cosyntropin and Adrenal-Hyperplasia--Congenital

Standard dose synacthen stimulation test (SDSST) is a gold standard screening test for evaluating adrenal gland function. Despite studies using SDSST to identify heterozygosity in. PubMed and MEDLINE databases were searched. A total of 1215 subjects (heterozygous carriers n=669, mutation-free controls n=546) were included in the meta-analyses.. Basal 17-OHP median/mean levels were 4.156 (3.05-10.5)/5.241 (±2.59) nmol/L and 3.90 (2.20-9.74)/4.67 (±2.62) nmol/L in symptomatic heterozygous carriers and symptomatic mutation-free controls, respectively. Stimulated 17-OHP median/mean levels were 17.29 (14.22-37.2)/19.51 (±7.63) nmol/L and 9.27 (7.32-15.9)/10.77 (±3.48) nmol/L in symptomatic heterozygous carriers and symptomatic mutation-free controls, respectively. Basal 17-OHP median/mean levels were 3.21 (2.64-4.78)/3.33 (±0.84) nmol/L and 3.12 (1.82-3.6)/2.83 (±0.71) nmol/L in asymptomatic heterozygous carriers and asymptomatic mutation-free healthy controls, respectively. Stimulated 17-OHP median/mean levels were 14.16 (12.73-16.37)/14.16 (±1.37) nmol/L and 6.26 (4.9-8.23)/6.48 (±1.2) nmol/L in asymptomatic heterozygous carriers and asymptomatic mutation-free healthy controls, respectively. The cut-off levels for stimulated 17-OHP were 10.48 nmol/L and 13.48 nmol/L for asymptomatic heterozygous and symptomatic heterozygous, respectively.. The meta-analyses support the idea that stimulated 17-OHP level has potential for use in identifying

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Cosyntropin; Heterozygote; Humans; Reproducibility of Results; Steroid 21-Hydroxylase

Moderate forms of 21-hydroxylase deficiency (D21OH-NC), the so-called non-classical or late-onset forms are a frequently reported cause of hyperandrogenism in women [1-5]. The purpose of this collective and synthetic work was to provide the endocrinologist, gynecologist and dermatologist with consensual information so as to detect the maximum cases with acceptable cost-benefit ratio and to define the main lines of optimal patient management, given the data currently available in medical literature.

Topics: Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Cosyntropin; Female; Genetic Counseling; Glucocorticoids; Hirsutism; Hormone Replacement Therapy; Humans; Hyperandrogenism; Infertility, Female; Steroid 21-Hydroxylase

The 46,XX disorders of sex development (DSDs) cause virilisation or masculinisation of the female foetus. The final common pathway of all 46,XX DSDs is excess dihydrotestosterone (DHT) or potent foreign androgen in the genital tissue during the critical period of sexual differentiation. Whereas the foetal testis is source of androgen in the male, it is the foetal adrenal that produces the DHT precursors in the female. By understanding the principles of human steroid biosynthesis, the pathogenesis of each disorder may be logically deduced, and treatment strategies are rationally constructed. In practice, however, therapies for many of these diseases are fraught with complications and caveats, and current approaches leave much room for improvement. This review discusses these diseases, their pathogenesis and approaches to therapy. We emphasise areas where improved treatments are sorely needed.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenal Glands; Adrenal Hyperplasia, Congenital; Adult; Antley-Bixler Syndrome Phenotype; Child; Cosyntropin; Dehydroepiandrosterone; Dihydrotestosterone; Disorders of Sex Development; Female; Gonadal Dysgenesis, 46,XX; Humans; Infant, Newborn; Sex Differentiation; Steroid 11-beta-Hydroxylase; Steroid 21-Hydroxylase; Steroids; Virilism

Recent work has taught us that our conventional approach to corticosteroid replacement therapy requires review. Specifically, the doses of hydrocortisone we have used are probably too high for the majority, and should ideally be administered in three or more doses through the day. Nevertheless, there is not much hard evidence that excessive glucocorticoid replacement per se will lead to adverse effects such as osteoporosis, even though it may exacerbate any tendency in those who are predisposed to it for other reasons. As such, there is no compelling need for using determinations of either UFC excretion or of the serum cortisol profile in the routine management of patients on replacement therapy. Nevertheless, such measures may be considered in those thought to be at particular risk of osteoporosis, and in whom it is felt that special effort should be made to ensure that they are receiving the minimum dose possible. In such circumstances, a cortisol day curve is likely to be of more value than measurement of UFC.

Topics: 17-alpha-Hydroxyprogesterone; Addison Disease; Adrenal Cortex Hormones; Adrenal Gland Diseases; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Adult; Corticotropin-Releasing Hormone; Cosyntropin; Cushing Syndrome; Glucocorticoids; Humans; Hydrocortisone; Hypoglycemia; Osteoporosis; Risk

Nonclassic congenital adrenal hyperplasia (NCCAH) requires exclusion before diagnosing polycystic ovary syndrome (PCOS). Increasing use of liquid chromatography and tandem mass spectrometry (LC-MS/MS) necessitates revision of immunoassay-based criteria for NCCAH. Measurement of 21-deoxycortisol (21DF) may simplify the diagnosis of heterozygosity (HTZ), the presence of 1 affected CYP21A2 allele, which currently relies on complex molecular studies.. We aimed to determine LC-MS/MS-specific criteria for NCCAH and HTZ and compare the diagnostic accuracy of 21DF and 17-hydroxyprogesterone (17OHP).. A cross-sectional study involving 99 hyperandrogenic females was performed. We identified females who had undergone both a synacthen stimulation test (SST) and CYP21A2 genotyping from 2010 to 2017, and prospectively recruited females referred for an SST to investigate hyperandrogenic symptoms from 2017 to 2021. Steroids were compared between genetically confirmed NCCAH, HTZ, and PCOS. Optimal 17OHP and 21DF thresholds for HTZ and NCCAH were determined by receiver operating characteristic analysis.. Basal 17OHP, stimulated 17OHP, and 21DF were measured in 99, 85, and 42 participants, respectively. Optimal thresholds for NCCAH were 3.0 nmol/L and 20.7 nmol/L for basal and stimulated 17OHP, respectively. Basal and stimulated 21DF thresholds of 0.31 nmol/L and 13.3 nmol/L provided 100% sensitivity with specificities of 96.8% and 100% for NCCAH, respectively. Diagnostic thresholds for HTZ of 8.0 nmol/L, 1.0 nmol/L, and 13.6 for stimulated 17OHP, 21DF, and the ratio (21DF + 17OHP)/cortisol each provided 100% sensitivity with specificities of 80.4%, 90.5%, and 85.0%, respectively.. LC-MS/MS-specific 17OHP thresholds for NCCAH are lower than those based on immunoassay. LC-MS/MS-quantified 17OHP and 21DF accurately discriminate HTZ and NCCAH from PCOS.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Androgens; Chromatography, Liquid; Cortodoxone; Cosyntropin; Cross-Sectional Studies; Female; Humans; Steroid 21-Hydroxylase; Tandem Mass Spectrometry

To define liquid chromatography tandem mass spectrometry (LC-MS/MS)-based cutoff levels and panels of steroid hormones, to improve diagnosis of nonclassic congenital adrenal hyperplasia (NCCAH) and other partial enzyme defects in the adrenals.. Prospective cohort analysis.. University hospital-based tertiary endocrine center.. One hundred and twenty-one healthy adults and 65 patients evaluated for possible NCCAH (validation cohort).. The LC-MS/MS-determined cutoffs for 11 steroids (basal and cosyntropin-stimulated) were defined by 2.5% and 97.5% percentile in healthy subjects. Validation cohort was used for comparison.. Percentage of patients diagnosed with NCCAH among patients with polycystic ovary syndrome (PCOS)-like symptomatology. Evaluation of the defined LC-MS/MS-based cutoff levels for steroid hormones among this patient group.. Of the 65 PCOS-like patients evaluated for possible NCCAH, 8 (12.5%) were discovered and genetically verified, and 2 had classic congenital adrenal hyperplasia. Cosyntropin-stimulated 17-hydroxyprogesterone (17OHP) showed the best diagnostic accuracy for NCCAH with an area under the curve of 0.95 (0.89-1.0 with a sensitivity of 86% and a specificity of 88%. In homozygote patients, 21-deoxycortisol and 17OHP levels were elevated, in heterozygote patients only 17OHP (basal or stimulated) was raised. Four healthy patients in the validation cohort had 17OHP above the basal cutoff.. The NCCAH syndrome is frequent in patients with suspected PCOS, and should be considered as a routine screening when assessing infertility. We suggest the use of serum steroid profiling, including 21-deoxycortisol, together with the cosyntropin stimulation test with 17OHP. Our data support a 17OHP cutoff of 8.5 nmol/L (2.8 ng/mL) 60 minutes after cosyntropin stimulation, when measured with LC-MS/MS, significantly lower than current European guidelines.. NCT0218660.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Adult; Chromatography, Liquid; Cosyntropin; Female; Hormones; Humans; Polycystic Ovary Syndrome; Prospective Studies; Steroids; Tandem Mass Spectrometry

