A detailed investigation of hirsutism in a Turkish population: idiopathic hyperandrogenemia as a perplexing issue.

Hirsutism is a common clinical problem in women and the treatment depends on the cause of hirsutism. The study was designed to determine the various causes of hirsutism and their prevalences in a Turkish population. 168 women with hirsutism attending to Endocrinology Outpatient Clinic of Erciyes University Hospital were investigated in detail. Medical history, physical examination, and basal levels of free testosterone (fT), androstenedione, follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone-sulphate (DHEAS), 17 hydroxyprogesterone (17-OHP), 11-deoxycortisol (11-S), thyroid hormones, thyroid stimulating hormone (TSH), and prolactin were determined. ACTH stimulation test was performed for the diagnosis of non-classic congenital adrenal hyperplasia (NCAH). Pelvic/vaginal and adrenal ultrasonographies were performed for the detection of tumors and polycystic ovarian changes. Polycystic ovary syndrome (PCOS) was diagnosed in 96 (57.1 %) patients, idiopathic hirsutism in 27 (16 %), NCAH in 12 (7.1 %), adrenal carcinoma in 3 (1.8 %), and Cushing's disease in 1 (0.6 %) patient. Among patients with NCAH, 11 (91.7 %) patients had 11-beta hydroxylase (11-beta OH) deficiency, and 1 (8.3 %) had 21-hydroxylase deficiency. The etiology of hyperandrogenemia was not clear in 29 (17.4 %) patients and these patients were named as idiopathic hyperandrogenemia. The clinical presentation of 11-beta OH deficiency is indistinguishable from that of other hyperandrogenic states and ACTH stimulation test is the only way to diagnose this entity. Although PCOS is the most common cause of hirsutism, it is notable that nearly one fifth of hirsute women have no apparent cause of hyperandrogenemia.     

Prevalence of late-onset 11 beta-hydroxylase deficiency in hirsute patients

Serum levels of 11-deoxycortisol were determined in 182 hirsute women. Three patients presented high basal 11-deoxycortisol levels and an exaggerated response of this steroid to ACTH stimulation. A fourth patient had normal basal 11-deoxycortisol but was hyperresponsive to ACTH stimulation. Therefore diagnosis of late-onset 11 beta-hydroxylase deficiency was made in 4 out of 182 hirsute women with a prevalence of 2.2% in the group studied. In these patients, clinical findings and other hormonal patterns were not different from those of other women suffering from hirsutism.     

The value of low dose (1 microg) ACTH stimulation test in the investigation of non-classic adrenal hyperplasia due to 11beta-hydroxylase deficiency.

Non-classic congenital adrenal hyperplasia (NCAH) is a rare cause of hirsutism and it results from a defect in the biosynthetic pathway of cortisol and/or aldosterone. 250 microg ACTH test (SDT) is used in the diagnosis of this disease. Our aim was to investigate the responses of 11-deoxycortisol to 1microg ACTH (LDT) test in women with NCAH due to 11-beta hydroxylase (11- beta OH) deficiency and to compare them with the values obtained after SDT in the patients and in the control subjects. Eleven patients with NCAH due to 11- beta OH deficiency and 15 control subjects were involved in the study. The main complaint of the patients with NCAH was hirsutism and the diagnosis was made if the adrenal 11-deoxycortisol response to SDT exceed threefold the 95th percentile of controls. ACTH stimulation tests were carried out consecutively by using 250 microg and 1 microg intravenous ACTH as a bolus injection after an overnight fast, and blood samples were drawn at 0,30 and 60 min. Peak cortisol, 17-hydroxyprogesterone (17-OHP) and DHEAS responses were similar in LDT and SDT while 11-deoxycortisol responses to LDT (15.7 +/- 1.8 nmol/L) were significantly (p < 0.005) lower than the results obtained after SDT (76.3 +/- 21.4 nmol/L) in women with 11- beta OH deficiency. Peak cortisol and 17-OHP responses to LDT in patients and control subjects were similar. Peak 11-deoxycortisol responses to LDT were significantly (p < 0.05) higher in NCAH patients (15.7 +/- 1.8 nmol/L) than in the control subjects (6.5 +/- 0.8 nmol/L). However, in LDT, all patients had peak 11-deoxycortisol level lower than threefold the 95th percentile (25.8 nmol/L) of controls. This study represents the first demonstration that LDT gives similar cortisol but not 11-deoxycortisol responses to SDT in patients with 11- beta OH deficiency. This study also showed that LDT can not replace SDT in every clinical situation.     

