Pituitary-dependent Cushing's Disease Research Articles

Pituitary hyperplasia.

Comprehensive article summarizing more than 25 years of experience with pituitary hyperplasia in surgical material. Morphologic forms of hyperplasia--diffuse and nodular--are defined and, for comparison, the normal morphology, frequency and intraglandular distribution of cell types are briefly reviewed. All cell types can give rise to hyperplasia, although their frequency, extent and clinical importance widely vary. Somatotroph hyperplasia is rare; it is limited to cases of GHRH overproduction by extrapituitary endocrine neoplasms and sporadic examples of gigantism. Prolactin cells display the highest propensity for non-neoplastic proliferation. Physiologic hyperplasia occurs in pregnancy and lactation. Pathological hyperplasia is mostly secondary to other, neoplastic or non-neoplastic, space occupying processes. Idiopathic lactotroph hyperplasia is very rare. The much-disputed corticotroph hyperplasia is infrequent cause of pituitary dependent Cushing's disease. Despite difficulties of diagnosis in fragmented biopsies, several well-documented cases prove the existence of corticotroph hyperplasia which is nearly always nodular. Thyrotroph hyperplasia, secondary to hypothyroidism, a treatable condition, is not expected to occur in surgical material, yet several cases have been identified. Operated lesions are massive nodular leading to significant pituitary enlargement thereby mimicking TSH- or PRL-producing adenoma. Hyperprolactinemia is a frequent concomitant of severe thyrotroph hyperplasia. Gonadotroph hyperplasia and proliferation of pars intermedia derived POMC cells are not likely to occur in surgical material and have no clinical significance. Adenoma formation may rarely be associated with any type of pituitary hyperplasia.

Cushing's syndrome in pregnancy treated by ketoconazole: Case report and review of the literature

We report on a 30-year-old female with a pituitary-dependent Cushing's disease, who refused transsphenoidal surgery and was treated with ketoconazole and cabergoline. After approximately 3 years of therapy, the patient herself decided, without the knowledge of her treating physician, to interrupt contraception. As the patient became pregnant she ceased the intake of all medication (between the third and seventh week), but resumed it soon after pregnancy was diagnosed because of relapsing clinical signs. Pregnancy and vaginal delivery at 31 weeks gestation passed uneventfully. The newborn male infant did not demonstrate any congenital malformations and was normally sexually developed.With reference to this case, we discuss the difficulties in the medical treatment of Cushing's syndrome during pregnancy. Whereas outside pregnancy only efficacy and side-effects are taken into account, teratogenicity is an important question in these patients. Experience with different drugs is listed. This is only the second time that ketoconazole has been used during pregnancy for the treatment of Cushing's syndrome. We argue that ketoconazole may be safe as well as effective in pregnancy and, furthermore, without any consequences for the child.

Growth hormone and prolactin responses to corticotrophin-releasing-hormone in patients with Cushing's disease: a paracrine action of the adenomatous corticotrophic cells?