The 250µg-cosyntropin stimulation test (CST) is used to diagnose non-classic congenital adrenal hyperplasia (NCCAH). The current recommendation is to perform CST when follicular 17-hydroxyprogesterone (17OHP) is 6-30 nmol/L, a cutoff derived from radioimmunoassay (RIA). Recently, enzyme-linked immunosorbent assay (ELISA) has replaced RIA.. We aimed to (1) determine the RIA and ELISA-based 17OHP cutoffs at which CST should be performed, (2) identify predictors of NCCAH.. A retrospective study at an Israeli Health Maintenance Organization. Data were retrieved from women with suspected NCCAH, referred for CST during 2001-2020. NCCAH was defined as a stimulated 17OHP >30 nmol/L. Serum 17OHP levels were assayed by RIA from 1/2000-3/2015, and by ELISA from 4/2015-12/2020. ROC curves were generated and optimal 17OHP thresholds were determined. Multivariate analysis was performed.. CST was performed in 2409 women (1564 in RIA, 845 in ELISA). NCCAH was diagnosed in 4.7% of the RIA group and 7.5% of the ELISA group. The optimal basal 17OHP cutoff values predicting NCCAH were 6.1 nmol/L in RIA (sensitivity=93.2%, specificity=91.7%) and 8.2 nmol/L in ELISA (sensitivity=93.7%, specificity=92.3%). In multivariate analysis, higher basal 17OHP, lower LH: FSH ratio, and oligomenorrhea were predictors of NCCAH in RIA. Higher basal 17OHP, androstenedione, and total testosterone were predictors of NCCAH in ELISA. A lower LH: FSH ratio showed similar trend in ELISA.. Optimal RIA-based basal 17OHP cutoff was comparable with that recommended in guidelines. The results suggest adopting a higher 17OHP cutoff when using ELISA. LH : FSH ratio improves the negative predictive value of basal 17OHP.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Cosyntropin; Female; Follicle Stimulating Hormone; Humans; Immunoassay; Retrospective Studies

The clinical presentation of patients with nonclassic 21-hydroxylase deficiency (N21OHD) is similar with that for other disorders of androgen excess. The diagnosis of N21OHD typically requires cosyntropin stimulation. Additionally, the management of such patients is limited by the lack of reliable biomarkers of androgen excess. Herein, we aimed to: (1.) compare the relative contribution of traditional and 11-oxyandrogens in N21OHD patients and (2.) identify steroids that accurately diagnose N21OHD with a single baseline blood draw.. We prospectively enrolled patients who underwent a cosyntropin stimulation test for suspected N21OHD in two tertiary referral centers between January 2016 and August 2019.. Baseline sera were used to quantify 15 steroids by liquid chromatography-tandem mass spectrometry. Logistic regression modeling was implemented to select steroids that best discriminate N21OHD from controls.. Of 86 participants (72 females), median age 26, 32 patients (25 females) had N21OHD. Age, sex distribution, and BMI were similar between patients with N21OHD and controls. Both testosterone and androstenedione were similar in patients with N21OHD and controls, while four 11-oxyandrogens were significantly higher in patients with N21OHD (ratios between medians: 1.7 to 2.2, P < 0.01 for all). 17α-Hydroxyprogesterone (6.5-fold), 16α-hydroxyprogesterone (4.1-fold), and 21-deoxycortisol (undetectable in 80% of the controls) were higher, while corticosterone was 3.6-fold lower in patients with N21OHD than in controls (P < 0.001). Together, baseline 17α-hydroxyprogesterone, 21-deoxycortisol, and corticosterone showed perfect discrimination between N21OHD and controls.. Adrenal 11-oxyandrogens are disproportionately elevated compared to conventional androgens in N21OHD. Steroid panels can accurately diagnose N21OHD in unstimulated blood tests.

Topics: Adolescent; Adrenal Hyperplasia, Congenital; Adult; Aged; Androgens; Biomarkers; Child; Cosyntropin; Female; Hormones; Humans; Male; Middle Aged; Prospective Studies; Young Adult

The cosyntropin test is used to diagnose adrenal insufficiency (AI) and nonclassical congenital adrenal hyperplasia (NCCAH). Current cutoffs for cortisol and 17-hydroxyprogesterone (17-OHP) are derived from nonstandardized immunoassays. Liquid chromatography tandem mass spectrometry (LC-MS/MS) offers direct measurement of steroids, prompting the need to re-establish normal ranges.. The goal of this study was to define cutoff values for cortisol and 17-OHP in serum by LC-MS/MS 30 and 60 minutes after intravenous administration of 250 µg tetracosactide acetate to healthy volunteers and to compare the results with LC-MS/MS with routine immunoassays.. Cosyntropin testing was performed in healthy subjects (n = 138) and in patients referred for evaluation of adrenocortical function (n = 94). Steroids were assayed by LC-MS/MS and compared with two immunoassays used in routine diagnostics (Immulite and Roche platforms). The cutoff level for cortisol was defined as the 2.5% percentile in healthy subjects not using oral estrogens (n = 121) and for 17-OHP as the 97.5% percentile.. Cortisol cutoff levels for LC-MS/MS were 412 and 485 nmol/L at 30 and 60 minutes, respectively. Applying the new cutoffs, 13 of 60 (22%) subjects who had AI according to conventional criteria now had a normal test result. For 17-OHP, the cutoff levels were 8.9 and 9.0 nmol/L at 30 and 60 minutes, respectively.. LC-MS/MS provides cutoff levels for cortisol and 17-OHP after cosyntropin stimulation that are lower than those based on immunoassays, possibly because cross-reactivity between steroid intermediates and cortisol is eliminated. This reduces the number of false-positive tests for AI and false-negative tests for NCCAH.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Adult; Aged; Aged, 80 and over; Chromatography, Liquid; Cosyntropin; Female; Humans; Hydrocortisone; Male; Middle Aged; Reference Values; Tandem Mass Spectrometry; Young Adult

To describe cortisol response to tetracosactide and to review the literature on adrenal function in non-classic congenital adrenal hyperplasia (NCCAH) patients.. We compared cortisol responses to tetracosactide (250 μg) between NCCAH patients and a comparison group (CG) of patients with premature pubarche and normal tetracosactide test. An adequate cortisol response was defined as a peak ≥18 μg/dl.. We included 35 NCCAH patients (26 girls, 9 boys), whose mean age at testing was 7.0 years (0.8-15.6), and 47 patients in the CG (39 girls, 8 boys), whose mean age was 7.2 years (0.5-9.9). Baseline cortisol was significantly higher in the NCCAH group than in the CG [12.9 (4.3-22.2) vs. 9.7 (4.2-16.2) μg/dl, respectively; p = 0.0006]. NCCAH patients had lower cortisol peak response compared to the CG [18.2 (6.3-40) vs. 24.9 (12-30.3) μg/dl, respectively; p < 0.0001]. Peak cortisol was <18 μg/dl in 21/35 (60%) NCCAH patients versus 1/47 (2.1%) in the CG. No NCCAH patients had acute adrenal insufficiency, but 2 reported severe fatigue that improved with hydrocortisone.. The cortisol response to tetracosactide was inadequate (<18 μg/dl) in 60% of patients with NCCAH. Hydrocortisone therapy may deserve consideration when major stress (surgery, trauma, childbirth) or objectively documented fatigue occurs in NCCAH patients with inadequate cortisol response.