The prevalence of late onset congenital adrenal hyperplasia in hirsute women from Central Anatolia

Late onset congenital adrenal hyperplasia (LO CAH) can be seen in association with polycystic ovary syndrome (PCOS) or idiopathic hirsutism (IH). The study aimed to find out the prevalence of LO CAH in Central Anatolia among hirsute women. Sixty-three patients with hirsutism were evaluated to determine the frequency of LO CAH by comparing them with their age and body mass index matched 28 healthy controls. Of those 63 hirsute women, 43 were diagnosed as PCOS, and 20 were diagnosed as IH. Following basal hormonal evaluation, all subjects underwent ACTH stimulation test and ACTH stimulated 17-hydroxyprogesterone (17-OH P), 11-desoxycortisol (11-DOC), cortisol (F), and dehydroepiandrosterone sulfate (DHEA-S) levels were determined in all subjects. ACTH stimulated 17-OH P, 11-DOC, and DHEA-S levels did not differ between groups. However, stimulated F levels were found to be higher in hirsute women (p<0.001). Six out of 63 (9.52%) patients with hirsutism met the criterion for 21 hydroxylase deficiency. We found no subject presumed to have 11-beta hydroxylase deficiency, but one subject in control group (3.57%) and two patients among PCOS subjects (4.65%) had exaggerated DHEA-S response which was suggestive of mild 3-beta hydroxysteroid dehydrogenase deficiency. In conclusion, the most frequent form of LO CAH seems to be due to 21 OH deficiency among women with PCOS and IH in Central Anatolia. Mild 3-beta HSD deficiency may also be an underlying cause for hirsutism and it may be seen without any clinical presentation. Adrenal hyperactivity is likely to be the main reason of hyperandrogenemia in women with hirsutism.     

11-DEOXYCORTISOL IN AMNIOTIC FLUID: PRENATAL DIAGNOSIS OF CONGENITAL ADRENAL HYPERPLASIA DUE TO 11 β-HYDROXYLASE DEFICIENCY

The mean control level of 11-deoxycortisol as determined by radioimmunoassay in eighty-one human amniotic fluid samples was 1·20 ± 0·07 ng/ml. Markedly elevated levels were found at term in amniotic fluid of two pregnancies with fetuses affected with 11 β-hydroxylase deficiency, congenital adrenal hyperplasia (135·0 and 64·0 ng/ml respectively) as well as in the maternal serum of one of these cases (28·0 ng/ml). It is suggested that the determination of 11-deoxycortisol in amniotic fluid be a prenatal diagnostic test for 11 β-hydroxylase deficiency congenital adrenal hyperplasia.     

Apparent activities of 21-hydroxylase, 17alpha-hydroxylase and 17,20-lyase are impaired in adrenal incidentalomas.