In patients with Cushing's disease multihormonal responses to ovine corticotrophin releasing hormone (oCRH) have been detected in blood from inferior petrosal sinuses. This finding has been explained by co-secretion of other hormones, in addition to ACTH, by the pituitary adenoma itself or by paracrine effects exerted by the adenoma on normal periadenomatous pituitary cells. To assess these hypotheses we compared the presence of a CRH induced GH and/or PRL response during inferior petrosal sinus sampling to the immunohistochemical detection of PRL and GH in adenomatous tissue removed from patients with Cushing's disease. Twenty-two patients with Cushing's disease and two patients with ectopic ACTH syndrome due to a bronchial carcinoid were studied; each patient had undergone preoperative inferior petrosal sinus sampling for diagnostic purposes with determination of GH and PRL in addition to ACTH, before and after administration of oCRH. Immunohistochemical studies for ACTH, GH and PRL detection were carried out on adenomatous tissue removed at surgery in the patients with pituitary dependent Cushing's disease and on the carcinoid tumours from the two patients with ectopic ACTH syndrome. All pituitary adenomas immunostained for ACTH, and four adenomas immunostained for GH or PRL in addition to ACTH. A PRL increase in the inferior petrosal sinus after oCRH administration was found in 11 of 22 patients, but none of their tumours immunostained for PRL. Immunostaining for PRL was found in the pituitary tumours from two patients but in neither patient was there a PRL response after oCRH. A GH response was found in 13 of 20 patients in whom it was sought; no patient showed immunostaining in their tumour. GH immunostaining was found in two tumours but in neither patient was there a GH response after oCRH. The oCRH-induced increase of GH and PRL was always recorded in the dominant inferior petrosal sinus. The ACTH response to oCRH was significantly higher in patients who showed oCRH induced increases in GH and/or PRL than in patients who did not, both in terms of area under the response-curve (22,032 +/- 9876 vs. 4371 +/- 2870 ng/l/10 min; P < 0.05) or mean percentage increase above baseline (754 +/- 229% vs. 147.2 +/- 67%, P < 0.02). A significant correlation was observed between ACTH and GH responses to oCRH. The two patients with ectopic Cushing's syndrome did not show ACTH, GH or PRL increases after oCRH administration and did not show immunostaining for GH or PRL in their tumours. The present data do not support the hypothesis of co-secretion of hormones by the pituitary adenoma as the cause of the GH and PRL responses to ovine corticotrophin releasing hormone observed in patients with Cushing's disease; it is suggested that a different mechanism, possibly involving an interaction between the ACTH secreting adenoma and the normal periadenomatous GH and PRL secreting cells, may be responsible.

ACTH precursors: biological significance and clinical relevance.

ACTH is synthesized as part of the precursor proopiomelanocortin or POMC (Fig. 1). In the human pituitary POMC is enzymatically processed to pro-ACTH, which is then cleaved to give ACTH. Processing of POMC in the pituitary takes place within the regulated secretory pathway and is accomplished by the protease PC1 located within mature dense core granules (Benjannet et al., 1991; Smeekens et al., 1991). The presence of ACTH precursors in plasma was first demonstrated in normal subjects after stimulation with metyrapone (Yalow & Berson, 1971) and was later observed after insulin-induced hypoglycaemia (Hale et al., 1986). However, complex chromatographic techniques were required to separate ACTH precursors from ACTH. Clearly, this approach could not be used for large numbers of patient samples and would not provide a quantitative assessment of the concentrations of the ACTH precursors in plasma. We have subsequently quantified the concentrations of ACTH precursors in the human circulation under basal conditions. Direct measurement of these peptides was made possible by the development of a two-site immunoradiometric assay for the ACTH precursors, POMC and pro-ACTH (Crosby et al., 1988). The assay is based on a labelled monoclonal antibody which binds within the ACTH region of POMC and a solid phase antibody which recognizes N-terminal POMC (N-POC, Fig. 1). As binding of both antibodies is required to generate a signal, the assay does not detect ACTH. Using this assay, the concentrations of ACTH precursors in normal subjects were found to be 5-40 pmol/l which is equivalent to or greater than those of ACTH, N-POC, b-lipotrophin (b-LPH) and b-endorphin (Gibson et al., 1994). The levels of ACTH precursors and ACTH in the circulation at any given time are dependent on regulatory mechanisms influencing expression of the POMC gene. However, the relative concentrations of ACTH precursors and ACTH will depend on precursor processing and mechanisms of secretion from the corticotroph cells. Evidence from studies with the mouse corticotroph adenoma cell line, AtT20, suggests that in the absence of stimulation, corticotroph cells ‘leak’ newly synthesized POMC (Kelly, 1985). Furthermore, results we have obtained in normal subjects and from clinical studies indicate that acute regulation of secretion of ACTH and ACTH precursors differs (see below).

