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Background: The preferred treatment of Cushing's disease (CD) nowadays is transsphenoidal pituitary surgery (TPS). Prior to TPS, patients at the Leiden University Medical Centre were treated by unilateral adrenalectomy followed by external pituitary irradiation (UAPI). We report on long-term results of both UAPI and TPS and compare remission, relapse rates, and complications., Patients and Methods: A retrospective study was carried out on 130 patients with CD. Patients with pituitary macroadenoma were excluded. Eighty-six and 44 patients underwent UAPI and TPS, respectively. Of these patients, 85 and 41 were evaluable for long-term results., Results: Remission following UAPI and TPS was identical at 64% (54/85 and 27/41). Cumulative relapse was also comparable - 17% (9/54) and 22% (6/27), respectively, - for UAPI and TPS, although the mean follow-up periods were different - 21.4 years and 8.5 years, respectively. Cumulative disease-free survival curves after UAPI and TPS are identical until 5 years of follow-up, but diverge thereafter indicating more sustained remissions following UAPI (P = 0.17, Wilcoxon statistic). Pituitary dysfunction following UAPI (36%) and pituitary surgery (55%) likewise did not differ significantly. However, pituitary dysfunction was an immediate event after TPS, whereas it developed after a mean interval of 17.8 years following UAPI.Low-dose dexamethasone testing during follow-up had no value in predicting therapeutic outcome., Conclusions: The results of unilateral adrenalectomy followed by external pituitary irradiation do not justify that this therapy is totally abandoned in favour of transsphenoidal pituitary surgery. Unilateral adrenalectomy followed by external pituitary irradiation is a valid therapeutic modality for the treatment of Cushing's disease, and could be considered as alternative to bilateral adrenalectomy and under some circumstances to transsphenoidal pituitary surgery.

The objective of this study was to present the long-term results of total adrenalectomy for Cushing's disease. Forty-four patients undergoing total adrenalectomy for Cushing's disease between 1953 and 1989 at Leiden University Medical Center, The Netherlands, were studied retrospectively. Remission was achieved in 42 patients (95%), with a mean duration of 19 years. Adrenal remnants were observed in 12 patients (27%), and were without clinical consequence in the majority of patients, but caused early recurrent disease in 2 patients. Nine patients (20%) experienced Addisonian crises up to 30 years following treatment. Nelson's syndrome developed in 10 patients (23%) 7-24 years following total adrenalectomy. Prior pituitary irradiation was a protective factor against Nelson's syndrome as it delayed its onset (p = 0.025). On the other hand, subnormal dose or noncontinuous glucocorticoid replacement therapy was associated with increased risk of development of Nelson's syndrome (p = 0.047). The incidence of Nelson's syndrome increased with prolonged follow-up, and female patients seemed to be at increased risk. Quality-of-life assessment showed less favorable scores on mental health and health perception scales, for which no explanation can be found except the long-lasting metabolic effects of Cushing's disease, even when successfully treated. In conclusion, total adrenalectomy remains the final treatment for Cushing's disease. The presence of adrenal remnants which can cause recurrent disease and the development of Nelson's syndrome during prolonged follow-up enhance the need for continued regular follow-up. Pituitary irradiation prior to total adrenalectomy delays the onset of Nelson's syndrome.

The effect of radiotherapy (24- > 50 Gy) on serum prolactin levels was studied in 28 patients with macroprolactinomas. All had been treated with surgery and 21 had also received bromocriptine interim therapy. Serum prolactin levels decreased in a log-linear fashion with time, both in the patients who never received bromocriptine and those who were treated with this drug. The decline rate of serum prolactin, which thus represented the effect of radiotherapy, was independent of intercurrent bromocriptine therapy, radiation dose and variables such as pre-radiation prolactin levels, tumour grade and tumour extension. During the course of follow-up (3-24 years) serum prolactin normalized in eight patients (28.6%). It is proposed to use the decline rates as a dynamic parameter to predict normalization time and time required for continuance of dopaminergic drug therapy.

