[Manifestations and prognosis of thyrotropin-secreting pituitary adenomas: a case series of three patients]. / Présentation et pronostic des adénomes thyréotropes: à propos de trois observations.

INTRODUCTION: Among pituitary adenomas, thyrotropinomas were previously considered as extremely rare and resistant to therapy. However, the common use of the sensitive TSH measurement and the improvement of pituitary imaging have modified their clinical and hormonal presentation. CASE REPORTS: We here report three cases of TSH secreting pituitary adenoma that highlight the great diversity of the clinical, hormonal and morphological presentation, and their better prognosis. In the presence of an inappropriate TSH secretion, the main differential diagnosis is the syndrome of thyroid hormone resistance. The role of somatostatin analogue prior to the surgical treatment of TSH secreting pituitary adenoma is also underlined in this report. CONCLUSION: The increasing frequency and early diagnosis of TSH secreting pituitary adenoma may be explained by ultrasensitive methods now used for TSH measurement and progress in pituitary imaging, mainly with MRI. This changing spectrum in the presentation and the excellent response to somatostatin analogues improved in the prognosis of the disease.

Luteinizing hormone pulsatility in patients with major ovarian hyperandrogenism.

Hyperandrogenism and ovulatory dysfunction are common in women with either polycystic ovary (PCOS) or ovarian virilizing tumor. However, contrasting with the numerous studies that have extensively described gonadotropin secretory abnormalities, principally increased LH pulse amplitude and frequency, few studies have concerned gonadotropin secretion in patients with ovarian virilizing tumors; low gonadotropin levels have occasionally been reported, but never extensively studied. The goal of the present study was to further evaluate the pulsatility of LH secretion in women with ovarian virilizing tumor compared with that of PCOS patients. Eighteen women with major hyperandrogenism (plasma testosterone level >1.2 ng/ml) were studied (5 women with ovarian virilizing tumor, 13 women with PCOS, and 10 control women). Mean plasma LH level, LH pulse number and amplitude were dramatically low in patients with ovarian tumors when compared to both PCOS (p<0.001) and controls (p<0.001). In case of major hyperandrogenism, LH pulse pattern differs markedly between women with ovarian virilizing tumor or PCOS, suggesting different mechanisms of hypothalamic or pituitary feedback.

[Cushing's syndrome and adrenal insufficiency in pregnancy]. / Pathologie de l'axe corticotrope et grossesse.

During pregnancy, major changes of the corticotroph axis activity are observed. The placenta synthetizes Corticotropin-Releasing Hormone (CRH) and pro-opio-melanocortin (POMC), and the plasma levels of both peptides are highly increased during pregnancy. The cortisol plasma levels are two-fold elevated compared to the levels observed in non pregnant women. This increase in cortisol level is mainly due to the doubling of the Cortisol Binding Globulin (CBG). Untreated Cushing's syndrome during pregnancy is associated with a high maternal as well as fetal morbidity (hypertension, preeclampsia, diabetes mellitus, premature birth.). Adrenocortical tumors are the major cause of Cushing's syndrome diagnosed in pregnancy. The treatment of hypercortisolism during pregnancy required a multidisciplinary approach by highly specialized teams. Adrenal insufficiency is rarely diagnosed during pregnancy. Untreated adrenal failure is associated with a high maternal and fetal morbidity and mortality. On the other hand, steroid replacement therapy appropriately monitored during pregnancy is associated with a very favorable outcome in pregnant women with adrenal insufficiency. During labor steroid replacement therapy should be adapted as for any surgical procedure.

Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Complete analysis of the CYP21 gene was performed in 56 unrelated French women with symptomatic nonclassical congenital adrenal hyperplasia. The mutational spectrum and the phenotype-genotype correlation were examined. The overall predominant mutation was V281L, which was present on 51% of alleles and in 80% of women. Three novel mutations were found: L317M, R435C, and a 5'-end gene conversion. Sixty-three percent of the women were carrying a severe mutation of the CYP21 gene, and hence risk giving birth to children with a classical form of the disease. In such cases, screening for heterozygosity in the partner is crucial. Potential genotype/phenotype correlations were examined by classifying the patients into three groups according to the CYP21 allelic combinations: A (mild/mild), B (mild/severe), and C (severe/severe). Primary amenorrhea was more frequent, and mean basal and stimulated 17-hydroxyprogesterone levels were higher in compound heterozygotes for mild and severe mutations (group B) compared with women with two mild mutations (group A), but there was a considerable overlap for individual values. Surprisingly, in two women, a severe mutation was found on both alleles (group C). Therefore, the phenotype cannot be accurately predicted from the genotype. Variability in phenotypic expression may be conditioned by mechanisms other than genetic heterogeneity at the CYP21 locus.