OBJECTIVE: An increased response of 17-hydroxyprogesterone to ACTH stimulation has been observed in adrenal incidentaloma and linked to an impairment of either 21-hydroxylase or of 11beta-hydroxylase activity. To analyse this question further, we investigated the steroidogenic pathways in a series of 17 adrenal incidentalomas. DESIGN AND PATIENTS: 17 patients (7 women, 10 men; mean age, 62 +/- 12 years) with non-histologically analyzed adrenal incidentalomas were prospectively evaluated. METHODS: The following variables were investigated: 24-h urinary methanephrines and free cortisol excretion; plasma levels of ACTH and dehydroepiandrosterone; overnight dexamethasone suppression test; 1-24 ACTH stimulation test with measurement of: cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, aldosterone, 11-deoxycorticosterone, progesterone, 17-hydroxypregnenolone, Delta4-androstenedione, dehydroepiandrosterone and 21-deoxycortisol. RESULTS: Discordant features of subclinical hypercorticism were noted in one case. No patient had dehydroepiandrosterone sulfate levels in the normal range for his or her age. Peak 17-hydroxyprogesterone and peak 21-deoxycortisol disclosed impairment of 21-hydroxylase in 11 and 10 cases respectively. An increased 11-deoxycortisol/cortisol ratio identified reduced activity of 11beta-hydroxylase in 11 patients. Eight patients displayed features of mild 17,20-lyase impairment, which was related to 21-hydroxylase dysfunction. Whereas only 2 patients showed no enzyme modification, 9 displayed alterations of at least two pathways. CONCLUSION: In our hands, a combination of enzyme dysfunction was frequently observed. Shared biochemical mechanisms could explain combined 17,20-lyase and 21-hydroxylase alterations, whereas coexistence of 21-hydroxylase (particularly when based on peak 21-deoxycortisol) and 11beta-hydroxylase is more puzzling.     

11β-Hydroxylase deficiency: management of a difficult case by laparoscopic bilateral adrenalectomy

A 14-year-old girl presented with short stature and progressive virilization. She had not undergone the menarche. On investigation, she had elevated testosterone, androstenedione, dihydroepiandrosterone sulphate and 17α-hydroxyprogesterone levels, which were all suppressed by overnight dexamethasone to within their normal ranges. An initial diagnosis of 21-hydroxylase deficiency was revised to 11β-hydroxylase deficiency after a tetracosactrin stimulation test, which showed only a modest rise in 17α-hydroxyprogesterone level (from 92 nmol/l at baseline to 133 nmol/l at 60 minutes) and measurement of the basal 11-deoxycortisol, which was grossly elevated. Treatment with dexamethasone 0.5 mg nocte resulted in suppression of androgens in the daytime, but not in the evening, particularly androstenedione. Treatment with hydrocortisone 10 mg b.d. failed to suppress testosterone or androstenedione over a 24-hour period. Addition of cyproterone and oestrogen supplements had no effect and significant virilization persisted. Laparoscopic bilateral adrenalectomy was therefore performed as definitive treatment and resulted in remarkable clinical and biochemical improvement. This case illustrates difficulties in correct diagnosis, choice of appropriate steroid regimen and monitoring efficacy of treatment in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. More aggressive management with earlier bilateral adrenalectomy may be appropriate in selected cases.     

Radioimmunoassay for 21-deoxycortisol: clinical applications

A radioimmunoassay for 21-deoxycortisol is described. The immunogen, 21-deoxycortisol-3-(0-carboxymethyl) oxime-bovine serum albumin, was prepared, the antisera raised against it were studied and the reliability of the assay was checked. The antiserum selected cross-reacted with 11-deoxycortisol (0.08%), corticosterone (0.25%), cortisol (0.6%) and 17-hydroxyprogesterone (1.6%). 21-deoxycortisol was separated by celite partition chromatography and eluted in the 70/30 (v/v) isooctane/ethyl acetate fraction together with 11-deoxycortisol and corticosterone. The radioimmunoassay was used to measure 21-deoxycortisol in the plasma of normal subjects and patients with androgen excess. In normal subjects, men (0.19 ng/ml +/- 0.08) and women (0.18 ng/ml +/- 0.09) had similar basal levels (mean +/- SD). One hour after ACTH stimulation, these levels were increased by a factor of 3.5. In 7 patients treated for classical congenital adrenal hyperplasia associated with 21-hydroxylase deficiency, basal values varied between 9.1 and 39.9 ng/ml (measured at 8 a.m.). In 7 untreated women with late-onset congenital adrenal hyperplasia (with 21-hydroxylase deficiency), ACTH-stimulated levels were increased to between 9 and 25.5 ng/ml. In 14 heterozygous carriers of 21-hydroxylase deficiency, diagnosed by HLA genotyping, all ACTH-stimulated levels were well above the highest corresponding levels in normal subjects, whereas 17-hydroxyprogesterone levels remained within the normal range in 9 of the cases.     