Topics: Adolescent; Adrenal Hyperplasia, Congenital; Child; Child, Preschool; Cosyntropin; Female; Humans; Infant; Male; Pituitary-Adrenal Function Tests; Retrospective Studies; Sensitivity and Specificity

Adrenalectomy is an experimental treatment option for select patients with congenital adrenal hyperplasia who have failed medical therapy. After adrenalectomy, adrenal rest tissue can remain in extraadrenal locations, cause recurrent hyperandrogenism, and be difficult to localize.. The aim of the study was to investigate the usefulness of positron emission tomography/computerized tomography (PET/CT) in identifying adrenal rest tissue.. A female with salt-wasting 21-hydroxylase deficiency who had bilateral adrenalectomy at age 17 yr presented with hyperandrogenism at age 32 yr. Pelvic magnetic resonance imaging and ultrasound imaging were nondiagnostic for the source of androgen production.. A baseline F-18 labeled fluoro-2-deoxy-d-glucose (18F-FDG) PET/CT scan showed no active uptake; however, a second scan preceded by a 250-μg cosyntropin injection identified three areas of active uptake near both ovaries. Subsequent ovarian venous sampling showed elevations in 17-hydroxyprogesterone, androstenedione, and 21-deoxycortisol in both ovarian veins compared to a peripheral vein at baseline and more so after cosyntropin administration. At laparoscopy, three well-circumscribed nodules (2.4 × 0.9 × 1.3 cm, 1.2 × 1.5 × 1.5 cm, and 2 × 1.5 × 1 cm) lying lateral to the fallopian tubes adjacent to the broad ligaments were removed. The paraovarian nodules and previously removed adrenal glands had similar histology and immunohistochemistry. Postoperatively, androgen concentrations were undetectable, with no response to cosyntropin stimulation.. Patients with CAH after an adrenalectomy may experience recurrent hyperandrogenism due to adrenal rest tissue. 18F-FDG PET/CT with cosyntropin stimulation accurately identified adrenal rest tissue not visualized with conventional imaging, allowing for successful surgical resection.

Topics: Adrenal Glands; Adrenal Hyperplasia, Congenital; Adrenalectomy; Adult; Cosyntropin; Female; Humans; Multimodal Imaging; Positron-Emission Tomography; Tomography, X-Ray Computed; Treatment Outcome

Virilising ovarian tumours are a rare cause of hyperandrogenism in women, accounting for less than 5% of all ovarian neoplasms. It occurs most often in - and postmenopausal women. We report a case of a 64 year-old woman with signs of virilisation that had started 3 years before. Blood hormone analysis revealed increased levels of testosterone, and 17-hydroxyprogesterone. The tetracosactin test revealed 21-hydroxylase deficiency. Radiological imaging demonstrated a nodule in her left ovary. The patient was submitted to bilateral laparoscopic oophorectomy, and histopathological examination revealed a luteoma of the left ovary. Postoperative serum testosterone level and 17-hydroxyprogesterone returned to normal levels in one month. Virilism regressed within six months. Our patient also showed an elevation in 17-OHP serum levels. Normalization of 17-OHP after oophorectomy suggests a case of intratumoral 21-hydroxylase deficiency. To our knowledge, this is the first description of ovarian intratumoral 21-hydroxylase deficiency in a postmenopausal woman.

Topics: Adrenal Hyperplasia, Congenital; Cosyntropin; Female; Hirsutism; Humans; Luteoma; Middle Aged; Ovarian Neoplasms; Postmenopause; Testosterone

To comprehensively phenotype parents identified with nonclassic congenital adrenal hyperplasia (NCCAH) by family genetic studies, termed here as cryptic NCCAH and to define the incidence of cryptic NCCAH in the parents of a large cohort of patients with 21-hydroxylase deficiency.. Genotyping was performed on 249 parents of 145 unrelated congenital adrenal hyperplasia (CAH) patients. Parents with two CYP21A2 mutations underwent extensive evaluation.. Of the 249 parents, ten (4%; seven females and three males) were identified as having cryptic NCCAH. The majority was of ethnicities previously reported to have a higher incidence of NCCAH. Cosyntropin stimulation performed in eight parents provided biochemical confirmation (17-hydroxyprogesterone range 56-364 nmol/l) and cortisol response was ≤500 nmol/l in three parents (38%). Of the seven women (27-54 years) with cryptic NCCAH, four had prior infertility, two reported irregular menses, two had treatment for hirsutism, one had androgenic alopecia. Men were asymptomatic. All cryptic NCCAH parents reported normal puberty and had normal height. Adrenal hypertrophy and a small adrenal myelolipoma were observed in two parents; testicular adrenal rest tissue was not found.. Parents diagnosed with NCCAH by genetic testing are mostly asymptomatic. Temporary female infertility and suboptimal cortisol response were commonly observed. Ongoing glucocorticoid therapy is not indicated in adults with CAH identified by family genotype studies unless symptomatic, but glucocorticoid stress coverage should be considered in select cases. Parents of a child with CAH have a 1:25 risk of having NCCAH; if the mother of a child with CAH has infertility, evaluation for NCCAH is indicated.

Topics: Adrenal Glands; Adrenal Hyperplasia, Congenital; Adult; Aged; Anthropometry; Bayes Theorem; Body Height; Cosyntropin; DNA; Female; Hormones; Humans; Hyperandrogenism; Infertility; Male; Middle Aged; Parents; Phenotype; Puberty; Steroid 21-Hydroxylase; Testis; Tomography, X-Ray Computed

P450c17 deficiency (17alpha-hydroxylase/17,20-lyase deficiency, 17OHD) is a rare form of congenital adrenal hyperplasia caused by CYP17A1 gene mutations. The D487_F489 deletion in exon 8 and Y329fs in exon 6 are relatively frequent mutations of the CYP17A1 gene in China that completely abolish the enzyme activity of P450c17. However, little remains known about steroid biosynthetic functions in carriers with these mutations in a single allele of the CYP17A1 gene, who are assumed to have 50% P450c17 activity. We investigated adrenal steroidogenic function in genotype-proven heterozygotes carrying such mutations in the CYP17A1 gene in vivo.. Eight patients and fourteen family members from five families with 17OHD were recruited. The mutations of the CYP17A1 gene in these individuals were screened by sequencing. The hormonal response to cosyntropin (ACTH) was evaluated in the 14 genotype-proven carriers and 45 age- and gender-matched normal controls.. Fourteen carriers of the CYP17A1 mutation - seven with the D487_F489 deletion, six with Y329fs and one with H373L - were identified from the five families with 17OHD. Compared with normal controls, carriers showed lower basal and ACTH-stimulated cortisol levels but higher ACTH-stimulated corticosterone levels. The ratios of corticosterone to cortisol in the genotype-proven heterozygotes were higher than those of the normal controls at the baseline and after cosyntropin stimulation. Similarly, the progesterone levels and the ratios of progesterone to 17-hydroxyprogesterone in the male heterozygotes were also higher than those of the normal controls, both before and after ACTH stimulation.. Genotype-proven carriers of the CYP17A1 mutation who lack apparent clinical symptoms exhibit decreased adrenal 17alpha-hydroxylase activity and altered adrenal gland reserve for steroid biosynthesis.

Topics: 11-Hydroxycorticosteroids; Adolescent; Adrenal Hyperplasia, Congenital; Adult; Case-Control Studies; Cosyntropin; DNA Mutational Analysis; Female; Genotype; Hormones; Humans; Male; Middle Aged; Pedigree; Steroid 17-alpha-Hydroxylase; Young Adult

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Age of Onset; Child; Cosyntropin; Female; Genes, Recessive; Genetic Testing; Hormones; Humans; Hydrocortisone; Nurse Practitioners; Phenotype; Puberty, Precocious; Referral and Consultation

