Pituitary-dependent Cushing's Disease Research Articles

8034 Putting the Pieces Together: Carney Complex, A Hyper-Rare Congenital Neoplastic Syndrome

Abstract Disclosure: G. Fontanazza: None. A.R. Conforti: None. K. Bird: None. M. Caplan: None. Intro: Carney complex (CNC) is an autosomal dominant disorder characterized by multisystem neoplasia that primarily affects the thyroid, pituitary, and adrenal glands. Its prevalence is not well established, as only 750 cases have been reported worldwide. This condition arises when an inactivating PRKAR1A gene mutation results in dysregulated cell proliferation and tumorigenesis. Complications include the potential for malignant transformation and systemic manifestations, necessitating comprehensive management and ongoing surveillance of disease progression. Case: The patient is a 58-year-old woman who initially presented as a teenager with complaints of hirsutism, truncal obesity, and violaceous abdominal striae. Initial workup revealed a low-dose dexamethasone suppression test that resulted in a non-suppressed cortisol levels. She also had undetectable adrenocorticotropic hormone (ACTH) levels. Imaging revealed no pituitary masses and demonstrated slight bilateral adrenal enlargement without adenomas. Despite these results, she was empirically treated for presumed pituitary-dependent Cushing's disease and received external beam radiation. Despite treatment, she continued to have episodes of hypercortisolism that were apparent clinically and biochemically. Over time, she developed a cardiac myxoma with six cerebrovascular accidents and multiple benign tumors. As an adult, she underwent extensive endocrine evaluation, which revealed urine cortisol excretion that paradoxically rose in response to dexamethasone. ACTH levels were always undetectable, even when she was significantly hypercortisolemic. Genetic testing revealed a homozygous mutation in the melanocortin-2 receptor (MC2R). Accordingly, she elected to have a bilateral adrenalectomy and was started on hydrocortisone and fludrocortisone. Discussion: The patient exhibited ACTH-independent micronodular adrenal hyperplasia and its most frequent variant, primary pigmented nodular adrenocortical disease. Bilateral pigmented nodular hyperplasia is a finding which can occur in association with CNC and cause episodic hypercortisolism. These patients have been shown to respond to dexamethasone with a paradoxical increase in glucocorticoid excretion. While management requires ongoing surveillance, this patient had not been diagnosed until later in life and did not have regular screening. When speculating on the late detection, her story reflects the parable of the blind men and the elephant: endocrinology managed Cushing's disease, cardiology managed atrial myxoma, and oncology managed osteochondromyxomas. Limited perspective with specialized management and an inability to see the whole picture led to prolonged diagnosis with unfortunate sequelae. This report encourages physicians to develop perspective awareness and to consider the entire picture when treating patients. Presentation: 6/2/2024

Use of osilodrostat alongside 11C-Methionine PET CT in pituitary-dependent Cushing's disease may improve radiological detection and lead to better outcomes

Use of osilodrostat alongside 11C-Methionine PET CT in pituitary-dependent Cushing's disease may improve radiological detection and lead to better outcomes

Nasal and Sellar Anatomic Variations in Pituitary-Dependent Cushing Disease.

Adrenocorticotrophic hormone excessive secretion in pituitary-dependent Cushing disease (CD) patients may lead to anatomic variations of the nasal-sphenoidal corridor as a result of hormone-induced abnormal soft tissue change. However, there is still a lack of data on anatomic dimensions in CD patients. In this study, magnetic resonance images were analyzed to determine the anatomic variations of the nasal cavity and sphenoid sinus in CD patients. A retrospective radiographic analysis was conducted on CD patients undergoing endonasal transsphenoidal surgery as primary treatment between January 2013 and December 2017. A total of 97 CD patients and 100 controls were included. The nasal and sphenoidal anatomic dimensions of CD patients were compared with the control group. Both sides of nasal cavity height, middle nasal meatus width, and inferior nasal meatus width in CD patients were narrower than that of controls. When compared with controls, the ratio of the middle turbinate to middle nasal meatus and the ratio of inferior turbinate to inferior nasal meatus was found to increase on both sides in CD patients. Intercarotid distance of CD patients was shorter than that of controls. The most prevalent pneumatization pattern of CD patients was postsellar, followed by sellar, presellar, and conchal. Cushing disease patients have nasal and sphenoidal anatomic variations affecting the endonasal transsphenoidal surgical corridor, especially the shorter intercarotid distance. The neurosurgeon should be aware of these anatomic variations, and adapt surgical techniques and optimal approaches to reach the sella safely.

Quality of Life in Cushing's disease: A long term issue?