O-11-158 - Treatment of pituitary-dependent Cushing's disease: Long-term outcome

O-11-158 - Treatment of pituitary-dependent Cushing's disease: Long-term outcome

Risk factors and long-term outcome in pituitary-dependent Cushing's disease.

Although transphenoidal pituitary microsurgery has become the treatment of choice in Cushing's disease, other procedures, such as bilateral adrenalectomy and pituitary irradiation, are currently in use in its management. Indeed, no treatment has proven to be fully satisfactory for this condition. The rates of cure and recurrence after pituitary surgery or irradiation and the incidence of Nelson's syndrome after bilateral adrenalectomy are still open issues. A population of 162 patients with pituitary-dependent Cushing's disease was studied at 1 institution and had a follow-up of at least 2 yr after treatment (median, 7 yr). Patients were divided in subgroups according to the type of treatment: transsphenoidal pituitary microsurgery, bilateral adrenalectomy, or pituitary irradiation. Survival analysis was employed to characterize the outcome of treatment in each subgroup. Predictive factors for success of pituitary surgery were also evaluated. The estimated cumulative percentage of patients remaining in remission after successful pituitary surgery (n = 79) was 93.7% after 2 yr, 80.6% after 5 yr, 78.5% after 7 yr, and 74.1% after 10 yr. Of 8 risk factors examined, the following attained statistical significance: age, clinical severity, presence of major depression, pre- and posttreatment urinary cortisol levels, and posttreatment ACTH level. Pituitary surgery was successful in 79 of 103 patients (76.7%). Surgical failure was significantly associated with lack of pituitary adenoma and the clinical severity and presence of major depression. Of patients treated by bilateral adrenalectomy (n = 63), the estimated cumulative percentage remaining free of Nelson's syndrome was 87.1% after 2 yr, 79.3% after 7 yr, and 71.2% after 10 yr. The occurrence of Nelson's syndrome was significantly related to the pretreatment urinary cortisol level and the presence of pituitary adenoma at previous pituitary surgery. After cure by pituitary irradiation (n = 23), the estimated cumulative percentage of patients remaining in remission was 100% after 2 yr, 81.8% after 5 yr, 71.6% after 7 yr, and 65.1% after 10 yr. Previous pituitary surgery, although unsuccessful, appeared to be a protective factor for relapse. The results indicate that relapse after cure by either pituitary surgery or irradiation is a considerable clinical problem that increases over time. Our findings ascribe new importance to the clinical presentation of patients and indicate subgroups that are at high risk for relapse after pituitary surgery or irradiation and for developing Nelson's syndrome after bilateral adrenalectomy.

Risk factors and long-term outcome in pituitary-dependent Cushing's disease

Risk factors and long-term outcome in pituitary-dependent Cushing's disease

Pre- and Postoperative Investigations of Hepatic Glucose Production and Leucine Turnover in Cushing's Disease Utilizing Stable Isotope Techniques

Impairment of glucose tolerance and muscle wasting indicating a disorder of glucose metabolism are characteristic features of Cushing's syndrome. We have examined glucose and amino acid metabolism in eleven patients with pituitary dependent Cushing's disease in comparison to nine healthy controls. Furthermore, the therapeutic effect of selective pituitary microsurgery was studied by repeated stable isotope measurements of hepatic glucose production and leucine turnover rates. Eight patients remitted after surgery and 3 had persistent disease. All patients were investigated prior to surgery and again 1 week and 3 months after the operation with (6,6-2H2)-glucose and (5,5,5-2H3)-leucine by means of a primed (4 mg/kg.min and 0.27 mg/kg.min), continuous (0.05 mg/kg.min and 0.005 mg/kg.min) infusion. In Cushing's disease, both the preoperatively elevated mean glucose production rate (2.34 +/- 0.63 mg/kg.min) and the reduced mean leucine turnover (0.213 +/- 0.025 mg/kg.min) were found to be linked with hepatic insulin resistance and an insulin-induced reduction in protein breakdown combined with a reduced protein synthesis. Mean glucose production and leucine flux both normalized after surgery in the remitting patients (2.18 +/- 0.15 mg/kg.min and 0.244 +/- 0.047 mg/kg.min 3 months after the operation). The metabolic disorders thus were reversible following successful correction of hormonal oversecretion by transsphenoidal surgery.