The incidence of late-onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency among hirsute women

Late-onset congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a cause of hirsutism in adult women. Its reported frequency of occurrence in hirsute women has varied from 0-30%, but the number of patients studied was small. To establish the incidence of CAH, 83 unselected hirsute women were studied prospectively with a standard ACTH stimulation test. On the basis of an exaggerated response of serum 17 alpha-hydroxyprogesterone to ACTH, 1 patient with CAH was found, for an incidence of 1.2%. The 95% confidence limits for the incidence of CAH among hirsute women were 0% and 3.4%. Five of seven hirsute women without CAH whose serum 17 alpha-hydroxyprogesterone levels rose above 3 ng/ml in response to ACTH had simultaneous serum progesterone values consistent with recent ovulation. Since routine screening of all hirsute women by means of ACTH stimulation does not appear to be cost effective, reported cases of CAH were reviewed in order to discern potentially helpful clinical clues. Severe hirsutism, virilization, early onset of symptoms, short stature, familial occurrence, and regular menses were identified as the clinical characteristics associated with late-onset CAH.     

Adrenal 21-hydroxylase gene mutations in Slovenian hyperandrogenic women: evaluation of corticotrophin stimulation and HLA polymorphisms in screening for carrier status.

OBJECTIVE: To study the incidence of 21-hydroxylase deficiency in Slovenian hyperandrogenic women, at the gene level. Previous endocrine studies indicated large differences in the incidence of 21-hydroxylase deficiency in hyperandrogenic women. The predictive values of the 17-hydroxyprogesterone (17-OHP) response to ACTH stimulation and of HLA typing in screening for carrier status were re-evaluated. DESIGN: Molecular analysis of CYP21 gene, ACTH stimulation and human leucocyte antigen (HLA) typing were performed in 83 consecutive Slovenian hyperandrogenic women. MEASUREMENTS: Cortisol and 17-OHP concentrations were measured at baseline and 60 min after ACTH stimulation. Basal adrenal androgen concentrations were also measured. RESULTS: None of 83 hyperandrogenic patients was affected with non-classical 21-hydroxylase deficiency, but 12 of 81 patients (14.8%) had high concentrations of 17-OHP after stimulation, indicative of carrier status. The increase in 17-OHP concentrations could be explained by a carrier status for CYP21 gene mutations in only three of 12 patients (25%), whereas seven of 69 patients (10. 1%) with normal concentrations of 17-OHP after stimulation were found to be carriers of CYP21 gene mutations, indicating low positive predictive values of ACTH stimulation as a screening test for carriers of 21-hydroxylase deficiency. In total, 11 carriers were identified among 83 patients: seven CYP21 gene deletions/conversions, two Gln(318)Stop and one Val(281)Leu mutation and one gene conversion extending from exon 4 to exon 7 were found. The association between Val(281)Leu mutation and HLA-B14 antigen was confirmed in this Slovenian population. CONCLUSIONS: Basal or ACTH-stimulated 17-OHP concentrations are not a good indicator of the carrier status for 21-hydroxylase deficiency among Slovenian hyperandrogenic patients. Reliable screening for carriers of 21-hydroxylase deficiency is possible only by molecular analysis of the CYP21 gene.     

