Late-onset Adrenal Hyperplasia Research Articles

Cushing syndrome secondary to late onset adrenal hyperplasia: presentation and challenges of management

Cushing’s syndrome is a clinical disorder caused by overproduction of cortisol. Adrenal adenoma is the cause in 5% of cases of Cushing syndrome. ACTH-independent Cushing’s syndrome in 90% is caused by unilateral adrenal tumors. Of these, adenomas are the cause in 80% of the cases, while the others are adrenocortical carcinoma. Rare causes of Cushing’s syndrome include adrenal hyperplasia. Overproduction of cortisol results in weakened protein structures leading to protuberant abdomen and poor wound healing, glucose is converted to fat and deposited in the abdomen, supraclavicular fossa and cheeks. Other presentations are diabetes, hypertension, osteoporosis, fractures, impaired immune function, glucose intolerance, and psychosis. We report a 21-year-old female who presented with clinical symptoms of newly diagnosed hypertension and diabetes mellitus which after poor response to treatment she was evaluated and diagnosed to have Cushing syndrome. She subsequently had left adrenalectomy and did very well with resolution of patients’ symptoms. The histology came out to be diffuse adrenal hyperplasia.

IS SUBCLINICAL HYPOTHYROIDISM IN PATIENTS WITH POLYCYSTIC OVARY SYNDROME ASSOCIATED WITH BMI?

To investigate the impact of body weight on the subclinical hypothyroidism observed in patients with PCOS. The study included 95 normal weight (Group-1) and 122 overweight or obese women (Group-2) with PCOS. The control group consisted of age and BMI matched healthy individuals and grouped as normal weight (n: 66, Group-3) and overweight or obese (n: 65, Group-4. Women with chronic disease such as overt thyroid dysfunction, late-onset adrenal hyperplasia, and diabetes were excluded from the study. Plasma glucose and lipid profile, thyroid hormones, insulin, FSH, LH, total testosterone, estradiol, progesterone and DHEA-S were measured. While fasting glucose was similar, insulin and HOMA-IR were higher in Group-2 and Group-4 (p: 0.001). The groups were similar with respect to FSH, Estradiol, prolactine, DHEAS. While total testosterone and LH levels were higher (ptestosterone: 0,009), progesterone was lower in both PCOS groups (pprogesterone: 0.041). Free T3, free T4, thyroid antibodies were similar between the groups, but the prevalence of subclinical hypothyroidism was greater in Group-2 and -4 than in Group-1 and -3 (p: 0.044). TSH was only correlated with BMI (r: 0.122, p: 0.02). The increased prevalence of subclinical hypothyroidism in women with PCOS might be the result of increased BMI.

Hiperplasia adrenal congênita: dosagem da 17-hidroxiprogesterona basal para seleção e casos para realização do teste de estímulo com ACTH sintético

INTRODUCTION: adrenal hyperplasia is a common genetic disorder and 95% of the cases are due to a 21-hydroxylase deficiency. Clinical presentation varies from life-threatening salt-losing adrenal hyperplasia to simple androgenic states, which can be of late-onset and very similar to polycystic ovary syndrome. Diagnosis is usually made by synthetic ACTH provocative tests but efforts are being made to simplify this investigation. OBJECTIVE: to evaluate basal 17-hydroxyprogesterone as a predictor of the provocative test for the diagnosis of late-onset congenial adrenal hyperplasia. METHODS: A total of 122 patients under clinical suspicion of diagnosis of late-onset congenial adrenal hyperplasia were included and retrospectively evaluated in the study. Such suspicion included signs and/or symptoms of hyperandrogenism (hirsutism, acne, oily skin, menstrual irregularity etc.). All the patients were submitted to the 0.25mg synthetic ACTH provocative test (Synacthen®). After resting for 60 minutes, the samples were taken in the basal time and 60 minutes after the administration of 0.25mg synthetic ACTH, in order to assay 17-hydroxiprogesteron, the venous access being kept through a heparinized catheter. Radioimmuoessay was the method used to accomplish the assay of seric 17-hydroxiprogesteron. The sensitivity and specificity of the basal 17-hydroxiprogesteron were measured, assessing several cutoff points. ROC curves were made to analyze the test performance, using the software Medcalc®. RESULTS: ROC curve analysis showed that the best cutoff point was 181 ng/dl, which was very similar to the most common recommendation of 200 ng/dl of the literature. The cutoff point of 200 ng/dl shows positive and negative predictive values of 75 and 100%, and accuracy of 98,4% as a diagnostic test for late-onset adrenal hyperplasia. CONCLUSIONS: considering our data, we suggest that all hyperandrogenic patients should start the investigation with basal 17-hydroxyprogesteron and in case it is above 181 ng/dl, then they should do the synthetic 17-hydroxyprogesteron provocative test.