Congenital adrenal hyperplasia is the most frequent cause of adrenal insufficiency and ambiguous genitalia in newborn children. In contrast to congenital adrenal hyperplasia due to 21-hydroxylase and 11 beta-hydroxylase deficiencies, which impair steroid formation in the adrenal cortex, exclusively, classical 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency affects steroid biosynthesis in the gonads as well as in the adrenals. The structures of the highly homologous type I and II 3 beta-HSD genes have been analyzed in three male pseudohermaphrodite 3 beta-HSD deficient patients from unrelated families in order to elucidate the molecular basis of classical 3 beta-HSD deficiency from patients exhibiting various degrees of severity of salt losing. The nucleotide sequence of DNA fragments generated by selective polymerase chain reaction amplification that span the four exons, the exon-intron boundaries, as well as the 5'-flanking region of each of the two 3 beta-HSD genes have been determined in the three male patients. The five point mutations characterized were all detected in the type II 3 beta-HSD gene, which is the gene predominantly expressed in the adrenals and gonads, while no mutation was detected in the type I 3 beta-HSD gene, predominantly expressed in the placenta and peripheral tissues. The two male patients suffering from severe salt-losing 3 beta-HSD deficiency are compound heterozygotes, one bearing the frame-shift mutation 186/insC/187 and the missense mutation Y253N, while the other bears the nonsense mutation W171X and the missense mutation E142K. The influence of the detected missense mutations on enzymatic activity was assessed by in vitro expression analysis of mutant recombinant enzymes generated by site-directed mutagenesis in heterologous mammalian cells. Recombinant mutant type II 3 beta-HSD enzymes carrying Y253N or E142K substitutions exhibit no detectable activity. On the other hand, the nonsalt-losing patient is homozygous for the missense mutation A245P. This mutation decreases 3 beta-HSD activity by approximately 90%. The present findings, describing the first missense mutations in the human type II 3 beta-HSD gene, provide unique information on the structure-activity relationships of the 3 beta-HSD superfamily. Moreover, the present findings provide a molecular explanation for the enzymatic heterogeneity responsible for the severe salt-losing form to the clinically inapparent salt-wasting form of classical 3 beta-HSD deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)

Based on a large number of studies in various species, cholecystokinin (CCK) is considered to function as an important regulator of satiety. The present study was undertaken to determine the relationship between hunger score and basal and postprandial plasma CCK secretion, in six obese subjects before and after weight loss with modified fasting. Modified fasting (modifast, 240 kcal/day) for ten weeks induced a mean weight loss of 23 kg. The hunger score was reduced by about 75%. However, basal and plasma CCK release induced by 80 kcal of modifast were not different before and after ten weeks of modifast treatment. Thus, the reduction of hunger during modified fasting is not mediated by circulating CCK.

Many doctors frequently encounter hirsute patients. Quantification of hair growth may be useful for diagnosis and follow-up. To establish the reference range for distribution and density of hair in females, and to determine the regions yielding the best discrimination between normal and hirsute women, we studied the distribution and density of terminal hair on 12 body regions assessed on a scale of 0-4. Prospectively, 81 healthy female volunteers and 71 hirsute patients of child-bearing age and Dutch ancestry, who were not receiving medication, and who had not had a recent pregnancy were studied. The reference hair pattern was established for each body region, and the threshold value yielding the highest sensitivity and specificity to evaluate hirsutism was calculated. None of the women in the reference population displayed a score of more than 1 for chin, upper back, upper abdomen and upper arm, or more than 2 for upper lip, side-burns, chest, lower back, lower abdomen, thighs or forearm. The best discrimination between the reference and hirsute populations was obtained with the sum of the scores for four regions: upper lip, chin, lower abdomen and thighs. Independent assessment of hair growth by two investigators revealed excellent agreement. We conclude that a score of more than 1 for chin, upper back, upper abdomen and upper arm, or more than 2 for upper lip, side-burns, chest, lower back, lower abdomen, thighs or forearm is abnormal for Dutch women, and that assessment of hair growth on the upper lip, chin, lower abdomen and thighs is the most suitable way to evaluate hirsutism.

The presence of P-glycoprotein, associated with multiple drug resistance and present in the normal adrenal cortex, was studied in 15 cases of adrenocortical carcinoma. P-glycoprotein was found in eight tumours; no correlation was found with clinical presentation, steroid production or histological index. 10 patients received mitotane. Remarkably, 3 patients with P-glycoprotein-positive tumours achieved complete remission. On the other hand, 2 patients with P-glycoprotein-negative tumours showed progression of the disease despite mitotane treatment. These findings suggest that the expression of P-glycoprotein in adrenocortical carcinoma is not related to clinical manifestations, steroid production, histological index or response to mitotane therapy.