RAPID ASSAY OF PLASMA 21-DEOXYCORTISOL AND 11-DEOXYCORTISOLIN CONGENITAL ADRENAL HYPERPLASIA

Plasma assays using highly specific antisera to 21-deoxycortisol, 21-deoxycortisone and 11-deoxycortisol were developed to provide a rapid means of diagnosis in patients with congenital adrenal hyperplasia (CAH). The assays were done on plasma extracts with and without Celite chromatography to compare the results of direct assays on plasma extracts and assays on purified plasma extracts. Both methods showed elevations of metabolites that permitted the correct diagnosis of the specific enzyme deficiency. Untreated patients with 21-hydroxylase deficiency had elevated levels of 21-deoxycortisol, 21-deoxycortisone and 17-hydroxyprogesterone. One of the untreated patients with 21-hydroxylase deficiency had elevated levels of these metabolites due to inadequate glucocorticoid treatment. In one newborn patient, who developed a salt-losing syndrome, a combined deficiency of 11- and 21-hydroxylase appeared to be present based on elevations of plasma concentrations of 11-deoxycortisol (2.7 μg/dl), 21-deoxycortisol (10.3 μg/dl), 21-deoxycortisone (8.6 μg/dl), and 17-hydroxyprogesterone (> 20 μg/dl). After treatment was begun the levels of all four metabolites returned to normal. This patient had XX/XO karyotype and ambiguous genitalia. Fourteen normal neonates were studied as controls for this subject. Normal neonates all had low plasma levels of these compounds. Their 21-deoxycortisol concentrations were all less than 0.5 μg/dl and their 11-deoxycortisol concentrations were all less than 0.1 μg/dl. The study shows that accurate, rapid plasma diagnosis is possible in patients with congenital adrenal hyperplasia, using specific radioimmunoassay procedures.     

Synergistic effects of growth hormone therapy on plasma levels of 11-deoxycortisol and cortisol in growth hormone-deficient children

We have studied the response of blood levels of progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, and cortisol to acute ACTH stimulation in children with isolated GH deficiency. Patients with isolated GH deficiency had generally higher levels of 11-deoxycortisol and lower levels of cortisol than controls both before and after ACTH stimulation. The steroid levels were almost completely restored to control levels after 3 months of treatment with GH. The pre-ACTH treatment levels of 11-deoxycortisol and cortisol were low in patients with both GH and ACTH deficiencies before and during GH therapy. Therefore, GH alone did not appear to have any effect on the hydroxylation of 11-deoxycortisol to cortisol. Before GH therapy, ACTH increased the concentrations of the two steroids. After GH therapy was started, the increase in 11-deoxycortisol was much smaller, but the increase in cortisol was much larger than before therapy. These results suggest a synergistic effect of GH on ACTH action on the biosynthesis of cortisol in the adrenals. Variations in the levels of 11-deoxycortisol and cortisol during hormonal manipulations lead to the identification of the mitochondrial hydroxylation of 11-deoxycortisol as one of the possible sites of action of GH.     

Thyroid function in idiopathic oedema

BACKGROUND  The role of abnormal thyroid function in the aetiology of idiopathic oedema is unclear. Previous studies of small samples of patients have suggested a high prevalence of latent hypothyroidism and a possible deiodination defect in the conversion of T4 to T3 in this condition. There is a need to clarify the possible significance of abnormal thyroid function in a larger sample of idiopathic oedema patients.
OBJECTIVE  The study was undertaken to compare basal thyroid function in idiopathic oedema patients and in an age and sex-matched control group.
PATIENTS AND DESIGN  After excluding one idiopathic oedema patient and three control subjects with abnormal thyroid function, basal thyroid function was compared in 44 idiopathic oedema patients and in 44 age and sex-matched controls.
MEASUREMENTS  Basal thyroid function was assessed in patient and control groups by measuring serum T4, fT4, T3, fT3 and TSH by standard methods.
RESULTS  There were no significant differences in basal thyroid function between patient and control groups except for an elevated mean fT4 concentration in the idiopathic oedema group ( P  = 0.03). Exclusion of patients and controls taking oestrogen abolished this difference. T4 : T3 ratios were similar in patient and control groups.
CONCLUSION  Abnormalities of basal thyroid function are uncommon in patients with idiopathic oedema and appear unrelated to the pathogenesis of this disorder. Similar T4 : T3 ratios between patient and control groups exclude a deiodination defect in idiopathic oedema.     

Adrenal androgen hyperresponsiveness to adrenocorticotropin in women with acne and/or hirsutism: adrenal enzyme defects and exaggerated adrenarche