Urinary 6-sulfatoxymelatonin excretion in hyperandrogenic women: the effect of cyproterone acetate-ethinyl estradiol treatment.

Evidence for a relationship between melatonin and the reproductive hormones in humans is based on observations of abnormal melatonin secretion in clinical disorders of the pituitary-gonadal axis. The aim of this study was to investigate melatonin production in hyperandrogenic women before and during treatment with cyproterone acetate and ethinyl estradiol (Diane 35). Twelve women with polycystic ovary syndrome (PCOS), 10 women with idiopathic hirsutism (IH), and 10 women with late onset adrenal hyperplasia due to 21-hydroxylase deficiency (LOCAH) were studied. Patients were treated with Diane 35 for four months. Fasting blood samples for the determination of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and dihydroepiandrosterone sulfate (DHEAS) and 24-hour urine collections for the determination of 6-sulfatoxymelatonin (aMT6s) excretion were obtained from all patients at baseline and after 4 months of treatment. Results were compared with those obtained in 15 control women. At baseline, women with PCOS and LOCAH had significantly higher testosterone and aMT6s values than women with IH and controls. Diane 35 treatment significantly decreased testosterone, LH, FSH and aMT6s values in PCOS and LOCAH patients compared with pretreatment values. These results indicate that hyperandrogenic women with PCOS and LOCAH have increased melatonin production. The decrease in aMT6s excretion together with reduced serum LH, FSH, DHEAS and testosterone values during treatment with cyproterone acetate-ethinyl estradiol, suggest that sex steroids either directly or through the suppression of gonadotropins, modulate melatonin secretion in these patients.

Reproductive disorders in late-onset adrenal hyperplasia

Reproductive disorders in late-onset adrenal hyperplasia

The Frequency of Late-Onset 21-Hydroxylase and 11 beta-Hydroxylase Deficiency in Women With Polycystic Ovary Syndrome

Objective: To determine the frequency of late-onset adrenal hyperplasia (LOCAH) due to 21-hydroxylase (21-OH) and 11b-hydroxylase (11b-OH) deficiency in women with clinical and biochemical features of polycystic ovary syndrome (PCOS). Design: Eighty-three consecutively selected women with PCOS and eighteen normal women were included in the study. Methods: Ultrasound, clinical and hormonal parameters were used to define PCOS. Basal FSH, LH, testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S), sex hormonebinding globulin (SHBG) and cortisol levels were measured. Serum 17-hydroxyprogesterone (17-OHP) and 11-deoxycortisol (11-DOC) levels were also measured before, 30 and 60 min after a single bolus injection of 0.25 mg ACTH (1‐24) at 0900 h during the mid-follicular phase of the cycle. ACTHstimulated 17-OHP levels >30 nmol/l were considered as the criteria of 21-OH deficiency. The diagnosis of 11b-OH deficiency was made if the adrenal 11-DOC response to ACTH stimulation exceeded threefold the 95th percentile of controls. Results: Basal serum testosterone, free testosterone, androstenedione, DHEA-S, cortisol and 11-DOC levels were significantly higher in PCOS than in control subjects. ACTH-stimulated 17-OHP (P < 0:05) and 11-DOC (P < 0:0005) levels were found to be significantly higher in patients with PCOS than in controls. Seven (8.4%) patients had an 11-DOC response to ACTH higher than threefold the 95th percentile of controls, while no patients showed evidence of 21-OH deficiency. Conclusions: We have found that 8.4% of the women with clinical and biochemical features of PCOS could be presumed to have 11b-OH deficiency. No patients among the women with PCOS showed evidence of 21-OH deficiency. 11b-OH deficiency is unexpectedly more common than 21-OH deficiency in women with PCOS.