The purpose of this review is to describe how quality of life (QoL) is impaired in patients with hypercortisolism due to Cushing's syndrome of any aetiology, including pituitary-dependent Cushing's disease. It is worse in active disease, but improvement after successful therapy is often incomplete, due to persistent physical and psychological co-morbidities, even years after endocrine “cure”. Physical symptoms like extreme fatigability, central obesity with limb atrophy, hypertension, fractures, and different skin abnormalities severely impair the affected patients’ everyday life. Psychological and cognitive problems like bad memory, difficulties to concentrate and emotional distress, often associated with anxiety and depression, make it difficult for many patients to overcome the aftermath of treated Cushing's syndrome. Recent studies have shown diffuse structural abnormalities in the central nervous system during active hypercortisolism, thought to be related to the wide distribution of glucocorticoid receptors throughout the brain. Even though they improve after treatment, normalization is often not complete. Shortening the exposure to active Cushing's syndrome by reducing the often long delay to diagnosis and promptly receiving effective treatment is highly desirable, together with preparing the patient for the difficult periods, especially after surgery. In this way they are prepared for the impairments they perceive in every day life, and live with the hope of later improvement, which can be therapeutic in many instances.

Prolactin measurement during inferior petrosal sinus sampling improves the localization of pituitary adenomas in Cushing's disease

Inferior petrosal sinus sampling (IPSS) distinguishes pituitary-dependent Cushing's disease (CD) from ectopic ACTH syndrome with a high degree of certainty, but has not been reliable in predicting the location of an adenoma within the pituitary gland. We investigated whether prolactin measurements during IPSS would improve pituitary tumour localization. Fifty-four patients with suspected ACTH-dependent Cushing's syndrome who underwent IPSS between 1997 and 2009 were studied retrospectively. Twenty-eight patients who had an identifiable tumour that stained for ACTH on histopathology are the subject of this study. Intersinus ACTH gradients before and after adjustment for prolactin were compared with surgical findings and pathology. Magnetic resonance imaging localized a pituitary adenoma in 17/28 (61%) patients. Using a maximum intersinus ACTH gradient of ≥1·4 before or after CRH stimulation, we could diagnose the tumour location correctly in 15/28 (54%) patients. By comparison, tumour lateralization by means of a dominant (≥1·4) prolactin-adjusted ACTH intersinus gradient was correct in 21/28 (75%) patients (P = 0·041). Tumour localization was correct in 23/28 (82%) patients when MRI and prolactin-adjusted ratio data were combined. Fourteen patients with proper bilateral IPS venous sampling (as determined by concurrent IPS to peripheral prolactin ratio ≥1·8) either had correct localization of the tumour (n = 12) or had a central lesion (n = 2). In none of these 14 patients was the dominant prolactin-adjusted ACTH ratio associated with a tumour on the opposite side of the gland. Prolactin measurement, during IPSS, improves our ability to correctly localize the pituitary adenoma site in CD.

Pituicytoma in a patient with Cushing’s disease: case report and review of the literature

Pituicytoma is an exceptionally rare low-grade glioma (WHO grade I) of the neurohypophysis and infundibulum. We are reporting the case of a 48-year-old man who presented with severe Cushing's syndrome. Endocrinological evaluation unequivocally confirmed pituitary-dependent Cushing's syndrome (=Cushing's disease). Cranial MR-imaging displayed a conspicuous area in the dorsal and basal pituitary gland and a minimal bulging of the pituitary gland paramedian of the pituitary stalk on the right side. Transsphenoidal inspection revealed a small tumor in the basal and dorsal pituitary gland. Surprisingly, the definite postoperative histopathological diagnosis of the removed tumor was pituicytoma and not pituitary adenoma. Hence, the microadenoma responsible for Cushing's disease was not yet removed and persistent hypercortisolism necessitated transsphenoidal re-operation. During re-operation, hemihypophysectomy was performed on the right side. The non-tumorous specimen of the adeno-hypophysis showed signs of Crooke's hyalinization consistent with Cushing's disease. Undetectable postoperative ACTH- and cortisol levels provided clear evidence that the underlying ACTH-source was successfully removed during re-operation. Coincidence of pituicytoma and pituitary-dependent Cushing's disease has not previously been reported.

MORTALITY IN CUSHING’S DISEASE

The causes of premature death in untreated Cushing's syndrome are vascular disease (myocardial infarction/stroke), uncontrolled diabetes mellitus and complications and infections. Long-term mortality outcome studies on pituitary-dependent Cushing's disease (CD) are limited to six studies in the English language literature. This paper reviews these studies on CD, other causes of Cushing's syndrome being excluded, because CD represents 80% of patients with the syndrome. The period covered by these studies (1970-1990) is when transsphenoidal surgery was well established as primary treatment for CD. Two studies were exclusively from surgical centres and are likely biased in favour of surgically resectable adenomas, so this needs to be borne in mind when interpreting their results. The criteria for remission of hypercortisolism and persistent disease were variable. The overall number of patients in each report is small, and the number of deaths even smaller by epidemiological standards giving very wide confidence intervals to the standardised mortality ratios (SMR). Moreover, follow-up time was relatively short (median 10-12 years) for a disease diagnosed in the patients' late 30s. Notwithstanding the above limitations of retrospective studies, and potential for positive bias, the overall SMR of around 1.5 was not significantly different from the relevant normal population for those patients deemed in remission. However, SMR was significantly worse for those patients with persistent disease. Where it was possible to analyse contributing factors to mortality, the presence of hypertension and diabetes mellitus, in addition to persistence of hypercortisolism, was shown to be significant. It remains possible that an overall SMR in 'cured' patients would be significant given a larger cohort, followed for longer, and with more deaths. What is clearly required is a multicentre prospective cohort study with >30 years' follow-up to answer the question definitively and identify the contributing factors in detail in order to achieve optimum long-term outcome.