To analyse critically a protocol for the investigation of girls presenting with virilisation in childhood.. Twenty five girls aged 1.6-8.7 years with features of virilisation were evaluated. Twenty four had presented with pubic hair, eight with auxilliary hair, seven with facial acne, four with clitoromegaly, and 10 with tall stature. They underwent clinical assessment (height, weight, height velocity, staging of puberty, physical examination for acne, body odour, and clitoromegaly) and laboratory assessment comprising basal concentrations of cortisol, 17 OH-progesterone (17 OHP), androstenedione, dehydroepiandrosteronesulphate (DHEAS), testosterone, and oestradiol. The above steroids were also measured during the short synacthen test (0.25 mg intramuscularly) in 16 subjects and low dose dexamethasone suppression tests (0.5 mg at six hourly intervals over 48 hours). Pelvic ultrasound, computed tomography and magnetic resonance imaging of adrenals were carried out when the biochemical findings suggested that there might be an autonomous source of androgen secretion.. Clinical and laboratory assessments differentiated the patients into three diagnostic categories: adrenarche (18 cases), congenital adrenal hyperplasia (five cases), and adrenocortical tumour (two cases). The last had elevated concentrations of DHEAS, 1.5 and 19.1 mumol/l (normal value < 0.5 mumol/l), androstenedione, 24.6 and 21.8 nmol/l (normal < 1 nmol/l), and testosterone, 4.5 and 2.4 nmol/l (normal < 0.8 nmol/l), with none suppressing on dexamethasone suppression. Congenital adrenal hyperplasia subjects had elevated basal serum concentrations of 17 OHP (n = 4): 250, 140, 14, and 14.1 nmol/l (normal < 10 nmol/l) and elevated peak values of 17 OHP after synacthen (n = 3): 76, 179.5, and 175 nmol/l. Adrenarche patients had elevated basal concentrations of DHEAS (median: 2.3 mumol/l; n = 17) and androstenedione (median 2.6 nmol/l; n = 17). Nine patients also had elevated basal serum testosterone concentrations (median 0.9 nmol/l). Peak values of 17 OHP after synacthen were significantly different from baseline (n = 12) and were < 50% of the lowest value in congenital adrenal hyperplasia. Serum DHEAS, androstenedione, and testosterone suppressed following dexamethasone suppression (n = 16), thereby distinguishing adrenarche patients from adrenal tumour patients. Clinical details did not distinguish patients, except for clitoromegaly which was present only in the tumour and congenital adrenal hyperplasia patients.. This protocol proved useful and practical in cases of virilisation presenting particular diagnostic difficulty.

Topics: Adrenal Cortex Neoplasms; Adrenal Hyperplasia, Congenital; Androgens; Child; Child, Preschool; Clinical Protocols; Cosyntropin; Dehydroepiandrosterone; Dexamethasone; Diagnosis, Differential; Female; Humans; Infant; Virilism

The present study was designed to determine the prevalence of 11 beta-hydroxylase deficiency in adult women with hirsutism in a Turkish population.. One hundred and twenty-four consecutive unselected hirsute patients were studied. An ACTH stimulation test was performed in the midfollicular phase of the cycle on the patients and 20 age-matched controls by administration of a single bolus of 0.25 mg ACTH (1-24) at 0900 h.. Serum 11-deoxycortisol levels were measured before, 30 and 60 minutes after ACTH injection. Basal free testosterone (fT), SHBG, cortisol and androstenedione (A) were also measured. The diagnosis of 11 beta-hydroxylase deficiency has been presumed when the serum 11-deoxycortisol response to ACTH stimulation exceeded three times the 95th percentile of controls.. Basal hormone levels including fT and A were significantly higher in the hirsute women than in the healthy women. SHBG was significantly lower in the hirsute patients. Basal and ACTH stimulated 11-deoxycortisol levels were found to be significantly increased in the patients compared with the controls. Eight patients (6.5%) had an 11-deoxycortisol response higher than three times the upper normal limit.. Using stringent diagnostic criteria, we have found that 6.5% of the hirsute women in a Turkish population could be presumed to have 11 beta-hydroxylase deficiency.

Topics: Adolescent; Adrenal Hyperplasia, Congenital; Adult; Androstenedione; Cortodoxone; Cosyntropin; Female; Hirsutism; Humans; Prevalence; Testosterone; Turkey

To evaluate the heterogeneity of 21-hydroxylase deficiency with delayed symptoms, clinical and laboratory findings at presentation in 29 patients whose first symptoms occurred after three years of age were analyzed retrospectively. In 12 patients, these data were confronted with the results of molecular CYP21B gene analysis. Age at onset was 7 years on average and was comparable in boys and girls. Premature puberty was the most common presenting symptom [n = 24], whereas hirsutism, clitoral enlargement, and menstruation disorders were less frequent. Six cases were diagnosed as the result of routine studies of family members of index patients. The bone age over statural age ratio was greater than 1 in 19 of the 27 patients. Baseline 17-OH-progesterone levels were elevated in 22 of the 27 patients; magnitude of the elevation varied widely. Levels of 17-OH-progesterone after stimulation with immediate-action tetracosactide were closely correlated with baseline values and established the diagnosis in doubtful cases. Four patients had post-stimulation 17-OH-progesterone levels under 10 ng/ml, suggesting that were heterozygous for the disease. An important finding was that the magnitude of the devation in 17-OH-progesterone was not clearly correlated with clinical findings at presentation (age at onset, growth rate, advance in bone age). Molecular CYP21B gene analysis performed in 12 patients disclosed a homozygous 281 Val Leu mutation in 6 cases. This is the most commonly reported mutation in delayed onset forms. Two patients were heterozygous for the 281 Val Leu mutation and had an allele associated with severe disease, suggesting that the least severely affected chromosome governed clinical presentation of the disease. One boy had an allele associated with neonatal onset on both chromosomes; molecular analysis indicated a risk of antenatal masculinization of female fetuses in this family. This study showed that delayed onset 21-hydroxylase deficiency is a heterogeneous entity and that molecular analysis is essential to genetic counseling.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Age Determination by Skeleton; Alleles; Blotting, Southern; Child; Cosyntropin; Female; Genetic Carrier Screening; Genetic Counseling; Humans; Hydroxyprogesterones; Male; Mutation; Polymerase Chain Reaction; Puberty, Precocious; Retrospective Studies; Severity of Illness Index; Sex Factors; Steroid 21-Hydroxylase

Deficient adrenocortical 3 beta-hydroxysteroid dehydrogenase activity has been reported in 5% to 30% of hyperandrogenic women. Our objective was to determine the incidence and degree of 3 beta-hydroxysteroid dehydrogenase deficiencies in hyperandrogenism.. A prospective study of adrenal function in patients with hyperandrogenism was performed in a tertiary care university medical center. Eighty-six consecutive patients with hirsutism or hyperandrogenic oligomenorrhea were studied; 26 healthy eumenorrheic women served as controls. All subjects underwent serum sampling at rest and a 1-hour adrenal stimulation test with 1 mg of intravenously corticotropin-(1-24). Dehydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin, total and free testosterone, and luteinizing and follicle-stimulating hormones were measured in basal serum; dehydroepiandrosterone, 17-hydroxyprogesterone, and 17-hydroxypregnenolone were measured in basal and corticotropin-stimulated serum. On the basis of experience with genetically defined 21-hydroxylase late-onset adrenal hyperplasia, patients were presumed to suffer from 3 beta-hydroxysteroid-deficient late-onset adrenal hyperplasia if they demonstrated a dehydroepiandrosterone or 17-hydroxypregnenolone response to corticotropin-(1-24) stimulation (absolute poststimulation level or net increment) greater than threefold the upper 95th percentile of controls.. Three women of two families (2.3%) had a 17-hydroxyprogesterone response consistent with 21-hydroxylase-deficient late-onset adrenal hyperplasia and were excluded from further study. Eighteen (21%) of the remaining patients had a 17-hydroxypregnenolone poststimulation increment above the upper 95th percentile of controls (13.9 nmol/L), and two had an elevated dehydroepiandrosterone increment (> 19.5 nmol/L). However, no patient exceeded threefold the upper control limit for either steroid response. Patients with an exaggerated dehydroepiandrosterone or 17-hydroxypregnenolone increment had higher circulating dehydroepiandrosterone sulfate levels but similar basal total and free testosterone, sex hormone-binding globulin, luteinizing and follicle-stimulating hormone concentrations, basal or stimulated androstenedione, dehydroepiandrosterone/androstenedione, and 17-hydroxypregnenolone/17-hydroxyprogesterone than their less responsive counterparts.. Although an exaggerated response of 17-hydroxypregnenolone to adrenal stimulation is common in hyperandrogenism, a response severe enough to merit consideration as 3 beta-hydroxysteroid dehydrogenase-deficient late-onset adrenal hyperplasia was not encountered in this unselected patient population, suggestive of the rarity of this disorder.