The frequency of late-onset 21-hydroxylase and 11 beta-hydroxylase deficiency in women with polycystic ovary syndrome.

To determine the frequency of late-onset adrenal hyperplasia (LOCAH) due to 21-hydroxylase (21-OH) and 11 beta-hydroxylase (11 beta-OH) deficiency in women with clinical and biochemical features of polycystic ovary syndrome (PCOS). Eighty-three consecutively selected women with PCOS and eighteen normal women were included in the study. Ultrasound, clinical and hormonal parameters were used to define PCOS. Basal FSH, LH, testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S), sex hormone-binding globulin (SHBG) and cortisol levels were measured. Serum 17-hydroxyprogesterone (17-OHP) and 11-deoxycortisol (11-DOC) levels were also measured before, 30 and 60 min after a single bolus injection of 0.25 mg ACTH (1-24) at 0900 h during the mid-follicular phase of the cycle. ACTH-stimulated 17-OHP levels > 30 nmol/l were considered as the criteria of 21-OH deficiency. The diagnosis 11 beta-OH deficiency was made if the adrenal 11-DOC response to ACTH stimulation exceeded threefold the 95th percentile of controls. Basal serum testosterone, free testosterone, androstenedione, DHEA-S, cortisol and 11-DOC levels were significantly higher in PCOS than in control subjects. ACTH-stimulated 17-OHP (P < 0.05) and 11-DOC (P < 0.0005) levels were found to be significantly higher in patients with PCOS than in controls. Seven (8.4%) patients had an 11-DOC response to ACTH higher than threefold the 95th percentile of controls, while no patients showed evidence of 21-OH deficiency. We have found that 8.4% of the women with clinical and biochemical features of PCOS could be presumed to have 11 beta-OH deficiency. No patients among the women with PCOS showed evidence of 21-OH deficiency. 11 beta-OH deficiency is unexpectedly more common than 21-OH deficiency in women with PCOS.

3β-Hydroxysteroid dehydrogenase deficiency in hyperandrogenism

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.

Fertility in Women With Late-Onset Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

Fertility was evaluated in 53 female patients with late-onset adrenal hyperplasia (LAH) due to 21-hydroxylase deficiency. The majority of patients (n = 33) were seen for isolated postpubertal hirsutism, 9 patients consulted for sterility, and 11 for irregular menstrual cycles. At the time of diagnosis, the ages of patients ranged from 15-40 yr (mean +/- SD, 24.6 +/- 5.2). No patient had major signs of virilization. The plasma 17-hydroxyprogesterone level was higher than normal in all patients (26.8 +/- 18.9 nmol/L; range, 3.4-139.4) and dramatically increased to 140.1 +/- 80.6 nmol/L (range, 35.2-324.2) after ACTH treatment. Plasma androgen levels were high (testosterone, 3.25 +/- 2.03 nmol/L; delta 4-androstenedione, 13.65 +/- 5.60 nmol/L). Plasma basal and LHRH-stimulated values were normal for FSH and high for LH. Basal and TRH-stimulated plasma PRL levels were normal. Among these 53 LAH patients, only 20 desired a pregnancy. These had a total of 38 pregnancies. Ten patients became pregnant before the ...