[Diabetes insipidus with a hypothalamo-hypophyseal morphologic anomaly during a pregnancy]. / Diabète insipide avec anomalie morphologique hypothalamo-hypophysaire au cours d'une grossesse.

BACKGROUND: Diabetes insipidus is uncommon in pregnancy. Despite physiological modifications in hydroelectrolytic balance during normal pregnancy, the capacity of the kidney to concentrate urine is preserved, partially due to lower vasopressin secretion. CASE REPORT: A young woman developed diabetes insipidus during the third trimester of normal pregnancy. The disease regressed totally after delivery. However, magnetic resonance imaging revealed a persistent expansive intrasellar image with a high-intensity signal. DISCUSSION: Onset of diabetes insipidus is usually rapidly progressive in pregnancy. Occurring generally during the third trimester in normal pregnancies, diabetes insipidus is generally well tolerated and responds to dDAVP, usually without pituitary abnormally, and regresses after delivery. Two types are distinguished: partially latent diabetes insipidus occurring during pregnancy and due to a central rather than nephrogenic origin; and excessive vasopressinase activity leading to diabetes insipidus usually associated with liver anomalies and high frequency of pre-eclampsia. During normal pregnancy, the size of the anterior pituitary increases and the normal high-intensity signal in the posterior pituitary seen on MRI usually regresses or disappears. In diabetes insipidus, the posterior pituitary hypersignal image generally disappears, reflecting reduced vasopressin storage. Few observations of diabetes insipidus occurring during pregnancy have been reported with morphological explorations. Most have described a "normal" aspect of the pituitary, specifically in the post partum period. In our patient, the weak vasopressin response to the end of water restriction at post partum when the diabetes insipidus symptoms had disappeared would suggest partial central diabetes insipidus revealed by pregnancy. Other pathologies involving this region could also be involved due to the unusual and persistent sellar image, with an expansive process showing a high intensity signal on MRI. An asymptomatic craniopharyngioma cyst was hypothesized and would be more compatible with the observed symptoms.

[Differentiated thyroid carcinomas manifesting as toxic adenoma]. / Carcinomes thyroïdiens différenciés se manifestant comme un adénome toxique.

BACKGROUND: Hot thyroid nodules are generally benign. We report two exceptional cases of thyroid carcinomas mimicking toxic adenomas. CASE REPORTS: A 35-year-old man and a 55-year-old woman had thyroid carcinoma behaving as an autonomously hyperfunctioning nodule. DISCUSSION: Only twenty similar cases have been reported in the literature. While a hot nodule on radio-iodine scan is unlikely to be malignant, the possibility of carcinoma should not be overlooked. Surgery should therefore be the preferred treatment of toxic adenoma.

[Prolactin adenoma developed during puberty. Diagnosis and long-term course. 9 cases]. / Adénomes à prolactine développés pendant la puberté. Diagnostic et évolution à long terme. 9 observations.

Nine patients (2 boys, 7 girls) with prolactinomas diagnosed at puberty were followed for 2 to 20 years. The presenting signs were sexual infantilism (n = 2), amenorrhea-galactorrhea (n = 6) and hypogonadism (n = 1). Growth retardation was also present in 3 cases. The pituitary tumor induced endocranial manifestations in only 2 cases, whereas a suprasellar extension was found in 5 cases with visual field defects in 2 cases. Initial prolactin levels ranged between 132 and 2,400 ng/ml and were unresponsive to TRH (n = 6/7). The hormonal work-up showed decreased GH (n = 4/4); LH, FSH (n = 9/9) or ACTH, TSH (n = 1/9) functions. Seven patients underwent trans-sphenoidal adenomectomy associated with dopaminergic agonist treatment. Two patients were treated with bromocriptine. In the long term, clinical signs (n = 6), hyperprolactinemia (n = 7) or prolactinoma (n = 4) persisted or recurred. These data stress the severity of this disease at this period of life, the therapeutic difficulties and the need for long term follow up of these patients.

[Cushing syndrome during pregnancy. New diagnostic methods used in 3 cases of adrenal cortex carcinoma]. / Syndrome de Cushing pendant la grossesse. Nouvelles méthodes diagnostiques appliquées à 3 cas de carcinome du cortex surrénalien.