This report describes a patient with a recurring, one stemline-aneuploid, adrenocortical carcinoma. The condition showed a number of unusual characteristics over a period of 22 yr. It changed from a biochemically functioning, low-grade malignant tumour into a non-functioning malignancy with pronounced mitotic activity, accompanied by an ovarian carcinosarcoma 1 yr before death. Quality of life was reasonable for many years despite chemotherapy, consisting of a total of almost 10 kg of o,p'-DDD administered over a period of 8 yr, and the subsequent side effects (e.g. low T4; increased bleeding time). A reduced mineralocorticoid activity, induced by o,p'-DDD, was reversed after discontinuation of o,p'-DDD treatment. During o,p'-DDD administration the substitution requirements for both hydrocortisone and fludrocortisone acetate increased, leading to periods of hypoadrenocorticism with prerenal uraemia.

A large family with adrenoleukodystrophy is described and the case histories of two clinically symptomatic and related male patients are presented. Clinical, biochemical and genetic screening of their family demonstrated two clinically affected males, one biochemically affected male and five carrier females. Two women were symptomatic; one suffered an acute exacerbation. One female was diagnosed as a carrier, based on genetic analysis and the family history only. Endocrinological screening was performed in the five affected males, demonstrating an elevated adrenocorticotrophic hormone level and a normal cortisol level in two, as evidence of compensated adrenocortical failure.

We found that the distribution of the lipophilic chemotherapeutic agent o,p'-DDD (mitotane) among serum (lipo)proteins was altered in hypertriglyceridemia, with relatively more o,p'-DDD accumulating in the chylomicron and very-low-density lipoprotein (VLDL) fraction. Intralipid, an artificial chylomicron emulsion, or isolated VLDL could extract o,p'-DDD from the other serum (lipo)proteins. There was an inverse relationship between the relative amount of o,p'-DDD found in the fraction exhibiting a density of less than 1.006 g/ml (chylomicrons plus VLDL) and the relative amount observed in the LDL or HDL fractions of serum. Our results indicate that hypertriglyceridemia may impede the entry of o,p'-DDD into the brain or the adrenals. For therapeutic monitoring of o,p'-DDD levels in severe hypertriglyceridemia, we recommend that the chylomicron and VLDL fraction first be removed from the serum by ultracentrifugation.

In 3 patients with adrenocortical carcinoma the effects of long-term mitotane therapy on the serum levels of three hormone-binding globulins and vitamin D-binding protein were studied. Within the first month of treatment cortisol-binding globulin increased two to three times, in close correlation with sex hormone-binding globulin. The rises in thyroxine-binding globulin and vitamin D-binding protein were considerably less. Elevated cortisol-binding protein appeared to be associated with increased binding of cortisol, whereas the binding of thyroxine and vitamin D remained below normal. Binding proteins returned to normal in 2 patients within a year after mitotane discontinuation. This phenomenon of hormone-binding protein enhancement invalidates the use of total serum hormone levels to monitor the effects of mitotane on endocrine function and could provide an explanation for the increased cortisol substitution requirement during mitotane therapy.

After finding prolonged bleeding times in 2 patients treated with mitotane, we prospectively studied 7 patients with adrenocortical cancer on mitotane therapy. Before and 1 and 2 or more weeks after starting mitotane we determined the platelet counts, bleeding times and global coagulation parameters. All patients had a normal bleeding time before treatment. In 6 cases the bleeding time became prolonged (245-555 s). 4 patients exhibited platelet aggregation responses compatible with an aspirin-like defect. It is concluded that mitotane may cause a clinically relevant defect of platelet function.

Data are presented concerning a 60-year-old woman with untreated congenital adrenocortical hyperplasia due to 21-hydroxylase deficiency, who presented with a tumour of the left adrenal gland. Steroid excretion was partly suppressed with dexamethasone. After removal of the tumour, the excretion of several steroid fractions decreased substantially, but suppression by dexamethasone remained inadequate. Preoperatively, plasma ACTh was elevated in the afternoon and decreased only slightly after dexamethasone administration. After surgery, cortisol secretion decreased markedly, whereas ACTH dysregulation became more prominent. Negative feedback failure precluded the use of normal suppressive therapy with low doses of glucocorticosteroids and led to the therapeutic removal of the right adrenal gland, which showed histological signs of nodular hyperplasia.

Thirty-four patients with adrenocortical carcinoma were treated with o,p'-DDD. Twenty-eight patients presented with metastases at entry, and spillage of tumour cells occurred at surgery in 6 other patients. Eight patients had objective tumour regression, of whom 7 had serum levels over 14 micrograms/ml. The 3 patients with a lasting remission had levels of greater than 15, greater than 25, greater than 25 micrograms/ml respectively during prolonged periods. Increased survival times were found in the group of 14 patients with o,p'-DDD serum levels higher than 14 micrograms/ml when compared with patients not treated after discovery of metastases. In the patients with levels less than or equal to 10 micrograms/ml no therapeutic effect was seen. Levels of over 20 micrograms/ml are associated with symptoms of reversible neuromuscular toxicity. Monitoring of serum levels during treatment is mandatory. It is suggested that serum levels of about 25 micrograms/ml during longer periods may be curative.