Fertility in women with late-onset adrenal hyperplasia due to 21-hydroxylase deficiency.

Fertility was evaluated in 53 female patients with late-onset adrenal hyperplasia (LAH) due to 21-hydroxylase deficiency. The majority of patients (n = 33) were seen for isolated postpubertal hirsutism, 9 patients consulted for sterility, and 11 for irregular menstrual cycles. At the time of diagnosis, the ages of patients ranged from 15-40 yr (mean +/- SD, 24.6 +/- 5.2). No patient had major signs of virilization. The plasma 17-hydroxyprogesterone level was higher than normal in all patients (26.8 +/- 18.9 nmol/L; range, 3.4-139.4) and dramatically increased to 140.1 +/- 80.6 nmol/L (range, 35.2-324.2) after ACTH treatment. Plasma androgen levels were high (testosterone, 3.25 +/- 2.03 nmol/L; delta 4-androstenedione, 13.65 +/- 5.60 nmol/L). Plasma basal and LHRH-stimulated values were normal for FSH and high for LH. Basal and TRH-stimulated plasma PRL levels were normal. Among these 53 LAH patients, only 20 desired a pregnancy. These had a total of 38 pregnancies. Ten patients became pregnant before the diagnosis of LAH and without any treatment; they had a total of 18 pregnancies, 12 of which were successful. Moreover, 19 normal pregnancies without any spontaneous abortion were carried to term by 14 of 16 hydrocortisone-treated patients. One patient needed the association of one cure of clomiphene citrate. Hypofertility in LAH patients seems, therefore, to be relative. Its mechanism is hormonal, with anovulation or dysovulation, due to the continuous steroid feedback of adrenal origin on the hypothalamo-pituitary axis. Hydrocortisone is the appropriate treatment in most cases, reducing adrenal androgen overproduction and relieving hypothalamic-pituitary gonadotropin function, thereby making possible cyclic ovarian activity and ovulations.

Fertility in women with late-onset adrenal hyperplasia due to 21- hydroxylase deficiency

Fertility in women with late-onset adrenal hyperplasia due to 21- hydroxylase deficiency

Hormonal profiles in Italian late-onset adrenal hyperplasia correlate with HLA class III polymorphisms.

To investigate the genetic polymorphisms of the HLA region in late-onset adrenal hyperplasia, 13 Italian patients affected by the disease were analyzed for: (1) HLA-A and -B typing; (2) restriction fragment length polymorphism (RFLP) of DR beta, DQ beta, DQ alpha, 21-hydroxylase A and B genes; (3) fourth complement fraction loci A and B (C4A and C4B), second complement fraction (C2) and properdin B factor (Bf) complement typing; (4) hormonal characteristics associated with some HLA haplotypes. HLA alleles B14 and DR beta 1 were found to be significantly more frequent in patients with respect to controls (relative risk: 8.7 and 7.2, p less than 0.001 and p less than 0.0001, respectively). Also C4B*2, 1 duplication was more frequent in patients than in normal subjects (23% vs. 1.5%, p less than 0.0001). Moreover, patients carrying a duplicated C4B (as well as those having the B14 antigen) showed higher 17-hydroxyprogesterone levels after ACTH stimulation. RFLP analysis of 21-hydroxylase genes with a specific probe revealed a duplication of 21-hydroxylase A gene in 40% of patients. All these individuals carried the C4A*2 B*2,1 phenotype and 75% of them displayed a clearly recognizable duplication at the C4B locus. These data support the hypothesis that in late-onset adrenal hyperplasia the 21-hydroxylase A pseudogene, even if inactive, may play a negative role in the regulation of 21-hydroxylase biosynthesis. Furthermore, we suggest analyzing class III phenotypes to screen the enzymatic defect.