Cushing's syndrome during pregnancy is most often caused by an adrenal cortical tumour; it is a rare event which bears poor foetal and maternal prognoses. We report 3 cases of adrenal cortex carcinoma diagnosed during pregnancy (after 24, 27 and 28 weeks respectively of amenorrhea) and revealed by local tumoral signs in 2 cases and by pulmonary embolism in the third. Because hair growth was moderate and weight gain as well as high blood pressure had mistakenly been attributed to the pregnant state, these clinical features of hypercortisolism has only lately been related to tumoral secretion. The hypercortisolic state was firmly established by comparing the patients' urinary cortisol levels (677, 941 and 2,167 micrograms/day) and 20-hour salivary cortisol levels (9.9, 15 and 25.3 micrograms/ml) with values obtained in women at the same stage (88 +/- 11.4 micrograms/day and 2.31 +/- 0.25 micrograms/ml). The aetiological diagnosis was made by the finding of a highly increased salivary testosterone levels (50, 34 and 95 pg/ml; normal = 8.6 +/- 4 pg/ml), and by magnetic resonance imaging which showed unilateral adrenal masses of 3, 8 and 20 cm in diameter respectively. These 3 cases illustrate the difficulty of the clinical diagnosis of hypercortisolism during pregnancy. Assessment of the unbound steroids and magnetic resonance imaging are the most useful methods for an early diagnosis, thus preventing the severe complications which may otherwise reveal this rare pathological condition.

Cushing's syndrome and pregnancy: aetiologies and prognosis in twenty-two patients.

OBJECTIVE: The association of an active Cushing's syndrome and pregnancy is a rare event which raises specific diagnostic difficulties and bears poor maternal and foetal prognoses. We report our series of 22 patients. PATIENTS: Age range was 19-34 (mean +/- SEM = 27.3 +/- 1.5) the onset of hypercorticism occurred before the pregnancy (n = 2), during the pregnancy (n = 15) or in the early post-partum (n = 5). The diagnosis was made during the pregnancy of 4 patients and in the post-partum of 18. RESULTS: Cushing's syndrome was revealed by the local manifestations of an adrenocortical tumour in 3 patients and by the clinical features of hypercorticism in 19 patients: mainly morphological changes (n = 19), high blood pressure (n = 12), and/or accelerated hair growth (n = 7). Aetiological distribution was noteworthy by the unusual predominance of primary adrenocortical tumours (n = 16) especially adrenocortical carcinomas (n = 8). Cushing's disease was present in only 4 patients and in 2 an ectopic ACTH secretion was observed. This association implied a high rate of complications for the mother: high blood pressure (n = 12), diabetes (n = 3), preeclampsy (n = 3) and pulmonary embolism (n = 1) and for the infant: prematurity (n = 16), hypotrophy (n = 4), adrenal insufficiency (n = 1), virilization (n = 1), stillbirth (n = 1). During their pregnancy 18 patients had a symptomatic treatment while only 4 patients (3 with adrenocortical carcinoma and one with an ACTH-secreting phaeochromocytoma) had a unilateral adrenalectomy. CONCLUSION: This condition is difficult to recognize: the diagnosis of Cushing's syndrome may be obscured by normal hormonal modifications of the pregnant state; it also forbears particular severity because of maternal and foetal complications, the unusual prevalence of malignant tumours and the particular difficulty in curing or merely controlling the hypercorticism.

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.

[Nodular adrenomegalies in congenital adrenal hyperplasia in adults. Implications]. / Adrénomégalies nodulaires au cours des hyperplasies congénitales des surrénales chez l'adulte. Implications.

The presence of adrenal nodules in patients with congenital adrenal hyperplasia seems to be relatively frequent but is seldom reported. We observed such nodular formations in 3 women and 2 men aged from 19 to 71 years. Four patients had enzyme deficiency revealed in childhood (3 were deficient in 21-hydroxylase and 1 in 11-hydroxylase); the fifth patient had a virilizing form of an unrecognized 21-hydroxylase deficiency. In 3 patients the nodular formations had a diameter of 10 millimetres or less. In the other 2 patients the diameter was greater than 30 millimetres, and an adrenocortical adenoma was found at surgery. In one case a preoperative increase of medical treatment resulted in partial regression of the nodules. Our findings show that young subjects may have adrenal nodules, and their dependence on ACTH is discussed. We also discuss the possible influence of these nodules on the difficulty of medical treatment, the need for a life-long therapy and the necessity to look for a congenital adrenal hyperplasia when confronted with an "incidentaloma".

Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy.