Ectopic ACTH syndrome.

Ectopic ACTH syndrome represents a cancer-induced amplification of a property [proopiomelanocortin (POMC) peptides production] normally present in the cells from which the cancer originated but with aberrant posttranslational processing of POMC resulting in a greatly elevated secretion of ACTH precursors. The classic ectopic ACTH-producing tumors described in the 1960s were highly malignant but more recently slowly growing tumors such as carcinoids are reported with increasing frequency. Clinical features of patients with ectopic ACTH were analyzed, including biochemical abnormalities, plasma ACTH, cortisol and urinary steroids. Dynamic tests such as high-dose dexamethasone suppression, metyrapone and ovine-CRH (oCRH) stimulation were explored, as well as inferior petrosal sinus ACTH sampling before and after oCRH. Among the tumor markers examined, elevation of ACTH precursors was uniformly present followed by increased output of calcitonin, gut hormones, oncofetal and placental hormones in decreasing order. Since more than 90% of ectopic ACTH tumors are neuroendocrine in nature exhibiting APUD characteristics, their 2 markers, neuron-specific enolase and chromogranins are very useful. The imaging procedures for localization of the tumor ranged from chest X-rays to computed tomography and magnetic resonance of the chest and abdomen. Abdominal ultrasonography was also useful. Finally somatostatin receptor scintigraphy permitted demonstration of unrecognized tumors and/or metastases, even when the tumors were occult. The ACTH content, immunostaining for APUD markers and altered POMC processing were evaluated in ectopic tumors and/or metastases. Occult ectopic ACTH syndrome of more than 4-6 months of symptoms without the emergence of an obvious source was reviewed. Since the tumors are often clinically and biochemically undistinguishable from pituitary-dependent Cushing's disease, inferior petrosal sinus sampling for ACTH after oCRH stimulation established the diagnosis in over 90% of the cases. 60% of the occult tumors were thoracic carcinoids (3/4 bronchial carcinoids), followed by small cell lung cancer and pancreatic neuroendocrine tumors. In 12% the primary etiology was not detected. The rare syndrome of ectopic CRH syndrome (6 published cases) leading to excessive stimulation of the pituitary which became hyperplastic and secreted excessive amounts of ACTH is discussed. Finally, the 12 published cases and 1 unreported patient with ectopic CRH-ACTH tumors were reviewed, the majority being metastatic small cell lung carcinomas, bronchial and thymic carcinoids.

Gamma knife surgery for Cushing's disease

BACKGROUND The efficacy of gamma knife surgery on Cushing's disease is not well known to date. In most reported cases of Cushing's disease treated with gamma knife, the area to be irradiated was determined with computed tomography or pneumoencephalography. We report two cases of recurrent pituitary-dependent Cushing's disease treated with gamma knife using stereotactic magnetic resonance imaging (MRI). MATERIALS AND METHODS Recurrent microadenomas were visualized as hypointense areas using gadolinium enhanced MRI after two transaphenoidal surgeries in both cases. The doses of irradiation given were 35 Gy and 20 Gy to the margin of the tumors, and less than 8 Gy and 21 Gy to the optic apparatus and cranial nerves in the cavernous sinus., respectively. RESULTS Both patients had clinical remission with normal serum cortisol and adrenocorticotrophic hormone levels, during 2-year follow-up after radiosurgery, without endocrinologic deficiency or neutrologic deterioration. CONCLUSIONS Gamma knife surgery can be an alternative therapy for Cushing's disease when pituitary adenomas are apart from the optic apparatus and can be visualized clearly by MRI, even if tumors are recurrent after microsurgery.

