Basal Serum 17-hydroxyprogesterone Research Articles

The prevalence of non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Russian women with hyperandrogenism

The aim of the study was to determine the prevalence of non-classic congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase (21-OH) deficiency among hyperandrogenic women in a Russian population and to evaluate diagnostic value of basal serum 17-hydroxyprogesterone (17-OHP) level to diagnose this disease. A total of 800 consecutive Caucasian women presenting with elevation of at least one serum androgen and/or manifestation of one of the clinical androgenic symptoms were prospectively recruited and evaluated by basal 17-OHP. The diagnosis of NCAH due to 21-OH deficiency was considered in patients when basal level exceeded 5.0 nmol/L and CYP21A2 gene mutation analysis was performed in this case. Eight (1.0%) of the patients had NCAH due to 21-OH deficiency confirmed by genotyping. These women had a V281L mutation: five homozygous and three compound heterozygous with genotypes V281L/P453S, V281L/I2splice and V281L/I2splice. One patient was diagnosed with NCAH (genotype V281L/I2splice) before the study and was excluded from the analysis. Thus, the unbiased prevalence of NCAH was 0.9%. The 17-OHP basal level ranges from 16.8 to 17.7 nmol/L predicted NCAH with 100% sensitivity and 100% specificity.

Non-functioning adrenal incidentalomas caused by 21-hydroxylase deficiency or carrier status?

Adrenal incidentalomas (AI) are an escalating clinical issue due to the increasing use of imaging techniques. Occasional patients with AIs have been reported who have subsequently been diagnosed with congenital adrenal hyperplasia (CAH) due to CYP21A2 mutations (21-hydroxylase deficiency) or carrier status. The objective of this investigation was to describe a larger cohort of patients with AI suspected to be caused by 21-hydroxylase deficiency or carrier status. All patients with AI and suspected CYP21A2 mutations during the last decade at a single center in Stockholm, Sweden, were included. Nine patients were identified (54 ± 19-year-old at presentation). Two-thirds were females and two-thirds were from Sweden, while one-third was from the Middle East. Almost all (8/9) had children, but two had experienced fertility problems. Four of six women had symptoms of hyperandrogenism, and three had previously been diagnosed with polycystic ovary syndrome. The majority (7/9) had multiple AIs. In two cases, the initial suspicion had been adrenal cortical cancer, but increased urinary pregnanetriol had lead to the diagnosis of CAH. Basal serum 17-hydroxyprogesterone was 10 (1.75-338) nmol/L. Seven was diagnosed with CAH (six non-classic, one simple virilizing). Two patients were considered to be carriers. However, in four patients, no CYP21A2 mutation was found and thus no confirmation of the diagnosis could be achieved. Patient presented with multiple AIs with hyperandrogenism or a Middle East origin screening for CAH or carrier status may be indicated.

Adrenal Androgen Production Capacity Remains High up to Menopause in Women with Polycystic Ovary Syndrome

Hyperandrogenism is one of the main features of polycystic ovary syndrome (PCOS). Of circulating androgens, 50% of androstenedione and testosterone are of ovarian and adrenal origin, whereas dehydroepiandrosterone (DHEA) and DHEA sulfate are almost uniquely of adrenal origin. Our previous studies have indicated that ovarian androgen production capacity is enhanced in women with PCOS, and it remains high until late reproductive age. To study whether this also applies to adrenal androgen production, ACTH tests were performed in healthy women and in women with PCOS. Sixty-nine healthy women (aged 19-62 yr; body mass index 19.2-35.0 kg/m2) and 58 women with previously diagnosed PCOS (aged 18-59 yr; body mass index 19.0-42.9 kg/m2) participated in the study. The subjects underwent ACTH stimulation tests, and serum cortisol, 17-hydroxyprogesterone, androstenedione, testosterone, DHEA, and DHEA sulfate levels were analyzed at 0, 30, and 60 min. Basal and ACTH-stimulated levels of most adrenal androgens decreased in healthy women with age, whereas in women with PCOS, only the concentrations of basal serum 17-hydroxyprogesterone decreased, and all areas under the curve (AUCs) remained unchanged and significantly higher (except for DHEA) than those in control women. Likewise, at the menopausal transition, pre- and postmenopausal women with PCOS exhibited mainly unchanged and higher basal androgen and AUC levels. Similarly to ovarian endocrine function, serum adrenal steroid levels and adrenal steroid production capacity remain enhanced at least up to menopause in women with PCOS.

