Hormone; Menstruation; Metyrapone; Oligomenorrhea; Pituitary Function Tests; Pregnanediol; Pregnanetriol; Progesterone