We describe a patient who suffered from ophthalmic trigeminal neuralgia as an isolated symptom of a noninvasive pituitary tumor. Bromocriptine appeared to provoke the attacks within hours. This provocation could be prevented by domperidone. After adenomectomy, both spontaneous and induced attacks disappeared. Acute transient cell swelling may be the mechanism by which bromocriptine induced the neuralgic attacks.

The plasma growth hormone profiles and sleep patterns of 13 treated male acromegalic patients, aged 29-67 years, were studied. All patients had undergone selective pituitary transsphenoidal surgery 4-9 years previously; five patients had also undergone supplemental pituitary irradiation. Blood samples were taken at 20-min intervals; the sleep patterns were obtained by EEG. GH reserve was assessed after insulin-induced hypoglycaemia and GHRH (1-44) with and without pyridostigmine. The profiles were analysed with the aid of the Pulsar program. Seven out of eight non-irradiated patients had 1-3 nocturnal GH peaks; in the irradiated group only one patient had a normal profile. The GH reserve after insulin-induced hypoglycaemia was normal in seven out of eight non-irradiated patients, and subnormal in all five irradiated patients. In the latter group the GH reserve was diminished when tested with GHRH. One patient from each group had a severe apnoea syndrome; in both cases there was no nocturnal GH increase. The percentage sleep stage 1 was lower for irradiated patients when compared with non-irradiated patients, but the 14 other sleep parameters did not differ. From this study we conclude that the physiological regulation of GH secretion is restored in surgically treated patients. Radiation therapy may lead to pituitary and hypothalamic damage, which could affect spontaneous GH secretion.

Although CT should be used as the initial procedure, MRI potentially can identify most adrenal masses without the hazard of ionizing radiation or the injection of iodinated contrast material.

Over a 6-year period, 25 patients with non-functioning pituitary adenomas were treated with bromocriptine, while 18 other patients with this condition underwent surgery as the first therapeutic modality. The medically treated group, consisting of those patients without alarming eye symptoms, was analysed in retrospect. Eight of these patients had previously undergone surgery and radiotherapy. Bromocriptine was used in a dose of 5 to 22.5 mg per day; the mean duration of treatment was 18 months. For 11 patients, radiological findings obtained during the year before treatment with bromocriptine revealed progression in five cases and stable tumour size in the others. Three of the five patients with progression showed tumour size reduction during bromocriptine therapy while no further growth occurred in the other two. When medication was stopped in one responding patient, the tumour grew again. One other patient, without pretreatment radiological investigation, exhibited tumour size reduction during bromocriptine therapy, and one patient exhibited radiological progression during the study period. In one case visual fields improved and in one other deteriorated without parallel changes in tumour size on computerized tomography. The favourable reactions were equally divided between the groups with and without previous radiotherapy. We conclude that bromocriptine is rarely capable of reducing the size of non-functioning pituitary adenomas (16% in this series). However, pituitary adenomas exhibiting recent growth may be sensitive to this drug, leading to size reduction or growth arrest.

Report of a 61-year-old man with progressive mental deterioration and flexion contractures of abdominal muscles and legs as initial signs of hypopituitarism. Five years after onset of symptoms, an endocrinologically non-functioning pituitary adenoma was demonstrated. Thyroid replacement therapy had no effect, but administration of hydrocortisone was followed by rapid recovery. The opportunity to treat such cases of curable dementia is easily missed.

The distribution of o,p'-DDD in various body compartments of patients being treated for metastatic adrenocortical carcinoma was studied. A highly significant semilogarithmic relationship was found between plasma and adipose tissue concentrations during therapy and between plasma and brain at autopsy. A linear relationship was found at autopsy between concentrations in adipose tissue and those in various other tissues, such as tumour and brain. The semilogarithmic relationship can be explained by the assumption of two plasma pools for o,p'-DDD, one with low affinity and high capacity and one with high affinity and low capacity. Plasma concentrations must be carefully monitored to obtain an impression of the tumour concentration and to detect impending central nervous system intoxication.