Abnormalities of 21-Hydroxylase Gene Ratio and Adrenal Steroidogenesis in Hyperandrogenic Women with an Exaggerated 17-Hydroxyprogesterone Response to Acute Adrenal Stimulation*

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

Magnetic resonance imaging of the adrenal gland in women with late-onset adrenal hyperplasia

To determine the presence of structural abnormalities of the adrenal in late-onset adrenal hyperplasia, four consecutive patients were studied by MRI before beginning glucocorticoid replacement therapy. Three women were diagnosed as 21-hydroxylase deficient late-onset adrenal hyperplasia by a 17-OHP level greater than 1,000 ng/dL 30 minutes after acute adrenal stimulation, and one patient was diagnosed as 11-hydroxylase deficient late-onset adrenal hyperplasia when her 11-deoxycortisol level was threefold the upper 95th percentile of normal. Two patients with 21-hydroxylase deficient late-onset adrenal hyperplasia had normal adrenal glands on MRI. Another 21-hydroxylase deficient late-onset adrenal hyperplasia patient was noted to have a 2.5 x 3.3-cm left adrenal nodule, which had been documented some 4 years earlier on CT scan and had not changed in size during that interval. This patient was 40 years of age when the diagnosis of late-onset adrenal hyperplasia was established. The patient with 11-hydroxylase deficient late-onset adrenal hyperplasia demonstrated a diffuse enlargement of the left adrenal gland consistent with hyperplasia, with no focal lesions. In conclusion, although patients with late-onset adrenal hyperplasia may often demonstrate nodular or diffuse adrenocortical hyperplasia on MRI, not all patients with endocrinologically evident disease demonstrate such abnormalities, consistent with a lesser degree of ACTH stimulation compared with women with classical congenital adrenal hyperplasia.

11β-Hydroxylase deficiency in hyperandrogenism

to determine the 11-deoxycortisol (S) response and incidence of 11 beta-hydroxylase deficiency in hyperandrogenism. Hyperandrogenic women prospectively and consecutively underwent acute adrenal stimulation studies. Tertiary institution. Two hundred sixty women complaining of hirsutism and/or hyperandrogenic oligomenorrhea were studied, excluding five unrelated families (1.9% of total) suffering from 21-hydroxylase deficient late-onset adrenal hyperplasia. Forty-one healthy premenopausal eumenorrheic women served as controls. Only two unrelated women (0.8%) had a poststimulation or net increment S level value greater than or equal to threefold the upper 95th percentile of controls and were presumed to suffer from 11 beta-hydroxylase deficient late-onset adrenal hyperplasia. One hundred nine (42%) of hyperandrogenic women had at least one S value above the 95th percentile of controls. These women also demonstrated higher basal (F0) and stimulated cortisol levels, but a similar increment compared with controls. Patients with high S measures had higher testosterone, dehydroepiandrosterone sulfate, and androstenedione levels, but similar luteinizing hormone/follicle-stimulating hormone ratios, than hyperandrogenic cohorts with no abnormal S measures. Basal values of S (S0), F0, or S0/F0 were not useful to predict an abnormal S response to stimulation. Although adrenocortical hyperactivity was present in 42% of our hyperandrogenic patients, only 0.8% were presumed to suffer from 11 beta-hydroxylase deficient late-onset adrenal hyperplasia. A systemic search for this deficiency in hyperandrogenism is probably unwarranted.

Late onset adrenal hyperplasia: mutation at codon 282 of the functional 21-hydroxylase gene is not ubiquitous

Ten patients affected with 21-hydroxylase (21-OH) deficient late-onset adrenal hyperplasia were studied to determine the prevalence of a mutation at codon 281 of the functional 21-OH gene (CYP21B) that results in a valine to leucine amino acid shift. This mutation has been reported in eight unrelated late-onset adrenal hyperplasia patients of Ashkenazi Jewish descent possessing the human leukocyte antigen-B14,DR1 haplotype. Normally, there are two 21-OH genes; a pseudogene (CYP21A) and a functional gene (CYP21B). The aberrant codon 281 sequence is normally present only in CYP21A. In all of our late-onset adrenal hyperplasia patients, hybridization of an oligonucleotide probe specific for this mutation was demonstrated to CYP21A but not to CYP21B. The mutation at codon 281 of CYP21B does not appear to be a ubiquitous genetic marker for 21-OH deficient late-onset adrenal hyperplasia, suggesting that this disorder may demonstrate the same molecular heterogeneity as congenital adrenal hyperplasia.