Adrenocortical carcinoma is a rare tumor, and only limited information is available about its natural history and the effects of therapy. We studied 105 patients (75 female and 30 male; mean age, 46 years) with adrenocortical carcinoma who were referred to us between 1963 and 1987. The average duration of symptoms before diagnosis was 8.7 months. At the time of diagnosis, 68 percent of the patients had endocrine symptoms, and 30 percent had distant metastases. Hormonal studies showed that 79 percent of the tumors were functional. Eighty patients underwent surgery, and 59 also received the adrenal cytotoxic agent mitotane. The median disease-free interval after surgery was 12.1 months (range, 1 to 175). Tumor dissemination occurred in 82 percent of the patients, most commonly to the lung, liver, and adjacent organs. The median survival time was 14.5 months (range, less than 1 to 175), and the five-year survival was 22 percent. Age over 40 years and the presence of metastases at the time of diagnosis were the only factors recognized as indicating a poor prognosis. Mitotane controlled hormonal secretion in 75 percent of the patients. Eight mitotane-treated patients had partial tumor regression, but the drug did not have a significant effect on survival. We conclude that adrenocortical carcinoma carries a poor prognosis. Mitotane therapy may offer transient benefits, particularly in controlling endocrine symptoms.

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.

[Short term effects of ketoconazole in Cushing's syndrome]. / Effets à court terme du ketoconazole dans les syndromes de Cushing.

The effects of Ketoconazole (600 mg/day) were evaluated in 10 patients with Cushing's syndrome during a mean period of 4.5 weeks (range 1-12). The urinary free cortisol excretion (UFC) decreased by 21 +/- 15% (mean +/- SEM) (p less than 0.01) on day 1; 54 +/- 8% (p less than 0.0001) on day 2; 60 +/- 15% (p less than 0.0001) on day 3 and 87 +/- 3% (p less than 0.0001) on day 8 compared to baseline. Salivary cortisol at 0800 h decreased similarly. On day 3, 7 patients showed normal UFC values and on day 8, only 1 patient, with the ectopic ACTH syndrome, had persistent hypercortisolism. The cortisol decrease was associated with an increase in desoxycorticosterone values (p less than 0.01) and a decrease in dehydroepiandrosterone sulfate (p less than 0.001), delta 4 androstenedione (p less than 0.05) and testosterone (p less than 0.05). No significant variations were observed in ACTH, 11 desoxycortisol, aldosterone, plasma renin activity, corticosteroid-binding globulin and sex hormone-binding globulin. Side effects were few: mild clinical adrenal insufficiency (n = 5), oedema (n = 3) and reversible hepatic toxicity (n = 1). We conclude that Ketoconazole is an effective inhibitor of cortisol and androgens synthesis. It is well tolerated, rapidly effective and its efficacy persists unchanged for at least one month in all forms of Cushing's syndromes. For these reasons Ketoconazole may be a valuable drug for preoperative treatment of Cushing's syndrome.

Evening urinary free corticoids: a screening test in Cushing's syndrome and incidentally discovered adrenal tumours.

In this study, we investigated the usefulness of the determination of evening urinary free corticoids/creatinine in samples collected from 20.00 to 24.00 h as a screening test in Cushing's syndrome. In controls (N = 61) the ratio values ranged from 1.1 to 9.4 mumol/mol, whereas in patients with Cushing's syndrome (N = 20), they ranged from 27.5 to 855.5 mumol/mol. However, in 28% of patients with major obesity (greater than 50% overweight) and no hypercortisolism, the ratio values were between 9.4 to 27.8 mumol/mol. A short (10 days) hypocaloric diet induced a decrease in the values in 75% of these patients; the normal range was reached in 50% of them. In addition, the evening urinary free corticoids/creatinine was slightly abnormal in 8 out of 10 patients with incidentally discovered 'silent' adrenal adenomas, whereas it was normal in all 6 with other adrenal masses. In conclusion, evening urinary free corticoids/creatinine is easy to obtain and it reaches a higher sensitivity (100%) and specificity (97%) than the 24 h urinary free corticoids. In the case of borderline values, the presence of overweight should be taken into account.

[Adrenomegaly and other masses of the adrenal area. Diagnostic and therapeutic approaches]. / Adrénomégalies et autres masses de la loge surrénalienne. Approches diagnostique et thérapeutique.

During the 1982-1987 period 104 patients were surgically explored for a mass of the supra renal area. An adrenal tumor was found in 67%, an adrenal pseudo-tumor in 12.5%, a non adrenal pathology in 12.5%, and a tumoral involvement of the adrenal in 8%. Revealing circumstances were variable: 41% of the patients presented with endocrine symptoms (adrenal hypersecretion 83% or deficiency - 17%). In 30% abdominal pain was the chief complaint. In 24% the finding of the adrenal mass was totally fortuitous. In this latter circumstance the diagnostic difficulty is maximal and the strategy remains debated. Our approach would tend to be primarily surgical for fear of letting a malignant tumor evolve further.