Role of bilateral adrenalectomy in Cushing's disease.

Of 206 patients with Cushing's syndrome observed from 1975 through 1991, 144 (69.9%) had pituitary-dependent Cushing's disease. Of the 110 patients who underwent pituitary surgery, 31 (28%) developed an early recurrence and 23 patients (20%) had a late relapse 1 to 5 years after primary pituitary exploration. We performed a one- or two-step total bilateral adrenalectomy in 43 patients-9 men and 34 (79.4%) women, with an average age of 47.5 years (range 13-58 years). Thirty-three of these patients had already been treated by previous transsphenoidal surgery or alternatively by external pituitary irradiation over a period of 1 to 10 years prior to adrenal surgery. Thirty-one patients underwent adrenalectomy by a double lumbar access or left lumbar and right subcostal incisions. In our series of 55 operations, perioperative complications included two splenectomies and two hemorrhages (7.3%). The early mortality rate was 3.6% (two patients). Minor complications consisted of wound infection (13.5%), bronchopneumonia or pneumothorax (four cases) with a 7- to 12-day longer hospital stay. Nelson syndrome occurred in 6 of 41 patients (14.6%). We therefore believe that bilateral adrenalectomy does play a major role in the treatment of patients with pituitary-dependent Cushing's disease unsuccessfully managed by transphenoidal surgery. It represents the definitive therapy for those patients in whom hypophysectomy was not able to provide satisfactory control of the disease.

Steroid biosynthesis inhibitors in Cushing's syndrome

About one-third of all patients with Cushing's syndrome cannot be cured by surgery (at the pituitary or adrenal level) or radiation therapy and are therefore candidates for medical treatment. As a conservative therapeutic approach to lower hypercortisolism, the use of steroid biosynthesis blocking substances has the greatest importance. Trilostane, an inhibitor of the adrenal 3β-hydroxysteroid dehydrogenase Δ5,4-isomerase system, has been studied in only a few patients with Cushing's syndrome and was not potent enough to normalize hypercortisolism, especially in patients with pituitary-dependent Cushing's disease.

The value of inferior petrosal sinus sampling in diagnosis and treatment of Cushing's disease.

While microsurgical selective adenomectomy is the best method available at present for the treatment of Cushing's disease, its success depends to a large degree on precise preoperative intrapituitary microadenoma localization. This study compares the results of intrapituitary adenoma localization obtained with inferior petrosal sampling, computerized tomography and magnetic resonance imaging with the adenoma localization as found at surgery. The results of inferior petrosal sampling for intrapituitary localization of ACTH-producing pituitary adenomas were compared in a retrospective study with the results of computerized tomography, magnetic resonance imaging, surgical and pathological findings. Special attention was paid to the intersinus ACTH relation. Thirty-eight patients (33 women and 5 men) of 11-68 years of age suffering from pituitary-dependent Cushing's disease were studied. Patients with ectopic ACTH-secreting tumours and recurrent pituitary adenomas were excluded. Blood samples were obtained simultaneously from both inferior petrosal sinuses and a peripheral vein before and 5, 10, 15 and 20 minutes after stimulation with 60 micrograms/m2 human corticotrophin-releasing hormone (hCRH). Of the adenomas in our series, 42% had a diameter of 3 mm or less. Only 6 of 20 adenomas examined by computerized tomography and 11 of 29 examined by magnetic resonance imaging were identified correctly. Inferior petrosal sinus sampling produced significantly better results, particularly when combined with a stimulation test with hCRH: for 29 of 38 adenomas examined, the location was predicted correctly with these techniques. Analysis of the intersinus adrenocorticotrophin concentration ratio showed that the best right-central-left discrimination was obtained with values of 1.3 and 1.4. We conclude that inferior petrosal sinus ACTH sampling after hCRH stimulation is the best method available for the intrapituitary localization of microadenomas causing Cushing's disease provided that the appropriate technique of blood sampling is used meticulously.