Topics: 17-alpha-Hydroxypregnenolone; 17-alpha-Hydroxyprogesterone; 3-Hydroxysteroid Dehydrogenases; Adrenal Glands; Adrenal Hyperplasia, Congenital; Adult; Androgens; Androstenedione; Cosyntropin; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Female; Follicle Stimulating Hormone; Humans; Hydroxyprogesterones; Luteinizing Hormone; Prospective Studies; Sex Hormone-Binding Globulin; Testosterone

Nonclassical congenital adrenal hyperplasia (NCCAH) is well recognized among women who seek medical attention for hirsutism. However, the prevalence of this disorder among women self-referred for electrolytic treatment of hirsutism is unknown. We hypothesized that the prevalence of NCCAH among women attending an electrolysis clinic might be high. By measuring the morning salivary 17-hydroxyprogesterone (17-OHP) as a screening test for NCCAH in 46 women in the follicular phase of their menstrual cycle, we identified 12 subjects with a high basal salivary 17-OHP. Eleven agreed to have a 60-minute Cosyntropin-stimulation test, as did an additional 6 of 9 women with normal basal salivary 17-OHP, but with a particularly high hirsutism score. One of the women with high basal salivary 17-OHP had a 60-minute Cosyntropin response, which was diagnostic of NCCAH. She was of the Ashkenazi Jewish decent, a group previously reported to have a high prevalence of NCCAH. A second woman with high salivary 17-OPH had a Cosyntropin-stimulation response consistent with heterozygosity for 21-hydroxylase deficiency. None of the Cosyntropin-stimulation responses in those chosen for a high hirsutism score were diagnostic. Thus, 1 of 46 (2.2%) of the women who entered our study had unrecognized NCCAH, a prevalence only about 2-fold greater than that reported in the general population. Therefore, we recommend that electrolysis clinics advise clients from ethnic groups known to have a high frequency of NCCAH of the advisability of having a formal medical evaluation for NCCAH.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Adult; Cosyntropin; Electrolysis; Female; Hirsutism; Humans; Hydroxyprogesterones; Middle Aged; Prevalence; Saliva

Hyperandrogenic women appear to demonstrate an exaggerated 17-hydroxyprogesterone (17-HP) response to adrenal stimulation which is not due to the marked 21-hydroxylase deficiency of late-onset adrenal hyperplasia (LOAH). Furthermore, in hyperandrogenism the ovary also appears to secrete excessive amounts of 17-HP. It is not clear to what extent the elevated 17-HP levels after ACTH stimulation are due to extraadrenal production of the steroid. This investigation was undertaken to assess the adrenal contribution to the elevated 17-HP levels after ACTH stimulation observed in non-LOAH hyperandrogenism. One hundred and sixty consecutive unselected women with hirsutism and/or hyperandrogenic oligomenorrhea formed the clinical population. Excluded were 4 women with LOAH and all patients with hyperprolactinemia. For the purpose of investigating the relationship between adrenal response and clinical symptoms, hyperandrogenic patients were divided into 3 subgroups: hirsute only (n = 23), hirsute oligomenorrheic (n = 84), and oligomenorrheic only (n = 24). Subclassification for an additional 29 patients (18%) with hyperandrogenemia was not possible, since their symptomatology was not clearly stated in the record. However, these individuals were included in the patient group as a whole. Controls consisted of 21 healthy, regularly menstruating, nonhirsute female volunteers. Both patients and controls underwent acute adrenal stimulation with 1 mg ACTH-(1-24), and serum was obtained before and 30 min after ACTH administration. Hyperandrogenic patients had higher mean basal total testosterone (T), androstenedione (A), dehydroepiandrosterone sulfate (DHS), 17-HP, and LH/FSH levels, but not cortisol (F), compared to normal subjects (P less than 0.02). Oligomenorrheic only women had higher mean A and progesterone (P) levels than other hyperandrogenic patients (P less than 0.02). No correlation was noted between body mass index (BMI) and the levels of DHS, P, or A, while a weak positive association was noted between the BMI and the mean T (r = 0.31; P less than 0.002) and a weak negative correlation between the mean F and BMI (r = -0.21; P less than 0.05). The mean 17-HP level 30 min after ACTH administration (17-HP30) was significantly higher in hyperandrogenic women than in normal subjects whether analyzed in separate subgroups or together and was due to the higher basal 17-HP levels. Basal 17-HP correlated with the circulating levels of T, A, and P, steroids largely of o

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Cortex; Adrenal Hyperplasia, Congenital; Adult; Androgens; Androstenedione; Cosyntropin; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Female; Humans; Hydroxyprogesterones; Middle Aged; Polycystic Ovary Syndrome; Radioimmunoassay; Testosterone

The aims of this study were to determine the frequency of late-onset adrenal hyperplasia due specifically to 21-hydroxylase deficiency in a group of Irish women who presented at a Dublin Clinic with symptoms of hyperandrogenism, including hirsutism, menstrual irregularities and/or cystic acne, and to determine if those with 21-hydroxylase deficiency showed particular HLA associations. 119 women had blood samples taken basally and 1 h after an injection of 0.25 mg synacthen with the following hormones profiled: 17-hydroxyprogesterone, 11-deoxycortisol, androstenedione, testosterone, DHEAS and cortisol. Blood sampling was carried out between 0900 and 1000 h during the early follicular phase of the menstrual cycle (when applicable). Ninety-six subjects were new referrals to the Clinic for investigation of hyperandrogenism and 23 were acting as controls. In this study, 6% of patients showed evidence of partial 21-hydroxylase deficiency. In addition, 3 of the 6 with partial 21-hydroxylase deficiency had normal baseline levels of 17-hydroxyprogesterone, with the biochemical abnormality becoming manifest only on synacthen stimulation. Late-onset adrenal hyperplasia due to partial deficiency of this enzyme should always be considered as a possible diagnosis in women who present with symptoms of hyperandrogenism. Synacthen stimulation is an important diagnostic tool in elucidating partial enzyme deficiency as baseline 17-hydroxyprogesterone may be normal in such patients.

Topics: Acne Vulgaris; Adolescent; Adrenal Hyperplasia, Congenital; Adult; Cosyntropin; Female; Haplotypes; Hirsutism; Humans; Hydroxyprogesterones; Menstruation Disturbances; Steroid Hydroxylases

The diagnosis of non-classical 3 beta-hydroxysteroid dehydrogenase deficiency (NC-3BHSD) is made either on the basis of significantly elevated serum levels of basal and post-ACTH 5-ene-steroids or by the presence of elevated urinary 5-ene-steroid metabolites. There has been only one report to date describing a single patient where the diagnosis was based on both serum and urinary 5-ene-steroid levels. We, therefore, measured both serum 5-ene-steroid responses to ACTH 1-24 (by RIA) and urinary 5-ene-steroid metabolites (GC-MS) in 42 hirsute premenopausal women. While the serum 5-ene-steroid profile was consistent with NC-3BHSD in 5 women, only 2 of them had increased excretion of 5-ene-steroid metabolites. Elevated 5-ene-steroid excretion was also observed in several patients with normal serum 5-ene-steroids. Detection of NC-3BHSD by either elevated serum 5-ene-steroids or increased urinary excretion of their metabolites in isolation may not therefore be reliable.

Topics: 17-Ketosteroids; 3-Hydroxysteroid Dehydrogenases; Adolescent; Adrenal Hyperplasia, Congenital; Adult; Cosyntropin; Female; Humans; Male; Pregnenes; Stimulation, Chemical

21-deoxycortisol is a steroid produced mainly by the adrenal gland. Its normal plasma baseline concentrations (0.03 to 0.30 n/ml) and its concentrations after tetracosactide injection (0.15 to 0.76 ng/ml) do not significantly vary with age, sex and phases of the menstrual cycle. 21-deoxycortisol was assayed in plasma by a specific radioimmunological method and its values were compared with those of 17-OH progesterone in heterozygous subjects with the classical and non-classical forms of 21-hydroxylase deficiency, and in the amniotic fluid of foetuses with this deficiency. Baseline concentrations of 21-deoxycortisol in the classical forms of 21-hydroxylase deficiency (n = 12; 55.36 to 186.6 ng/ml) and post-tetracosactide concentrations in non-classical late onset forms (n = 31; 4.04 to 47 ng/ml) were much higher than in normal subjects, thus making this steroid as sensitive as, or even more sensitive than 17-OH progesterone in diagnosing 21-hydroxylase deficiency. Post-tetracosactide assays of 21-deoxycortisol in 84 heterozygous subjects with 21-hydroxylase deficiency (0.70 to 5.40 ng/ml) enabled these subjects to be detected with a more than 90 percent sensitivity, which cannot be obtained with 17-OH progesterone assays. 21-deoxycortisol concentrations in the amniotic fluid of foetuses with 21-hydroxylase deficiency (n = 11; 0.391 to 0.930 ng/ml) were constantly superior to those observed in normal foetuses (n = 38; 0.034 to 0.221 ng/ml), so that the deficiency can be diagnosed with the steroid as easily as with 17-OH progesterone.