[Tumor and pseudotumor lesions of the adrenal area not to be misdiagnosed]. / Lésions tumorales et pseudo-tumorales de la loge surrénalienne à ne pas méconnaître.

Thirteen patients with a mass in the adrenal gland area discovered at ultrasonography or computed tomography were studied. Hormone levels were normal in all but three patients with adrenal insufficiency. With the exception of three patients with metastatic tumours or adrenal lymphoma, all were operated upon on account of complications or for diagnostic purposes. The pre-operative diagnosis was confirmed by histology in 5 out of 10 cases (tuberculous abscess in 2, cysts in 2 and 1 haematoma in 1 case). In the remaining 5 cases the tentative diagnosis was erroneous: these patients had haematoma, neurofibroma, schwannoma, leiomyosarcoma and angiomyolipoma respectively. Thus, ultrasonography and computed tomography do not always differentiate between adrenal and extra-adrenal masses and between malignancy and non-malignancy; surgical excision therefore seems to be desirable in such cases.

Evaluation of diagnostic criteria for Leydig cell tumours in adult men revealed by gynaecomastia.

Gynaecomastia caused by Leydig cell tumours (LCT) in adult men may appear a long time before clinical evidence of testicular swelling. To evaluate the diagnostic criteria for LCT, hormonal status was studied in 14 cases and compared with results of a control group (CG) and 10 men with idiopathic gynaecomastia (IG). The mean plasma T level was significantly (P less than 0.005) lower in LCT (16.7 +/- 1.7 SEM nmol/l) than in CG (23.0 +/- 1.3 nmol/l). However, individual plasma T levels were in the normal range in 9/14 LCT. The mean plasma E2 level was significantly (P less than 0.001) higher in LCT (204.9 +/- 27.6 pmol/l) than in CG (87.9 +/- 7.7 pmol/l). However, individual plasma E2 levels were in the normal range in 5/14 LCT. In LCT, neither means of basal gonadotrophin levels nor the gonadotrophin responses to LHRH were different from CG. The mean of the plasma T responses to hCG did not differ between LTC, CG and IG. However the mean of E2 peak responses appeared significantly (P less than 0.005) higher in LCT (735.3 +/- 103.4 pmol/l) than in CG (420.5 +/- 40.4 pmol/l). The mean of the E2 peak responses was significantly (P less than 0.001) lower in IG (196.5 +/- 33.4 pmol/l) than in CG. Likewise the mean of plasma E2 levels, measured on day three following hCG administration, remained significantly (P less than 0.001) higher in LCT (662 +/- 94 pmol/l) than either in CG (228 +/- 14 pmol/l) or in IG (158 +/- 25 pmol/l). On day 3 following hCG administration, there was no overlap in individual plasma E2 levels between either LCT and CG or LCT and IG. In all LCT, plasma beta-hCG levels were in the normal range. A testicular echogram, performed in 12 LCT, confirmed the presence of a palpable tumour in 10 and revealed an occult tumour in two cases. We conclude that normal plasma beta-hCG levels, a prolonged plasma E2 response to hCG and testicular echogram appear to be the best criteria for early diagnosis of LCT responsible for gynaecomastia in adult men.

Late-onset adrenal hyperplasia in hirsutism.

We studied the incidence of late-onset adrenal hyperplasia as a cause of hirsutism, its association with the major histocompatibility complex, and its clinical expression. Twenty-four of 400 women seen because of hirsutism were found to have late-onset adrenal hyperplasia, diagnosed on the basis of a high plasma level of 17-hydroxyprogesterone, and its marked increase after ACTH stimulation. The degree of hirsutism varied widely. Plasma antigen levels were high, especially the level of androstenedione, whereas 5 alpha-reductase activity, considered to be a good index of peripheral androgen utilization, showed frequent normal or low values. The 24 patients were genotyped, along with 84 family members, and plasma hormones were measured in the family members. We found a high correlation between late-onset adrenal hyperplasia and HLA antigens B14 and Aw33. Similar biologic profiles were observed in the patients and those of their siblings who were HLA identical (n = 9), confirming that late-onset adrenal hyperplasia is linked to the histocompatibility complex. These nine siblings had no hirsutism. We therefore conclude that the role of skin sensitivity to androgens is important in determining the clinical expression of this disorder.