Thirteen adult patients with biochemically proven congenital adrenal hyperplasia (CAH) were examined by computed tomography (CT). Six patients had never received glucocorticoid therapy. In three of those six patients, CT revealed a tumorous transformation in one of the hyperplastic adrenal glands. In the seven patients with CAH who were treated since childhood, no mass could be demonstrated on CT. The development of an adrenocortical tumour due to chronic adrenal cortical stimulation by excessive adreno-cortico-trophic hormone (ACTH) production in adult patients with untreated CAH may not be a rare occurrence, as is demonstrated in this series. It is important not to confuse this entity with a primary virilizing adrenal tumour which requires a different form of treatment. In case of tumorous transformation in untreated adults with CAH, suppressive therapy with CT control should be favoured over surgery, as long as the tumour is ACTH-dependent. Moreover, these observations illustrate the desirability of lifelong glucocorticoid therapy in patients with CAH, including adult males who biochemically may not require suppression of steroid androgen excess.

A 19-year-old female, known to have had hypertension and hypokalemic alkalosis since the age of 9 months, was found to have suppressed renin, negligible plasma and urinary aldosterone and low plasma levels of other known sodium-retaining steroids. Despite the normal plasma cortisol the urinary excretion of 17-oxosteroids and 17-oxogenic steroids was low as was the cortisol secretion rate, suggesting a diminished metabolic clearance of cortisol. This was confirmed by the demonstration of a prolonged t 1/2 of 14C-cortisol. The abnormally high urinary excretion ratios of cortisol to cortisone, tetrahydracortisol to tetrahydrocortisone and 11-hydroxy-aetiocholanolone to 11-oxy-aetiocholanolone indicate that the diminished cortisol breakdown is the result of deficient 11 beta-oxidation. Moreover, the urinary excretion of free cortisol was elevated, probably due to diminished tubular reabsorption of cortisol. Hypokalemic alkalosis did not respond to spironolactone, but was partly corrected by amiloride. No response to dexamethasone was observed, but dexamethasone combined with aminogluthetimide normalized blood pressure and serum K. These findings support the involvement of a sodium-retaining, kaliuretic steroid in this rare syndrome.

Plasma levels of o,p'-DDD were measured after ingestion of a single oral dose. At the onset of therapy o,p'-DDD was administered as commercially available tablets and granules and in milk, chocolate, and an oil emulsion to 9, 12, 14, 10, and 6 patients, respectively. Following administration in chocolate, emulsion, and milk significantly higher mean plasma levels were recorded in the first 5- and 10-h periods than after tablets. Granules gave significantly lower plasma levels than all other forms. Plasma levels were also measured during maintenance therapy, when a total of 200 g o,p'-DDD was administered to 22 patients with adrenocortical carcinoma. The plasma disappearance rate after termination of long-term therapy was found to be between 18 and 159 days. The recovery of o,p'-DDD from faeces was about five times higher after ingestion of tablets than after administration in oil emulsion and milk. As far as the rapid increase in plasma levels and patient compliance are concerned, the best results were obtained with the milk powder mixture.

A urinary steroid profile from a patient with suspected 3 beta-HSD deficiency was prepared using capillary gas chromatography, employing only enzymatic deconjugation with Helix pomatia juice. In the chromatogram only very small peaks of dehydroepiandrosterone and 5-pregnenetriol were visible apart from other, for the diagnosis non-significant, peaks. However, after repeating the analysis including an additional solvolysis step, highly significant peaks of DHEA and 5-pregnenetriol became apparent, which suggests the necessity for a solvolysis step for a positive proof of 3 beta-HSD deficiency by urinary steroid profiling.

Three cases of pituitary adenoma with extension into the nasopharynx and nasal cavity are reported. The occurrence of this rare tumor underscores the need to consider a pituitary tumor whenever a patient presents with rhinologic complaints and destruction of the sellar floor. Epistaxis, although exceptional, may be the first manifestation of a pituitary tumor. Immunohistochemical analysis combined with staining for the pituitary hormones proved to be essential for reaching a definite diagnosis. Magnetic resonance imaging seems to be the modality of choice for differentiation between tumorous and nontumorous sinus obstruction.

This is a report of a case of almost complete external virilisation of a girl due to an adrenocortical adenoma of the mother. The tumour, though present for many years, caused only mild symptoms in the mother; therefore detection followed only after birth of the virilised girl.

Three adult patients with micropenis are described: two genetic females, reared as boys, with congenital adrenocortical hyperplasia (CAH), and one male with anorchia. The patients had a male gender identity/role. All three had established a satisfying heterosexual relationship. For only one of the patients intravaginal intercourse was possible. In one patient (with CAH), penile reconstructive surgery was attempted but failed. Nevertheless, he developed a satisfactory sexual relationship with a woman friend. This report illustrates that for patients with micropenis, penile reconstructive surgery is not obligatory for the establishment of a satisfying sexual relationship.