To determine the adrenal contribution to elevated plasma androgens in 31 young hyperandrogenemic women with acne and/or hirsutism, we compared their responses to ACTH with those of 14 normal women. Each subject was given a low dose (10 micrograms/m2) of synthetic ACTH-(1-24) (Cortrosyn) after administration of 1.5 mg dexamethasone the night before the test. Thirty and 60 min responses of plasma 17 alpha-hydroxypregnenolone (17-Preg), 17 alpha-hydroxyprogesterone, (17-prog), dehydroepiandrosterone (DHEA), androstenedione, 11-deoxycortisol, and cortisol were measured. Eighteen (58%) patients had increased responses of at least one 17-ketosteroid or adrenal androgen precursor. All patients had cortisol responses within the range of those of the 14 normal subjects. Nine patients (29%) had evidence of steroid biosynthetic enzyme deficiencies, either mild congenital adrenal hyperplasia or the heterozygote state; after ACTH, 4 of these patients had elevated 17-prog in the range of values in heterozygote carriers of 21-hydroxylase deficiency, 2 had elevated levels of 11-deoxycortisol compatible with 11 beta-hydroxylase deficiency, and 3 had elevated levels of 17-Preg and DHEA, suggestive of 3 beta-hydroxysteroid dehydrogenase deficiency. Another 9 subjects (29%) had 17-ketosteroid (DHEA and/or androstenedione) hyperresponsiveness to ACTH with associated elevated 17-Preg responses. As a group, their patterns suggested relatively deficient 3 beta-hydroxysteroid dehydrogenase and relatively hyperactive C lyase without impairment of cortisol secretion. This pattern resembles exaggerated adrenarche, and we postulate that these 9 patients have hyperplasia of the zona reticularis. Neither basal levels of plasma androgens (free testosterone and DHEA sulfate) nor menstrual history predicted which patients would have abnormal ACTH responses. Although 5 of 11 (45%) patients with acne alone had abnormal responses to ACTH, 10 of 14 patients with acne and hirsutism (71%) had abnormal responses to ACTH. We conclude that an adrenal contribution is found in about half of hyperandrogenemic women with acne and/or hirsutism. This adrenal androgen hyperresponsiveness is heterogeneous. Some patients may have mild forms of congenital adrenal hyperplasia. However, functional androgenic hyperresponsiveness to ACTH, which resembles an exaggeration of adrenarche, is the most common abnormality found. Such findings may provide an explanation for the clinical observation of exacerbations of acne with stress.     

Comparison between buserelin and dexamethasone testing in the assessment of hirsutism

Many hirsute women may present a form of functional ovarian hyperandrogenism (FOH), since they show an exaggerated 17-hydroxyprogesterone (17-OHP) response to GnRH agonists administration. As the failure of dexamethasone to reduce testosterone levels may be indicative of an ovarian source of androgen secretion, we evaluated the usefulness of dexamethasone suppression test, in comparison with buserelin challenge, in the assessment of hirsutism. Twenty-seven hirsute women (aged 15-42 yr) underwent ACTH and buserelin tests: 4 patients were heterozygotes for 21-OH deficiency and 8 patients were affected with FOH: 2 of the patients with hyperresponse to buserelin also had 21-hydroxylase deficiency. The results of the dexamethasone suppression test (2 mg/day for 7 days) were compared to those obtained after buserelin test. Basal T and delta4 levels (mean+/-SE) were higher than in controls (4.2+/-0.5 vs 2.2+/-0.2 nmol/l and 10.9+/-0.9 vs 5.9+/-0.6 nmol/l, p<0.02), while no differences were found in 17-OHP and DHEAS levels. A significant reduction (p<0.001) in T (1.8+/-0.4 nmol/l), delta4 (3.2+/-0.5 nmol/l) and DHEAS levels (2.4+/-0.3 micromol/l) was observed at the 3rd day of dexamethasone administration and no differences between sampling at 3rd, 5th and 7th day were found. Serum T was not suppressed in 6 cases, delta4 and DHEAS levels in 3 and 1 of them, respectively. Buserelin injection caused an excessive 17-OHP response in 8 patients, only 4 of them did not reduce T levels during dexamethasone. The sensitivity and specificity of the dexamethasone suppression test, with respect to the buserelin test, were 50% and 89%, respectively. In conclusion, 37% of hirsute patients had an abnormal responsiveness to buserelin and/or ACTH tests, indicating that hormonal investigations are mandatory. An ovarian origin of hirsutism was identified by buserelin test in 30% of patients and by dexamethasone in 22% of cases; only 4 of 8 patients showed concordant results to both tests. Therefore, buserelin challenge seems a more useful, cost-effective and less time consuming tool than dexamethasone administration in order to recognize the possible ovarian origin of hyperandrogenism.     

