[Post-radiotherapy hyperthyroidism: a rare complication of cancer treatment in the child]. / Hyperthyroïdie post-radique: une complication rare du traitement des cancers de l'enfant.

UNLABELLED: Abnormalities of thyroid function, specially hypothyroidism, are common complications of head and neck irradiation for childhood cancer. Hyperthyroidism is rare and can be misdiagnosed. We report two observations of this condition. OBSERVATIONS: The first patient received conventional craniospinal irradiation for a localized medulloblastoma. Three years later, he presented with profuse sweating, irritability and paroxysmal tachycardia. Biologic evaluation revealed a peripheral hyperthyroidism. The patient was treated with antithyroidian hormonal treatment. The second patient received an irradiation for an undifferentiated nasopharyngeal carcinoma. Three years later, she developed a progressive thyrotoxicosis which was attributed to hyperthyroidism after six months of evolution. Hormonal treatment improved the clinical state after several weeks. CONCLUSION: Hyperthyroidism is a rare complication of head and neck irradiation. This condition justifies a periodic and prolonged evaluation of thyroid function.

[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.

[Magnetic resonance imaging in Cushing disease. Prediction of surgical results]. / Imagerie par résonance magnétique dans la maladie de Cushing. Prédiction des résultats opératoires.

OBJECTIVES: The purpose of the study is to determine if pituitary Magnetic Resonance Imaging (MRI) can predict the outcome of transsphenoidal surgery in patients with Cushing's disease. METHODS: Fifty four patients were divided in three groups according to MRI findings: those with a well circumscribed focal lesion clearly separated from the cavernous sinus (group 1, n = 24), those with adenomas in close contact with the cavernous sinus (group 2, n = 18), and those with no identified lesion (group 3, n = 12). RESULTS: The adenoma is found on the predicted side in 97,6% of the cases with positive MRI. A histologically proven adenoma is found in 96, 100 and 33% of the cases in groups 1, 2 and 3, with successful outcome in 91, 94 and 58% of the patients respectively. In group 2, surgery failed in a patient in whom tumoral tissue surrounded the internal carotid artery, but succeeded in two other cases in whom a MRI involvement of the cavernous sinus was suspected. CONCLUSION: We confirm the excellent localization value of MRI. Failure due to cavernous sinus involvement can be predicted only when MRI shows that the adenomatous tissue surrounds the carotid artery. In cases of negative MRI, the outcome is less favorable.

Comparison of computerized tomography and magnetic resonance imaging for the examination of the pituitary gland in patients with Cushing's disease.

OBJECTIVE: The vast majority of patients with Cushing's disease have a corticotroph adenoma, the selective removal of which, through the transsphenoidal route, has the potential to offer a definitive and complete cure. This study was designed to compare the diagnostic accuracy of computerized tomography (CT) and magnetic resonance imaging (MRI) to identify the presence, evaluate the size, and assess the topographic characteristics of pituitary corticotroph adenomas. METHODS: Forty-two patients with Cushing's disease were included in this prospective study, of whom 16 were subsequently explored transsphenoidally. Computerized tomography used a CE 12,000 CGR apparatus with 1.5-mm coronal slices and a 2-mm interslice gap. Magnetic resonance imaging used an MR Max 0.5T GE apparatus; adjacent 3-mm slices were obtained with a T1-weighted gradient echo before and after gadolinium injection. RESULTS: Lesions compatible with an adenoma were identified in 29 patients by MRI and in 21 patients by CT (69 vs 50%, P < 0.02). Seven macroadenomas were identified as well by the two methods. Eight of the 22 microadenomas detected by MRI were not identified by CT. Evidence for intracavernous tumour extension was found in nine patients: it was more frequently detected by MRI (8 patients) than by CT (4 patients). Fourteen patients with positive MRI had a pituitary examination: in one case the adenoma could not be reached because of purely suprasellar location; of the other 13 all were found by the surgeon and the surgical outcome was successful in 12 cases. CONCLUSION: MRI is superior to CT for the examination of the pituitary gland in patients with Cushing's disease.

[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.

[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.

[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.

Transsphenoidal pituitary surgery for the treatment of Cushing's disease: results in 64 patients and long term follow-up studies.

Transsphenoidal pituitary surgery was performed in 64 patients with Cushing's disease in search of a corticotroph adenoma. In 4 patients, profuse local bleeding prevented completion of the exploration. Of the 60 patients who had an adequate exploration, 4 could not be followed after surgery. Short term assessment of the surgical outcome (3-6 months postoperatively) was performed on 60 patients, including the 4 who had incomplete pituitary exploration. Forty-two patients (70%) were judged as immediate successes [urinary cortisol excretion, less than 90 micrograms (less than 248 nmol)/day]; the mean urinary cortisol excretion and plasma ACTH level fell from 463 +/- 70 (+/- SE) to 26.7 +/- 3.6 micrograms/day (1277 +/- 193 to 74 +/- 10 nmol/day; n = 33) and from 111 +/- 33 to 36 +/- 14 pg/mL (24 +/- 7 to 8 +/- 3 pmol/L; n = 23) in patients who had both measurements pre- and postoperatively. Eighteen patients (30%) were judged as immediate failures; neither urinary cortisol excretion nor plasma ACTH levels changed significantly in patients who had both measurements pre- and postoperatively. The preoperative epidemiological, clinical, hormonal, and radiological characteristics of the 2 groups were similar. Histological examination of pituitary fragments removed in 58 of the 60 patients evaluated postoperatively revealed the presence of tumoral tissue in a higher percentage of patients in the immediate success group (72%) than in the immediate failure group (24%; P less than 0.01). The 42 patients in the immediate success group were followed from 6 months to 7 yr (median, 2 yr); 6 patients had recurrences from 2-3 yr after operation. Actuarial analysis indicates that the probability of a patient remaining well 6 yr after surgery is 72 +/- 20% (95% confidence limit). Most of the patients in the immediate success group had transient ACTH deficiency preceding a progressive return to normal pituitary-adrenal function.