Adrenal Androgen Production Capacity Remains High up to Menopause in Women with Polycystic Ovary Syndrome

Hyperandrogenism is one of the main features of polycystic ovary syndrome (PCOS). Of circulating androgens, 50% of androstenedione and testosterone are of ovarian and adrenal origin, whereas dehydroepiandrosterone (DHEA) and DHEA sulfate are almost uniquely of adrenal origin. Our previous studies have indicated that ovarian androgen production capacity is enhanced in women with PCOS, and it remains high until late reproductive age. To study whether this also applies to adrenal androgen production, ACTH tests were performed in healthy women and in women with PCOS. Sixty-nine healthy women (aged 19–62 yr; body mass index 19.2–35.0 kg/m2) and 58 women with previously diagnosed PCOS (aged 18–59 yr; body mass index 19.0–42.9 kg/m2) participated in the study. The subjects underwent ACTH stimulation tests, and serum cortisol, 17-hydroxyprogesterone, androstenedione, testosterone, DHEA, and DHEA sulfate levels were analyzed at 0, 30, and 60 min. Basal and ACTH-stimulated levels of most adrenal androgens decreased in healthy women with age, whereas in women with PCOS, only the concentrations of basal serum 17-hydroxyprogesterone decreased, and all areas under the curve (AUCs) remained unchanged and significantly higher (except for DHEA) than those in control women. Likewise, at the menopausal transition, pre- and postmenopausal women with PCOS exhibited mainly unchanged and higher basal androgen and AUC levels. Similarly to ovarian endocrine function, serum adrenal steroid levels and adrenal steroid production capacity remain enhanced at least up to menopause in women with PCOS.

A Prospective Study of the Prevalence of Nonclassical Congenital Adrenal Hyperplasia among Women Presenting with Hyperandrogenic Symptoms and Signs

The diagnosis of the polycystic ovary syndrome requires the exclusion of nonclassical congenital adrenal hyperplasia (NCAH). Our objective was to evaluate the actual prevalences of 21-hydroxylase and 11beta-hydroxylase deficiencies among women presenting with hyperandrogenic complaints. This study was performed at an academic hospital. A total of 270 consecutive unselected women presenting with hyperandrogenic symptoms were prospectively recruited. Basal and ACTH-stimulated 11-deoxycortisol and 17-hydroxyprogesterone concentrations were measured. The prevalences of 21-hydroxylase and 11beta-hydroxylase deficiencies were calculated, and the diagnostic performance of basal serum 17-hydroxyprogesterone levels for the screening of NCAH was evaluated by receiver operating characteristic curve analysis. Six of the 270 patients had 21-hydroxylase-deficient NCAH that was confirmed by CYP21 genotyping, whereas no patient was diagnosed with 11beta-hydroxylase deficiency, for an overall NCAH prevalence of 2.2% (95% confidence limits 0.5-3.9%). According to receiver operating characteristic analysis, a single basal serum 17-hydroxyprogesterone determination has a 0.97 (95% confidence interval: 0.934-1.008) chance of detecting NCAH in hyperandrogenic women. In our experience, the most appropriate cutoff value for the detection of NCAH is a 17-hydroxyprogesterone above 1.7 ng/ml, showing a 100% sensitivity and a 88.6% specificity. Five of the six 21-hydroxylase-deficient NCAH patients carried a severe CYP21 allele requiring genetic counseling and highlighting the importance of excluding this disorder among hyperandrogenic patients. The prevalence of NCAH among hyperandrogenic patients from Spain is 2.2%. Basal serum 17-hydroxyprogesterone measurements have an excellent diagnostic performance, yet the cutoff value should be established in each laboratory to avoid false-negative results.

Genotype-phenotype analysis in late onset 21-hydroxylase deficiency in comparison to the classical forms.

To establish the type and frequency of mutations causing late onset 21-hydroxylase deficiency and associated clinical and biochemical phenotypes and to compare these findings to those from heterozygotes and homozygotes for classical 21-hydroxylase deficiency. Analysis of the 21-hydroxylase genes by DNA amplification and mutation detection. Measurement of serum 17-hydroxyprogesterone following stimulation with adrenocorticotrophic hormone. Fifteen patients with late onset congenital adrenal hyperplasia, 18 obligate heterozygotes for classical congenital adrenal hyperplasia, 95 patients with classical 21-hydroxylase deficiency. 17-hydroxyprogesterone following adrenal stimulation with adrenocorticotrophic hormone; frequency of 10 common mutations in the 21-hydroxylase gene. Of alleles from patients with late onset CAH 46% carried V281L and 10% P30L mutations compared to 2.6% and 1.1% respectively of alleles from patients with the classical disease where the most common mutations are a splice site mutation in intron 2 (34%), deletions (25%) and I172N (15%). Serum 17-hydroxyprogesterone following Synacthen stimulation reliably differentiated the late onset patients from carriers for the classical disease, whereas there was overlap of the basal 17-hydroxyprogesterone concentration between these two conditions. Normal basal serum 17-hydroxyprogesterone levels cannot exclude late onset CAH, although response to adrenocorticotrophic stimulation clearly distinguished this disorder from carriers of the classical disease. The frequency of mutations causing less severe enzyme deficiency was higher in the late onset patients than in a group of classical patients, although other genes or environmental pressures may determine the age of onset of disease.