Adrenal androgen excess and defective 11 beta-hydroxylation in women with idiopathic hirsutism

We studied the simultaneous responses of four serum androgens (testosterone, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate) and five other steroids (deoxycorticosterone, corticosterone, 11-deoxycortisol, cortisol, and 17 alpha-hydroxyprogesterone) to the infusion of small amounts of cosyntropin in eight patients with idiopathic hirsutism and in six normal women. Serum testosterone and androstenedione concentrations were significantly higher in hirsute women after graded cosyntropin infusions than in controls, as were concentrations of plasma deoxycorticosterone and 11-deoxycortisol. Analysis of the substrate/product ratios 11-deoxycortisol/cortisol and deoxycorticosterone/corticosterone revealed defective 11 beta-hydroxylation in women with hirsutism. The presence of increased circulating androgen levels in response to physiologic amounts of adrenocorticotropic hormone thus appears to be a common response in women with idiopathic hirsutism, and, together with impaired adrenal 11 beta-hydroxylation, points to an adrenal defect as important components of this disorder.     

Hepatic 11beta-HSD1 mRNA expression in fatty liver and nonalcoholic steatohepatitis

Context  Nonalcoholic fatty liver disease represents the hepatic manifestation of the metabolic syndrome. Nonalcoholic steatohepatitis (NASH) is the progressive form of liver injury. The pathophysiology that leads to NASH is not well understood.
Objective  We hypothesize that an altered cortisol metabolism in the liver may be a pathogenetic factor.
Design and patients  75 patients (28 men, 47 women) underwent liver biopsy for elevation in liver enzymes. Histological diagnosis identified normal liver in eight, fatty liver in 20, NASH grade 1 in 22, grade 2 in nine, grade 3 in three patients, and other forms of hepatitis or cirrhosis in 13 patients. We quantified hepatic 11β-hydroxysteroid dehydrogenase type1 (11β-HSD1) and hexose-6-phosphate-dehydrogenase (H6PDH) mRNA expression by real-time PCR. In addition, analysis of 24 h urinary excretion of cortisol metabolites using GCMS was performed and compared with healthy controls.
Results  11β-HSD1 mRNA expression correlated significantly ( R ²= 0·809; P  < 0·001) with H6PDH mRNA expression, negatively with waist-to-hip ratio in women ( R ²= 0·394; P = 0·005), but not with urinary (THF + 5α-THF)/THE ratio, total cortisol metabolite excretion, age, BMI, degree of fatty liver or NASH stages. Total cortisol metabolite excretion was increased in patients with fatty liver or NASH compared with healthy controls.
Conclusions  Our data suggest that expression of hepatic 11β-HSD1 and H6PDH are closely interlinked. 11β-HSD1 gene expression does not seem to be involved in the pathogenesis of fatty liver or NASH. However, those patients showed an increased 5α- and 5β-reduction of cortisol leading to an increased cortisol turnover rate and an activation of the HPA axis.     

Combined 21- and 11 beta-hydroxylase deficiency in familial congenital adrenal hyperplasia