Cyproterone Acetate versus Hydrocortisone Treatment in Late-Onset Adrenal Hyperplasia

Thirty late-onset adrenal hyperplasia patients consulting for isolated hirsutism were randomly divided into two groups; group 1 (n = 16) was treated with hydrocortisone in order to suppress androgen adrenal secretion, and group 2 (n = 14) received cyproterone acetate (CPA) antiandrogen therapy to inhibit peripheral androgen activity. The clinical and hormonal effects of each type of treatment were evaluated. Before treatment, the clinical and hormonal profiles of the two patient groups did not differ significantly. Excellent clinical evolution in terms of the regression of hirsutism was observed in the CPA-treated patients (54% decrease in the clinical score in 1 yr), in contrast with the slight decrease in hirsutism (26%) after hydrocortisone treatment. In hydrocortisone-treated patients, plasma androgen decreased to normal levels: testosterone from 3.05 +/- 1.45 to 1.46 +/- 0.42 nmol/L and delta 4-androstenedione from 13.6 +/- 4.1 to 6.33 +/- 1.47 nmol/L. Conversely, in CPA-treated patients, only a slight decrease in testosterone from 2.98 +/- 1.98 to 2.29 +/- 0.64 nmol/L and in delta 4-androstenedione from 12.9 +/- 5.9 to 9.86 +/- 2.23 nmol/L was observed. This slight decrease in plasma androgens contrasts with the rapid clinical improvement after CPA. These results emphasize the importance of peripheral receptivity to androgens in the clinical expression of hyperandrogenism. Moreover, they indicate that peripheral antiandrogen therapy may be more appropriate in late-onset adrenal hyperplasia patients than conventional adrenal inhibition using cortisone therapy.

Pseudogene / functional gene ratio in late-onset 21-hydroxylase-deficient adrenal hyperplasia

Late-onset adrenal hyperplasia caused by 21-hydroxylase deficiency leads to hyperandrogenic symptoms in 1% to 6% of hyperandrogenic women. Normally there are two 21-hydroxylase genes present in a 1 :1 ratio. Gene CYP21 A is a nonfunctional pseudogene, whereas CYP21 B is an active gene. Abnormalities of the CYP21A/CYP21 B gene ratio may serve as a marker for late-onset adrenal hyperplasia. Eight hyperandrogenic patients with late-onset adrenal hyperplasia and five control subjects were studied by evaluation of autoradiograms of Taq I and Kpn I digests by means of laser densitometry. Seven of eight (87%) patients with late-onset adrenal hyperplasia had an abnormal CYP21A/CYP21B gene ratio on laser densitometry, suggestive of CYP21A gene duplication, CYP21B gene deletion, or the conversion of a CYP21B gene to a CYP21A gene. One of the five control subjects had a heterozygous deletion of the CYP21A gene. The CYP21A/CYP21 B gene ratio may serve as a useful genetic marker for late-onset adrenal hyperplasia in a non-high-risk population.