Salivary cortisol measurement: a practical approach to assess pituitary-adrenal function.

The salivary cortisol concentration is an excellent indicator of the plasma free cortisol concentration. To establish its normal and pathological ranges, salivary cortisol concentrations were measured in 101 normal adults, 18 patients with Cushing's syndrome, and 21 patients with adrenal insufficiency. The normal subjects had a mean (+/- SEM) salivary cortisol concentration of 15.5 +/- 0.8 nmol/L (range, 10.2-27.3) at 0800 h and 3.9 +/- 0.2 nmol/L (range, 2.2-4.1) at 2000 h (n = 20). The mean value 60 min after ACTH administration in 58 normal subjects was 52.2 +/- 2.2 nmol/L (range, 23.5-99.4), and it was 1.4 +/- 1.1 nmol/L (range, 1.6-3) at 0800 h in 23 normal subjects given 1 mg dexamethasone 8 h earlier. In patients with primary or secondary adrenal insufficiency (n = 21) the mean salivary cortisol level was 7.5 +/- 0.4 nmol/L (range, 1.9-21.8) 60 min after ACTH. In patients with Cushing's syndrome (n = 7), the mean value after the 1-mg dexamethasone suppression test was 16.1 +/- 7.8 nmol/L (range, 5.8-66.8). No overlap was found between the values in the normal subjects and those in the patients during the dynamic tests. Discrepancies between salivary and total plasma cortisol were found in 8 patients with adrenal insufficiency, which may be explained by the effects of drugs such as thyroid hormones, Op'-dichlorodiphenyldichloroethane, and psychotropic agents. We conclude that salivary cortisol measurements are an excellent index of plasma free cortisol concentrations. They circumvent the physiological, pathological, and pharmacological changes due to corticosteroid-binding globulin alterations and offer a practical approach to assess pituitary-adrenal function.

[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.

[The hormonal state of pregnancy: modification of cortisol and testosterone]. / Etat hormonal de la grossesse: modification du cortisol et de la testostérone.

The pattern of cortisol and testosterone levels during the normal pregnancy was investigated by measuring these hormones in the same 19 healthy pregnant women at 11th to 19th, 24th to 29th and 34th to 39th week post amenorrhea. We noted the well-known increase in total plasma cortisol and testosterone, due to the elevated concentration of their transport protein, i.e., Corticosteroid Binding Globulin (CBG) and Testosterone Estradiol Binding Globulin (TeBG), consecutive to the increase in plasma oestrogens. Morning (8h) and evening salivary cortisol (20 h) values, which are a good reflect of free plasma cortisol, were found increased since the second trimester of pregnancy, with a conserved circadian cycle. 24 h urinary free cortisol was slightly increased since the first trimester, yet remaining within the normal range; in the late pregnancy it reached sometimes higher levels. "Vesperal" urinary cortisol measured on a collected urine sample between 20 h and 24 h was higher in pregnant women since the beginning of pregnancy as compared to that of non pregnant women. Levels of salivary free testosterone measured in a few patients appeared similar to that of non-pregnant controls. We also report the data obtained in two pregnant women with Cushing's syndrome due to an adrenocortical carcinoma which showed a strong elevation of urinary and salivary free cortisol while a pregnant woman with a luteoma had a lower level as compared to normal pregnant. Moreover these three patients had a marked increase in free salivary testosterone opposite to normal pregnant women.

[Rapid beta 1-24-corticotropin test in the exploration of the corticotropic axis. 71 cases]. / Le test rapide à la beta 1-24 corticotrophine dans l'exploration de l'axe corticotrope. Soxiante et onze observations.

The reliability of the beta 1-24 corticotropin test, which is both cheap and safe, in the assessment of the hypothalamic-pituitary-adrenocortical function was re-evaluated by comparing its results with those of the metyrapone test in 71 subjects: 30 controls and 51 patients with suspected pituitary-adrenal dysfunction. Response to a 500 micrograms intramuscular injection of beta 1-24 corticotropin was evaluated by measuring the 60 min plasma cortisol levels; 4.5 g of metyrapone divided into 6 doses were then administered orally and response was evaluated by measuring plasma 11-desoxycortisol levels. A highly significant correlation (r = 0.79; p less than 0.001) was observed between plasma cortisol and plasma 11-desoxycortisol levels. The results were best interpreted by expressing the values obtained as plasma cortisol concentrations which, in normal subjects are at least 21 micrograms/100 ml. The rapid beta 1-24 corticotropin test was found to be very reliable (sensitivity 90%, specificity 100%) to detect adrenal insufficiency, irrespective of the organs affected on the hypothalamic-adrenocortical axis.