Topics: 17-alpha-Hydroxyprogesterone; 17-Hydroxycorticosteroids; Adrenal Hyperplasia, Congenital; Adult; Amniotic Fluid; Biomarkers; Child; Cortodoxone; Cosyntropin; Female; Heterozygote; Humans; Hydroxyprogesterones; Infant, Newborn; Male; Mixed Function Oxygenases; Prenatal Diagnosis; Radioimmunoassay

Sixty-three women with ultrasonically detected polycystic ovaries (PCO) were investigated for a disorder of adrenal steroid biosynthesis. Serum was obtained before, and at 30 and 60 min after, the administration of 250 micrograms tetracosactrin, and assayed for 17 alpha-OH-progesterone, 21-deoxycortisol, 17 alpha-OH-pregnenolone and dehydroepiandrosterone by radioimmunoassay following paper chromatography. Results were compared with those in 11 women with normal ovaries, seven adult females with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), and 15 women heterozygous for this defect. Although the basal-peak steroid concentration differences were significantly greater when ACTH tests were conducted between 1400 and 1700 h than between 0900 and 1000 h, absolute peak steroid concentrations were not different at either time of day. Four of 63 (6.4%) women with PCO had responses to ACTH characteristic of non-classical (late onset) 21OHD CAH, and about half the remainder had responses characteristic of 21OHD heterozygotes. There was no clear cut evidence for a deficiency in 3 beta-hydroxysteroid dehydrogenase activity in women with PCO.

Topics: 17-alpha-Hydroxypregnenolone; 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Adult; Cortodoxone; Cosyntropin; Dehydroepiandrosterone; Female; Heterozygote; Humans; Hydroxyprogesterones; Middle Aged; Polycystic Ovary Syndrome; Steroids

We present an unusual patient with a Leydig cell tumor to show that greatly elevated serum concentrations of 17-hydroxyprogesterone (17OHP) may not be diagnostic of congenital adrenal hyperplasia (CAH). A 3.5-yr-old boy had a small testicular mass and plasma 17OHP concentrations of 147-333 nmol/L (4,850-11,000 ng/dL), suggesting CAH with adrenal rests. However, normal plasma cortisol values and the unresponsiveness of the 17OHP concentration to dexamethasone suppression or ACTH stimulation suggested a diagnosis of Leydig cell tumor. A 4-fold elevation in plasma 21-deoxycortisol compared with a 200-fold elevation in 17OHP suggested that the elevated 17OHP derived from the normal pathway of testosterone synthesis in the testis. This was proven by normalization of all hormonal values after tumor resection. Compared to the abundance of mRNA for P450c17, the tumor contained unusually large amounts of mRNA for P450scc, the cholesterol side-chain cleavage enzyme, which is the rate-limiting step in steroid hormone synthesis. Increased P450scc activity, which increased the conversion of cholesterol to pregnenolone, apparently permitted the 17,20-lyase activity of P450c17 to become rate limiting, thus accounting for the increased secretion of 17OHP. Thus, Leydig cell tumors can produce quantities of 17OHP previously reported only in CAH due to 21-hydroxylase deficiency. The molecular characterization of steroidogenic mRNAs in this tumor indicates an unusual ratio in the expression of the genes for the steroidogenic enzymes, probably accounting for the unusual pattern of serum steroids.

Topics: 17-alpha-Hydroxyprogesterone; 17-Ketosteroids; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Child, Preschool; Cosyntropin; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Humans; Hydrocortisone; Hydroxyprogesterones; Leydig Cell Tumor; Male; Pregnanetriol; Testicular Neoplasms; Testosterone

Because of the increasing use of 17-hydroxyprogesterone (17OHP) levels with the short adrenocorticotrophic hormone (ACTH) test in the detection of 21-hydroxylase deficiency, the diagnostic efficiency of the test was evaluated in patient and family studies of congenital adrenal hyperplasia due to 21-hydroxylase deficiency and of congenital adrenal hyperplasia due to 11-hydroxylase (11OH) deficiency (the latter disorder now overlaps basally with the milder non-classical 21-hydroxylase deficiency [NC-CAH]). Stimulated 17-hydroxyprogesterone level (17OHP30), 17-hydroxyprogesterone increase (delta 17 OHP) and the ratio 17-hydroxyprogesterone increase to cortisol increase (delta 17OHP/delta cortisol) were the parameters from the short ACTH test derived for assessment. 17-OHP30 provided complete differentiation of NC-CAH from the controls and heterozygotes, but overlap between NC-CAH and 11-OH occurred. Complete differentiation of NC-CAH from 11-OH was achieved using delta 17OHP. The heterozygotes showed best differentiation from the controls using delta 17OHP/delta cortisol with a diagnostic accuracy of 70%, however marked overlap of heterozygotes and NC-CAH with 11-OH was found. The short ACTH test proved to be a valuable technique with the further detection of homozygotes (n = 3) and heterozygotes (n = 5) in the 13 families studied. However, when interpreting the short ACTH test a careful choice of parameters should be made. It should be kept in mind that mild NC-CAH patients can only be differentiated from 11OH patients by using delta 17OHP.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenal Hyperplasia, Congenital; Adult; Child; Child, Preschool; Cosyntropin; Female; Humans; Hydroxyprogesterones; Infant; Infant, Newborn; Male; Middle Aged; Pedigree

Late-onset congenital adrenal hyperplasia is a mild genetic defect in steroidogenesis that presents with hirsutism and menstrual irregularities and responds to specific treatment with dexamethasone sodium phosphate. Its incidence as a significant cause of hirsutism or amenorrhea is controversial because it cannot be distinguished clinically from other causes. However, it is readily diagnosed by a marked increase in 17 alpha-hydroxyprogesterone levels after adrenocorticotropic hormone stimulation. Seventy-seven randomly selected women with hirsutism or amenorrhea were tested, and eight women (10.4%) were found to have late-onset congenital adrenal hyperplasia. Plasma levels of other hormones were similar in patients with and without late-onset congenital adrenal hyperplasia and were of no benefit in making the diagnosis. It is concluded that the adrenocorticotropic hormone stimulation test should be more widely utilized in patients presenting with hirsutism or menstrual dysfunction.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenal Hyperplasia, Congenital; Adult; Amenorrhea; Cosyntropin; Female; Hirsutism; Humans; Hydroxyprogesterones; Mass Screening

ACTH tests were performed with and without dexamethasone (dex) pretreatment to clarify the nature of the relationship between the absolute and incremental response (delta) to ACTH in normal men and women, hirsute women, adrenarchal children, and women heterozygous for congenital adrenal hyperplasia (CAH). The purposes were to test the effect of dex preparation on adrenal responsiveness to ACTH and the efficacy of the dex-pretreated ACTH test in detecting heterozygosity for CAH. Cosyntropin was given as a 10 micrograms/m2 iv bolus dose at 0800-1000 h; dex (1 mg/m2) was given at 2200-2400 h the night before. Dex did not alter the absolute plasma steroid levels achieved in response to ACTH. However, since post-dex baseline concentrations of adrenal steroids were lower, the delta to ACTH was significantly greater for the major adrenal secretory products, 17 alpha-hydroxypregnenolone (3 beta, 17 alpha-dihydroxypregn-5-ene-20-one), dehydroepiandrosterone, and cortisol (F). For example, for all paired tests, the mean plasma F values achieved 30 min post-ACTH were 26.0 +/- 4.4 (+/- SD) micrograms/dl without dex and 23.8 +/- 5.5 micrograms/dl after dex. In contrast, the mean delta of plasma F 30 min post-ACTH was less without (13.3 +/- 4.8 micrograms/dl) than after (19.4 +/- 3.3 micrograms/dl) dex (P less than 0.001). Apparent 21-hydroxylase efficiency, computed from dex-prepared tests, was found in follicular phase women to have a markedly skewed distribution without clear demarcation between 15% of the population and CAH heterozygotes. Luteal phase responses differed from follicular phase responses in dex-pretreated women in the magnitude of the 17-hydroxyprogesterone response. In the luteal phase, although the plasma 17-hydroxyprogesterone level at 30 min was higher, a response to ACTH was not consistently found, averaging only 22 +/- 26 ng/dl, in contrast to the consistent 52 +/- 15 ng/dl response in the follicular phase. These findings have practical implications for interpreting rapid ACTH test results. The absolute plasma F level achieved post-ACTH is more important as an index of adrenocortical reserve than the increment. Dex pretreatment appears to offer no practical advantage in ACTH testing for mild defects in 21-hydroxylation; we postulate that this is because of considerable normal variability in the efficiency of 21-hydroxylation.