The radiological investigation of occult ectopic ACTH-dependent Cushing's syndrome

The radiological features of 14 patients with Cushing's syndrome due to 'occult' ectopic ACTH syndrome have been reviewed. In 11 of the 14 patients (79%), the ACTH-producing tumour was located in the thorax. Bronchial carcinoid tumours (eight patients) were the single most common source of 'occult' ectopic ACTH production with thymic carcinoid tumours (two patients) and mediastinal metastases from a medullary carcinoma of the thyroid gland (one patient) accounting for the other intrathoracic tumours. The tumours were usually small with five of the eight bronchial carcinoid tumours measuring between 4 and 10 mm in diameter. Since it remains difficult to distinguish between pituitary-dependent Cushing's disease and 'occult' ectopic ACTH-dependent Cushing's syndrome both clinically and biochemically, the role of radiology remains vital.

KETOCONAZOLE TREATMENT OF TWO ADOLESCENTS WITH CUSHING'S DISEASE

We evaluated the effect of ketoconazole (KT) treatment in two adolescents with pituitary dependent Cushing's disease. Case 1 :a girl, aged 12.9 years, was given orally KT (200 mg/day), which induced a significant decrease of plasma cortisol levels for 3-4 months (mean±SD: 29.1±8.3 at start vs 6.2±1.2 μg/dl at 3 months, p<0.01; blood samples were taken at 4-h intervals, 8 a.m.-12 p.m.) but not after 6 months(24.2 ± 4.0 μg/dl), despite an increase of KT dose up to 600 mg/day. Mean plasma ACTH levels were 36.2±4.7, 23.2±8.5 and 30.2±14.2 pg/ml, at start, 3 and 6 months, respectively. Similarly, in Case 2, a boy aged 14.8 years, KT (400 mg/day) reduced mean plasma cortisol levels for 3 months (25.8±2.3 vs 18.8±2.7 μg/dl; p<0.005) but not after 6 months (30.7±5.3 μg/dl), again despite an increase of KT dose up to 1000 mg/day. Mean ACTH levels remained unchanged for 3 months (45.1±5.3 at start vs 40.6±12.8 pg/ml at 3 months), but increased after 6 months (73.5±3.8 pg/ml; p<0.005 vs initial values). Both patients showed a good clinical improvement with reduction of body weight and normalization of blood pressure for six months; KT was well tolerated. Coincident with the reoccurence of clinical symptoms, magnetic resonance features of pituitary microadenoma became evident at six months and both patients underwent transsphenoidal surgery. Our experience shows that Ketoconazole may have a short reducing effect on plasma cortisol in children with pituitary dependent Cushing's disease while awaiting therapeutic surgery.

Investigation of Cushing's syndrome by inferior petrosal sinus sampling

Bilateral simultaneous inferior petrosal sinus sampling, in combination with CRH stimulation, is now able to confirm the diagnosis of pituitary-dependent Cushing's disease with near certainty. In expert hands, the procedure is straightforward and safe. As well as confirming the differential diagnosis, the test may aid surgical success, especially if no adenoma is apparent at transsphenoidal exploration. In this article, we review the technique and its interpretation and consider which patients should undergo the procedure.