Cyproterone AcetateVersusHydrocortisone Treatment in Late-Onset Adrenal Hyperplasia

Thirty late-onset adrenal hyperplasia patients consulting for isolated hirsutism were randomly divided into two groups; group 1 (n = 16) was treated with hydrocortisone in order to suppress androgen adrenal secretion, and group 2 (n = 14) received cyproterone acetate (CPA) antiandrogen therapy to inhibit peripheral androgen activity. The clinical and hormonal effects of each type of treatment were evaluated. Before treatment, the clinical and hormonal profiles of the two patient groups did not differ significantly. Excellent clinical evolution in terms of the regression of hirsutism was observed in the CPA-treated patients (54% decrease in the clinical score in 1 yr), in contrast with the slight decrease in hirsutism (26%) after hydrocortisone treatment. In hydrocortisone-treated patients, plasma androgen decreased to normal levels: testosterone from 3.05 +/- 1.45 to 1.46 +/- 0.42 nmol/L and delta 4-androstenedione from 13.6 +/- 4.1 to 6.33 +/- 1.47 nmol/L. Conversely, in CPA-treated patients, only a slight decrease in testosterone from 2.98 +/- 1.98 to 2.29 +/- 0.64 nmol/L and in delta 4-androstenedione from 12.9 +/- 5.9 to 9.86 +/- 2.23 nmol/L was observed. This slight decrease in plasma androgens contrasts with the rapid clinical improvement after CPA. These results emphasize the importance of peripheral receptivity to androgens in the clinical expression of hyperandrogenism. Moreover, they indicate that peripheral antiandrogen therapy may be more appropriate in late-onset adrenal hyperplasia patients than conventional adrenal inhibition using cortisone therapy.

21 -Hydroxylase Deficiency in Female Hyperandrogenism

21-Hydroxylase-deficient late-onset adrenal hyperplasia (LOAH) appears to affect 1-6% of hyperandrogenic women. Screening and diagnostic criteria for LOAH have not been well established, as these patients are clinically indistinguishable from other hyperandrogenic women. The following prospective study was undertaken to 1) determine the predictive value of screening hyperandrogenic women for LOAH with a morning follicular phase basal 17-hydroxyprogesterone (17-HP) level and 2) compare the various in vivo estimates of 21-hydroxylase activity after adrenal stimulation for the diagnosis of LOAH. Twenty-one euandrogenic control women (physically normal, without hirsutism, with regular menses, and a negative family history) were studied. The clinical population consisted of 164 consecutive unselected patients seen at the Division of Reproductive Endocrinology and Infertility of Johns Hopkins University School of Medicine between 1983 and 1987 demonstrating hirsutism and/or hyperandrogenic oligomenorrhea. Controls and patients underwent acute adrenal stimulation with 1 mg ACTH-(1-24), administered in the morning to fasting patients in the follicular phase of their menstrual cycle. Blood was sampled before and 30 min after ACTH-(1-24) administration. Steroid RIA determinations were performed for 17-HP, progesterone, testosterone, dehydroepiandrosterone sulfate, androstenedione, FSH, LH, and PRL. Three estimates of 21-hydroxylase activity were studied: the 17-HP level 30 min post-ACTH (17-HP30), the change in 17-HP (delta 17-HP0-30) and the summed rate of change in 17-HP and progesterone ([delta 17-HP0-30) + delta P0-30]/30 min). The upper 95th percentiles for these estimates of 21-hydroxylase activity in control women were 9.6 nmol/L (316 ng/dL), 8.8 nmol/L (292 ng/dL), and 0.39 nmol/L.min (13 ng/dL.min), respectively. Thirteen of 164 (7.9%) hyperandrogenic women had at least 1 abnormal 21-hydroxylase measurement. Four of these women (2.4%) had 17-HP measurements 3- to 20-fold above the upper normal 95th percentile (17-HP30 greater than 36.3 nmol/L or 1200 ng/dL) and were considered as suffering from LOAH. In our population the 3 measures of 21-hydroxylase studied clearly differentiated the LOAH women from all others, although a single 17-HP level 30 min post-ACTH was the simplest and most cost effective. Nine other hyperandrogenic women (5.5%) had at least 1 abnormal 21-hydroxylase measurement less than 3-fold the upper normal 95th percentile value and were designated as having mild 21-hydroxylase deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)