Studies in three families (A, B, and C) revealed five patients with congenital adrenal hyperplasia (CAH) due to partial and combined 21- and 11 beta-hydroxylase deficiency. One patient (A-11 1), a 23-yr-old severely virilized chromosomal female, was reared as a male, and two females (B-11 2 and C-1) complained only of hirsutism, acne, and menstrual abnormalities. Patients A-11 2 and B-11 8 (17 1/2 and 10 yr old) were asymptomatic and detected by finding an HLA genotype identical to that of their respectively affected brother and sister. Three patients (A-11 1, A-11 2, and C-1) had moderate hypertension. In spite of the wide range of clinical manifestations, all individuals had elevated androgen levels, while cortisol secretion was severely impaired only in A-11 2. 21-Hydroxylase deficiency was diagnosed on the basis of markedly increased plasma and urinary levels of 17-hydroxyprogesterone (17-OHP) and 21-deoxycortisol and their respective urinary metabolites pregnanetriol and pregnanetriolone. PRA was elevated in three patients, while urinary aldosterone was normal or increased. 11 beta-Hydroxylase deficiency was diagnosed on the basis of increased 11-deoxycortisol and deoxycorticosterone in plasma and tetrahydro-11-deoxycortisol and deoxycorticosterone in urine, particularly after ACTH administration. In contrast to classical 11 beta-hydroxylase deficiency CAH, urinary 18-hydroxycorticosterone and 18-hydroxy-11-deoxycorticosterone were normal or elevated. The nature and mechanism of a combined enzymatic defect are unknown. The coincidental presence in a single individual of the mutant genes for both 21- and 11 beta-hydroxylase deficiency CAH is very unlikely to occur. Two alternative hypotheses may explain our findings. One is the existence of a genetically inherited abnormal (or aberrant) 11 beta-hydroxylase, whose affinity for its normal substrate is changed for an abnormal one (17-OHP). As a result, 11 beta-hydroxylation of 11-deoxycortisol is deficient while 17-OHP 11 beta-hydroxylation is markedly enhanced. Thus, both 11-deoxycortisol and 21-deoxycortisol as well as their urinary metabolites accumulate. The ability for 18-hydroxylation, however, remains normal. In this case, 21-hydroxylase is not deficient, yet 21-deoxycortisol cannot be further hydroxylated to cortisol, since this steroid is not a suitable substrate for the enzyme. Such a disorder may represent a new allelic variant of 11 beta-hydroxylase deficiency CAH, which, similar to 21-hydroxylase deficiency, is completely linked to the HLA complex.(ABSTRACT TRUNCATED AT 400 WORDS)     

LATE ONSET ADRENAL HYPERPLASIA IN A GROUP OF IRISH FEMALES WHO PRESENTED WITH HIRSUTISM, IRREGULAR MENSES AND/OR CYSTIC ACNE

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.     

Late-onset adrenal steroid 3 beta-hydroxysteroid dehydrogenase deficiency. I. A cause of hirsutism in pubertal and postpubertal women

To investigate the adrenal cause of hyperandrogenism in peri- and postpubertal hirsute women, baseline and ACTH-stimulated serum concentrations of delta 5-17-hydroxypregnenolone (delta 5-17P), dehydroepiandrosterone (DHEA) and its sulfate, 17-hydroxyprogesterone (17-OHP), cortisol, delta 4-androstenedione, and testosterone were determined in 116 women with hirsutism or acne of peri- and postpubertal onset with or without menstrual abnormalities. The results were compared with the same steroid concentrations in 30 normal age-matched women. Sixteen of the 116 women with hirsutism whose ACTH-stimulated 17-OHP levels (mean +/- SD, 5404 +/- 3234 ng/dl; normal, 334 +/- 194) were markedly elevated while their ratios of delta 5-17P to 17-OHP (0.4 +/- 0.2; normal, 3.4 +/- 1.5) were low were diagnosed as having nonclassical symptomatic 21-hydroxylase deficiency. Seventeen other hirsute women, including 3 siblings, had very high responses of delta 5-17P (2276 +/- 669 ng/dl; normal, 985 +/- 327) and DHEA (2787 +/- 386 ng/dl; normal, 1050 +/- 384) to ACTH stimulation, with significantly elevated ratios of delta 5-17P to 17-OHP (11 +/- 2.0; normal, 3.4 +/- 1.5) and DHEA to delta 4-androstenedione (7.5 +/- 2.3; normal, 4.6 +/- 1.5). In these hirsute women, the morning serum delta 5-17P and DHEA concentrations were elevated, had a diurnal variation, and were suppressed with dexamethasone administration. We propose that partial adrenal 3 beta-hydroxysteroid dehydrogenase deficiency is the cause of hirsutism in these women. This may represent an allelic variant at the genetic locus for 3 beta-hydroxysteroid dehydrogenase deficiency similar to that reported for symptomatic nonclassical 21-hydroxylase deficiency producing peripubertal excess androgen syndrome.