The Incidence of 21α-Hydroxylase Deficiency in Greek Hyperandrogenic Women: Screening and Diagnosis

The purpose of this prospective study was to determine the incidence of any form of 21α.-hydroxylase deficiency among Greek women with hyperandrogenic symptoms, and to test the predictive value of basal serum 17-hydroxyprogesterone (17-OHP) in the early follicular phase as a screening index for patient preselection to adrenocorticotropic hormone (ACTH) testing. Eighty-eight unselected women with hyperandrogenic symptoms were examined in the Gynecological Endocrinology Unit of the Second Department of Obstetrics and Gynecology of Athens University. Using the ACTH-stimulated 17-OHP values at 60 minutes (17-OHP60) the study population was divided into four groups (A, B, C and D). Clinical and basal hormonal parameters as well as serum 17-OHP60 values and human leukocyte antigens were studied. Both clinical and basal hormonal parameters could be used to distinguish only patients with severe 21α-hydroxylase deficiency (group A). In contrast, patients with moderate non-classical congenital adrenal hyperplasia (NC-CAH; group B), heterozygotes for NC-CAH (group C), and unaffected females (group D) can be diagnosed and classified only by serum 17- OHP60 values.In conclusion, the incidence of NC-CAH in Greek females with hyperandrogenic symptoms is 3.4%. The positive predictive value of basal 17-OHP is only 13% for this disease. Only 17-OHP60 helps to diagnose and classify moderate and mild forms of NC-CAH. Thus, it seems that ACTH testing is imperative in every subject suspected of this enzymatic disorder.

Insulin insensitivity in adrenal hyperplasia due to nonclassical steroid 21-hydroxylase deficiency.

To determine whether hyperandrogenism caused by an inborn error of adrenal steroidogenesis could produce insulin resistance, we examined insulin sensitivity in females with 21-hydroxylase deficiency. Minimal modelling was used to analyze the results of tolbutamide-modified, frequently sampled, iv glucose tolerance testing. Insulin sensitivity [Si; (min-1) (microU/mL)-1] was plotted against body mass index (BMI; defined as kilograms per m2). Six patients with nonclassical 21-hydroxylase deficiency (mean age, 27 yr; mean BMI, 23.2) underwent testing. None of these patients was in active puberty, nor was any patient being treated with glucocorticoids at the time of the study. Twelve eumenorrheic nonhyperandrogenic young adult female control subjects (mean age, 27 yr; mean BMI, 22.4) were also tested. The basal 17-hydroxyprogesterone concentration, but not the total serum testosterone level, was significantly different in the two groups (mean +/- SEM, 11,987 +/- 2,761 vs. 4,059 +/- 802 pmol/L; P < 0.05). As a group the patients' Si values were significantly lower than those of the controls (mean +/- SEM, 4.1 +/- 0.6 vs. 9.7 +/- 1.2; P < 0.05). There was no correlation between Si and basal serum 17-hydroxyprogesterone, testosterone, delta 4-androstenedione, or dehydroepiandrosterone. We conclude that chronic hypersecretion of androgen precursors due to an inborn error of metabolism can induce a reduction in insulin sensitivity.

Combined 17-Hydroxylase and 17,20-Desmolase Deficiencies: Evidence for Synthesis of a Defective Cytochrome P450c17*

We studied in vivo and in vitro steroidogenesis in six phenotypic female children with 17-hydroxylase deficiency. The diagnosis was suspected as a likely cause of familial low renin hypertension and was confirmed by findings of reduced basal and ACTH-stimulated serum and urinary levels of cortisol and other 17-hydroxysteroids, together with hypergonadotropic hypogonadism in both 46,XY and 46,XX patients, and abnormally increased secretion of 17-desoxysteroids, such as progesterone, 11-deoxycorticosterone, and corticosterone. ACTH stimulation testing demonstrated a lesser degree of 17-hydroxylase deficiency in the obligate heterozygous parents; one father had increased basal serum 17-hydroxyprogesterone values, unresponsive to ACTH, suggesting partial Leydig cell 17,20-desmolase deficiency. In vitro kinetic analysis of testicular microsomal enzymes in the affected 46,XY male pseudohermaphrodites confirmed that both 17-hydroxylase and 17,20-desmolase activities were less than 2% of those in age-matched normal subjects. However, in spite of this virtual absence of both enzymatic activities of cytochrome P450c17, Northern blot analysis demonstrated abundant amounts of RNA in these tests that hybridized to a cDNA specific for this P450 enzyme. Moreover, immunoblot analysis of sodium dodecyl sulfate-polyacrylamide gel electrophoresis-resolved testicular microsomes showed an apparently normal content of an immunoreactive protein with a mol wt similar to that of authentic P450c17. These results suggest that these patients have a point mutation in the gene for P450c17; the mutant gene is transcribed, but gives rise to a protein defective in normal 17-hydroxylase and 17,20-desmolase activities.

Adrenal Steroid Secretion in Girls with Pseudoprecocious Puberty due to Autonomous Ovarian Cysts

CHASALOW, FRED I.; GRANOFF, ALICE B.; TSE, THOMAS F.; BLETHEN, SANDRA L. Author Information