Topics: Adolescent; Adrenal Cortex Hormones; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Adult; Androgens; Child; Cosyntropin; Dexamethasone; Drug Administration Schedule; Female; Genetic Carrier Screening; Hirsutism; Humans; Male; Menstrual Cycle; Progesterone; Steroid Hydroxylases

The plasma 17 alpha-hydroxyprogesterone (17-OHP) concentration was determined in the basal state and 60 minutes after cosyntropin, 0.25 mg, in 139 patients with idiopathic hirsutism (IH) and polycystic ovarian disease (PCOD). Although there was an increased response of 17-OHP in subjects with PCOD when compared with IH subjects, in no instance was stimulated 17-OHP abnormal in the presence of normal basal 17-OHP. Two subjects with 21-hydroxylase (21-OH) deficiency were discovered; both demonstrated elevated basal levels of 17-OHP. We therefore conclude that routine adrenocorticotropic hormone testing is not a useful tool in detecting 21-OH deficiency in hyperandrogenic women.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Adult; Cosyntropin; Female; Hirsutism; Humans; Hydroxyprogesterones; Middle Aged; Polycystic Ovary Syndrome; Stimulation, Chemical

In a population and family study we have examined the relationship between HLA types, classical congenital adrenal hyperplasia (CAH), and variants of 21 hydroxylase (21 OH) deficiency detected by increased blood levels of 17 hydroxyprogesterone (17 PO) in response to ACTH after overnight suppression with dexamethasone ('short Synacthen test'). In a non-CAH population, 7.7% of subjects were found to have raised 17 PO response suggesting reduced activity of 21 OH. Such subjects with raised 17 PO levels were designated simply as type 2 responders because the relationship with genotype was unknown. Post-ACTH levels of 17 PO were significantly greater in type 2 responders than in obligate carriers of CAH. A total of 2.5% of the population studied also had raised progesterone (PO) levels in the Synacthen test. HLA-A28 and B14 (in linkage disequilibrium) were significantly increased in frequency and HLA-B12 decreased in the type 2 responders. HLA-Bw47, which is known to be associated with CAH, was found only among obligate carriers of classical CAH. Because type 2 response and classical CAH are linked to HLA but are associated with different antigens, it is likely that they are determined by two (or more) alleles.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Age Factors; Complement Factor B; Cosyntropin; Female; Gene Frequency; Genetic Linkage; Heterozygote; HLA Antigens; Humans; Hydroxyprogesterones; Lactoylglutathione Lyase; Male; Pedigree; Progesterone; Steroid 21-Hydroxylase; Steroid Hydroxylases

21-Hydroxylase activity was measured in North American caucasian individuals with the HLA-B14 antigen to estimate the frequency of heterozygosity for the attenuated congenital adrenal hyperplasia trait. A 30-min iv ACTH stimulation test was administered to 9 normal HLA-B14-positive subjects and to a comparable HLA-B14-negative control group. Changes in plasma progesterone and 17-hydroxyprogesterone over 30 min were summed and expressed as a combined rate of rise. Six of 9 HLA-B14-positive individuals had a rate of rise greater than 2 SD above the mean control value. On this basis, about two thirds of B-14-positive individuals are heterozygote carriers for 21-hydroxylase deficiency. Thus, the frequency of the attenuated form of congenital adrenal hyperplasia linked to the HLA-B14 locus in women is approximately 1 in 6000 if there is only 1 B14, and 1 in 2000 if there are 2 B14s in the HLA type.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Adult; Cosyntropin; Female; Haploidy; Heterozygote; HLA Antigens; HLA-B Antigens; HLA-B14 Antigen; Humans; Hydroxyprogesterones; Male; Middle Aged; Progesterone; Steroid Hydroxylases

The authors describe a method for the radioimmunoassay of 17 alpha-hydroxyprogesterone in the saliva. The limit of detection is 1.96 fmole/tube. Salivary 17 alpha-hydroxyprogesterone was measured in control subjects. Values found were of 296 +/- 115 pmol/l in the male, and 251 +/- 23 pmol/l in the female during the follicular phase and 401 +/- 94 pmol/l during the luteal phase, and 115 +/- 30 pmol/l in the prepubertal child. Concentrations were much higher in the newborn and decreased during the first days of life. Variations in salivary concentrations were compared with those in plasma 17 alpha-hydroxyprogesterone during the 24-hour period and with the Synacthene stimulation test. The excellent correlation (r = 0.0969) between salivary 17 alpha-hydroxyprogesterone and plasma 17 alpha-hydroxyprogesterone in 28 patients being treated for 21 hydroxylase deficiency makes it possible to suggest salivary assay in place of plasma assay in the therapeutic follow-up of such patients.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenal Hyperplasia, Congenital; Adult; Age Factors; Child; Child, Preschool; Circadian Rhythm; Cosyntropin; Female; Follow-Up Studies; Humans; Hydroxyprogesterones; Infant, Newborn; Male; Middle Aged; Radioimmunoassay; Saliva; Sex Factors

Because severe hirsutism is difficult to reverse, the evaluation of the adolescent girl with progressive hirsutism should aim at the pathophysiology of androgen excess in order to select appropriate therapies. A prospective study was undertaken to determine the occurrence of late-onset 21-hydroxylase deficiency among adolescents with androgen excess. Twenty-two young women (mean age 17.3 +/- 2.6 years) with androgen excess had serum 17-hydroxyprogesterone measured before and after bolus intravenous infusion of synthetic ACTH (Cortrosyn), 0.25 mg. Two patients, aged 13 and 19 years old, had elevated base line 17-hydroxyprogesterone and 30- and 60-minute responses to Cortrosyn consistent with 21-hydroxylase deficiency. Chromosome 6p haplotypes provided supportive evidence of 21-hydroxylase deficiency. The base line androgen levels, clinical presentation, and a four-day dexamethasone test did not distinguish patients with 21-hydroxylase deficiency from other hirsute adolescents. The Cortrosyn test identifies a population of adolescents who need long-term corticosteroid therapy. The use of major histocompatibility complex haplotypes could be of help in identifying affected siblings prior to the development of significant hirsutism.

Topics: Adolescent; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Adult; Androgens; Child; Chromosomes, Human, 6-12 and X; Cosyntropin; Dexamethasone; Female; Follicular Phase; Hirsutism; HLA Antigens; Humans; Hydroxyprogesterones; Prospective Studies; Steroid Hydroxylases; Time Factors

Four untreated female patients with the nonsalt-losing form of congenital virilizing adrenal hyperplasia (21-hydroxylase deficiency) (21-OHD) maintained on a daily sodium intake of 120 m-equiv were studied by bilateral adrenal vein catheterization. Simultaneous right and left adrenal and peripheral blood samples were collected for determination of cortisol (F), progesterone (P), 17-hydroxyprogesterone (17-OHP), aldosterone (Aldo), and deoxycorticosterone (DOC). All patients were studied during sequential ACTH suppression (30 min after intravenous administration of 4 mg of dexamethasone) and stimulation (5 min after intravenous administration of 250 micrograms beta-ACTH [cosyntropin]). Basal peripheral concentrations of Aldo, DOC, P and 17-OHP were increased, whereas F concentrations were in the lower limit of the normal range. Dexamethasone suppressed adrenal secretion in all subjects. Subsequent adrenal stimulation by ACTH increased P, 17-OHP and DOC, whereas F returned to only control levels. DOC responses to ACTH in the adrenal vein effluents correlated significantly with Aldo responses but not with the 17-OHP increments, suggesting that the adrenal responses of Aldo and DOC to ACTH are events that probably occur in the same zone.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenal Glands; Adrenal Hyperplasia, Congenital; Adult; Aldosterone; Child; Cosyntropin; Desoxycorticosterone; Female; Humans; Hydrocortisone; Hydroxyprogesterones; Mineralocorticoids; Progesterone; Renin; Virilism

Detection of heterozygote carriers for congenital adrenal hyperplasia by use of a modified tetracosactide (a synthetic corticotropin) stimulation test with prior overnight dexamethasone suppression proved to have a diagnostic accuracy of 95%. Discrimination of heterozygotes from normals was best when we used a criterion based on the ratios of 17 alpha-hydroxyprogesterone to cortisol at baseline and at 30 min after intravenous administration of 250 micrograms of tetracosactide.