A role for life events in the pathogenesis of Cushing's disease

We have previously reported on 30 patients with Cushing's syndrome suggesting an aetiological role for stressful life events. The investigation about life events in the year before the first signs of disease onset was extended to a larger population of patients with Cushing's syndrome, allowing us to differentiate patients with pituitary-dependent and pituitary-independent forms. Case-control study. Sixty-six consecutive patients with Cushing's syndrome of various aetiologies (46 with pituitary-dependent forms and 20 with primary adrenal hyperfunction or ectopic ACTH production) and a control group of 66 healthy subjects, matched for sociodemographic variables, were studied. Paykel's Interview for Recent Life Events (a semistructured research interview covering 64 life events) was administered after the acute phase of illness while in remission. Patients with Cushing's syndrome reported significantly more stressful life events (P < 0.001), both events that had an objective negative impact (P < 0.001) and independent events (P < 0.001), than controls, confirming previous findings. Patients with pituitary-dependent Cushing's disease were compared with their matched controls and reported significantly more total events, events with an objective negative impact and independent events (all at P < 0.001). There were no significant differences between patients with pituitary-independent forms and their matched controls. These findings indicate a causal role for stressful life events exclusively in pituitary-dependent Cushing's disease, and suggest a limbic-hypothalamic involvement in the pathogenesis of this condition. The results are similar to those obtained in major depression, and add to other analogies between the two disorders.

Hypercortisolism with non-pigmented micronodular adrenal hyperplasia: transition from pituitary-dependent to adrenal-dependent Cushing's syndrome

We report on a female patient with Cushing's syndrome in whom we observed the transition from pituitary dependency to adrenal dependency. Basal ACTH and cortisol values, the CRH test, the dexamethasone suppression test as well as CT of the pituitary and the adrenal gland all reflected pituitary-dependent Cushing's disease in 1985. The patient refused treatment, but presented again five years later. At that time ACTH was suppressed before and after CRH injection. Plasma cortisol did not respond to CRH. After ketoconazole therapy, ACTH was within the high normal range. The patient underwent bilateral adrenalectomy. The adrenals exhibited a bilateral micronodular hyperplasia of the zona fasciculata. In vitro examination of adrenal cells revealed a maintained ACTH response. Some weeks postoperatively, the patient died from pneumonia. Histological examination later showed a chromophobe pituitary microadenoma; ACTH was demonstrated immunohistologically in the adenoma. We postulate that some cases of pituitary Cushing's disease initially exhibit a bilateral homogeneous adrenal hyperplasia which then develops into a nodular hyperplasia; in the next stage of the disease, single micronodules may become autonomous and elevated cortisol levels suppress ACTH secretion of the pituitary adenoma.

Acceleration of pubertal development following pituitary radiotherapy for Cushing's disease

A 7-year-old boy with pituitary dependent Cushing's disease was treated with pituitary irradiation following unsuccessful microadenomectomy. This led to normalization of the hypercortisolaemia, but was followed by GH deficiency. Two years after radiotherapy he had the onset of pubertal development with testicular enlargement to 8 ml bilaterally. Pubertal regression was induced using the long-acting GnRH analogue goserelin. Acceleration of skeletal maturation was also arrested, resulting in improvement of final height prediction. Irradiation directly to the hypothalamo-pituitary region, as well as whole brain irradiation, may thus be associated with accelerated pubertal development.

Potential Therapeutic Effects of Ritanserin in Cushing's Disease

To the Editor. —Several agents directed at neurotransmitter control of corticotropin secretion, such as cyproheptadine hydrochloride and bromocriptine, have been used in the treatment of Cushing's disease with conflicting results. 1 Ritanserin, a new, specific, very potent and long-acting serotonin (5-HT-2) antagonist, 2 is being evaluated for a variety of psychiatric disorders 3 and has been shown to impair corticotropin response to insulin-induced hypoglycemia in normal volunteers. 4 We investigated the potential therapeutic effects of ritanserin in three patients with pituitary-dependent Cushing's disease, from whom informed consent was obtained. Report of Cases. Case 1. —A 57-year-old woman showed recurrence of hypercortisolism and a pituitary microadenoma on magnetic resonance imaging 7 years after successful transsphenoidal surgery. She received 10 mg/d of ritanserin for 1 month. Her urinary hydrocortisone level showed only a slight and transient decrease at 1 week, with a subsequent rise to baseline values (Table). Case 2. —A 45-year-old