Topics: 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Cosyntropin; Dexamethasone; Female; Genetic Carrier Screening; Hirsutism; Humans; Hydrocortisone; Hydroxyprogesterones; Male; Polycystic Ovary Syndrome; Radioimmunoassay; Time Factors

In congenital adrenal hyperplasia the incidence of 21-hydroxylase deficiency is very high (approximately 1:7,000), whereas other enzyme defects such as 11-hydroxylase deficiency, 17-hydroxylase deficiency and 3 beta-hydroxysteroid dehydrogenase deficiency are much less frequent. The various forms of enzyme defects can be diagnosed by determining specific plasma steroids or specific urinary steroid metabolites. A new semi-automatic capillary gas liquid chromatography method has been introduced for the diagnosis of CAH and assessment of therapy. Heterozygous carriers of 21-hydroxylase deficiency can be detected in the general population by measuring 17-hydroxyprogesterone plasma levels after ACTH stimulation; however, results overlap with the general population. In families with a CAH index case, heterozygosity and homozygosity for the 21-hydroxylase deficiency gene can be detected by HLA-typing. 21-hydroxylase deficiency can be diagnosed prenatally by HLA-typing or by determining 17 OH-progesterone levels in the amniotic fluid.

Topics: Adrenal Hyperplasia, Congenital; Chromatography, Gas; Clinical Laboratory Techniques; Cosyntropin; Dexamethasone; Female; Genetic Carrier Screening; Homozygote; Hormones; Humans; Male; Menstruation; Pregnanes; Reference Values; Steroid Hydroxylases; Steroids

Adrenal steroidogenesis has been studied in vivo in eleven patients aged 13-68 years with 21-hydroxylase deficiency, in one patient with 11 beta-hydroxylase deficiency and in ten female control subjects. Serum levels of the delta 5 3 beta-hydroxysteroids, pregnenolone (Pe), 17 alpha-hydroxypregnenolone (17Pe), dehydroepiandrosterone (DHEA) and androstenediol (Adiol) and their delta 4 3-keto counterparts, progesterone (Po), 17 alpha-hydroxyprogesterone (17Po) androstenedione (Adione) and testosterone as well as of 11-deoxycortisol and cortisol were measured during acute adrenal suppression with dexamethasone followed by stimulation with synthetic 1-24 ACTH. In the seven patients with 21-hydroxylase deficiency who were on adequate glucocorticoid therapy, grossly exaggerated responses of 17Po and Po to ACTH were nevertheless preserved. In contrast, there was a grossly subnormal response of 17Pe, DHEA and Adiol to ACTH, and low basal levels of DHEA-sulphate. In the untreated patients the response of 17Pe and DHEA was normal. The Adione response was exaggerated in untreated and normal in treated cases. Similar findings obtained in the patient with 11 beta-hydroxylase deficiency who was studied after 6 weeks without replacement therapy. Our findings demonstrate that production of adrenal steroids that are associated with the adrenarche is not exaggerated in untreated CAH, and is grossly suppressed in treated cases. These findings are compatible with the hypothesis that intra-adrenal cortisol may initiate and/or maintain production of the delta 5 steroids by the zona reticularis that occurs in the human adrenarche.

Topics: Adolescent; Adrenal Cortex; Adrenal Glands; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Adult; Aged; Cosyntropin; Dexamethasone; Female; Gonadal Steroid Hormones; Humans; Male; Middle Aged; Mixed Function Oxygenases; Pregnanes

We describe a premature female infant exposed in utero to danazol during the first trimester of pregnancy. She was first observed in the newborn period with marked degree virilization and clinical findings suggestive of salt-losing congenital adrenal hyperplasia. This was supported by the high plasma levels of 17 alpha-hydroxyprogesterone and adrenocorticotropic hormone and low plasma cortisol level. Levels of testosterone, androstenedione, 11-deoxycortisol, and renin were also elevated. An excessive increase in the levels of 17 alpha-hydroxyprogesterone and 11-deoxycortisol to corticotropin administration associated with impaired increase in plasma cortisol level strongly suggests a partial block in the 21-hydroxylation of 17 alpha-hydroxyprogesterone. However, the high levels of 11-deoxycortisol also suggest a block of the steroid 11 beta-monooxygenase. A year later she was found to have normal basal levels of the adrenal steroids and normal response to corticotropin administration, pointing out the transitory nature of these abnormalities. It may be hypothesized that danazol produced a transitory block of the steroid 21- and 11 beta-monooxygenases in this child.

Topics: Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Androstenedione; Cortodoxone; Cosyntropin; Danazol; Female; Humans; Hydrocortisone; Hydroxyprogesterones; Infant, Newborn; Infant, Premature, Diseases; Maternal-Fetal Exchange; Pregnadienes; Pregnancy; Pregnancy Trimester, First; Renin; Testosterone

Four patients with untreated congenital virilizing adrenal hyperplasia (partial 21-hydroxylase deficiency) were studied by bilateral adrenal vein catheterization. Simultaneous right and left adrenal and peripheral blood samples were collected for determination of oestrone (E1) and oestradiol (E2). The concentrations of both were higher in the adrenal effluents than in the peripheral blood samples, indicating their secretion by the adrenals. All patients were also studied during a sequential test of suppression (0.5 h after i.v. administration of 4 mg dexamethasone) and stimulation (5 min after i.v. administration of 250 microgram ACTH 1-24; Synacthen). Mean peripheral E2 concentrations did not change significantly whereas E1 increased above control levels after stimulation. In contrast, suppression of adrenal venous blood concentrations with dexamethasone, and stimulation with ACTH, was demonstrated for every patient. The results indicate that in congenital adrenal hyperplasia the adrenal glands secrete significant amounts of E1 and E2.

Topics: Adolescent; Adrenal Glands; Adrenal Hyperplasia, Congenital; Adult; Child; Cosyntropin; Dexamethasone; Estradiol; Estrone; Female; Humans; Veins

The variations in plasma cortisol, testosterone and 17-hydroxyprogesterone (17-OHP) induced by an im injection of 0.25 mg cosyntrophin were studied in three groups of subjects: 16 healthy women, 16 hirsute women (HW) and 10 mild cases of congenital adrenal hyperplasia (CAH). The basal values of cortisol and testosterone were comparable between the three groups. In the patients with mild CAH, the mean 17-OHP concentration was increased: 483.9 ng/100 ml (113-1200 ng), but it should be noted that the individual values could overlap with the normal concentrations found in the controls and the HW during the luteal phase of the cycle. One hour after the injection of cosyntropin, a massive response of 17-OHP was observed in the mild cases of CAH, the mean basal concentration was multiplied by ten: 4843 ng/100 ml. The minimum concentration reached was 1740 ng/100 ml which is still 3-fold the highest level seen either in normal women (400 ng/ml) or in hirsute women (550 ng/100 ml). Determination of 17-OHP following a short-term ACTH stimulation, therefore provides evidence of partial 21-hydroxylase deficiency.

Topics: Adrenal Hyperplasia, Congenital; Adrenocortical Hyperfunction; Adrenocorticotropic Hormone; Adult; Cosyntropin; Female; Hirsutism; Humans; Hydrocortisone; Hydroxyprogesterones; Testosterone

Topics: Adrenal Glands; Adrenal Hyperplasia, Congenital; Adult; Cosyntropin; Dexamethasone; Female; Genetic Carrier Screening; Humans; Male; Steroid Hydroxylases; Steroids