Psychosomatic aspects of Cushing’s syndrome

There has been growing interest in the psychosocial aspects of Cushing's syndrome, such as the role of life stress as a pathogenetic factor, the association with affective disorders, and the presence of residual symptoms after treatment. Interestingly, a temporal relationship between stressful life events and disease onset is relevant only to pituitary-dependent Cushing's disease, and not to the pituitary-independent forms. A number of psychiatric and psychological disturbances may be associated with the active hypercortisolemic state, regardless of its etiology. Within the high frequency of mood disorders (about 60%), major depression is the most common complication. Other psychopathological aspects include mania, anxiety disorders, psychological symptoms (demoralization, irritable mood, somatization) and cognitive impairment. Cognitive symptoms are associated with brain abnormalities (mainly loss of brain volume). Quality of life may be seriously compromised during both active and post-treatment phases. Long-standing hypercortisolism may imply a degree of irreversibility of the pathological process. Recovery, thus, may be delayed and be influenced by highly individualized affective responses. Outcomes of Cushing's syndrome treatment are not fully satisfactory. Within its great complexity, a conceptual shift from a merely biomedical care to a psychosomatic consideration of the person and his/her quality of life appears to be necessary to improve effectiveness. It is time to translate the research evidence that has accumulated into clinical practice initiatives. To patients who show persistence or even worsening of psychological distress upon adequate endocrine treatment psychiatric/psychological interventions should be readily available. Applying interdisciplinary expertise and addressing the needs for rehabilitation would markedly improve final outcome.

Paradoxical Response of Plasma ß-Endorphin to Combined Administration of TRH and GnRH in Adrenal Disorders *)

The combined intravenous injection of TRH and GnRH elicited paradoxical responses of plasma beta-endorphin in active and successfully treated pituitary dependent Cushing's disease as well as in ectopic ACTH syndrome and in congenital adrenal hyperplasia. No response was observed in Cushing's syndrome due to adrenal tumours. It is concluded that an abnormal response to inappropriate releasing hormones cannot verify the existence of a pituitary corticotrophic microadenoma.

Treatment of Pituitary-Dependent Cushing's Disease with the Multireceptor Ligand Somatostatin Analog Pasireotide (SOM230): A Multicenter, Phase II Trial

Treatment of Pituitary-Dependent Cushing's Disease with the Multireceptor Ligand Somatostatin Analog Pasireotide (SOM230): A Multicenter, Phase II Trial

Evaluation of the accuracy of inferior petrosal sinus sampling in the differential diagnosis of ACTH-dependent Cushing’s syndrome

The differentiation of adrenocorticotropic hormone producing pituitary adenoma (Cushing's disease) from the ectopic ACTH syndrome is always a complex and difficult task, and in rare cases it is not possible to differentiate between the two disorders, even with the use of dynamic endocrine tests and the most advanced imaging techniques. Inferior petrosal sinus sampling (IPSS) with subsequent ACTH measurements became the gold-standard method of the differential diagnostic process. 34 patients with ACTH dependent Cushing's syndrome in whom the source of ACTH secretion couldn't be identified unambiguously with imaging techniques and/or dynamic endocrine tests underwent altogether 41 IPSS between 1999 and 2005. The sensitivity of the method was calculated on the basis of 31 samplings of 25 patients who had definite endocrinological diagnosis confirmed by the recovery from Cushing's syndrome after surgical intervention and/or by histological examinations (22 patients with ACTH-producing pituitary adenoma and 3 patients with ectopic ACTH syndrome). As a result of IPSS, pituitary-dependent Cushing's disease was diagnosed with a baseline central to peripheral ACTH ratio of >2.0 or with a ratio of >3.0 after corticotropin releasing hormone (CRH) administration. IPSS correctly identified ACTH-producing pituitary adenoma in 20 of 28 sampling procedures, with a sensitivity of 71.4%. Three patients had true negative and 8 had false negative results. There was no false positive result. Four of the 8 patients with false negative first sampling had a repeat sampling procedure leading to true positive result in each patient. In patients with Cushing's disease having true positive interventions, the basal and 5 minutes post-CRH ACTH concentrations were diagnostic in 14 and 19 cases, respectively. The sensitivity of IPSS within this series, reported for the first time from Hungary, was lower than it was found in much larger series published in international literature. In addition to technical difficulties, the lower sensitivity can be accounted also for the highly selected nature of the patient group.

The desmopressin test in the diagnosis of Cushing’s disease

Early and precise diagnosis is necessary in successful treatment of the patients with Cushing's disease. Transsphenoidal surgery is the first line treatment option in Cushing's disease. In patients in whom magnetic resonance imaging does not visualise pituitary adenoma patient selection for surgical treatment should be based on convincing results of functional tests. The diagnostic accuracy of the desmopressin test was compared with that of the CRH test and the overnight high-dose dexamethasone suppression test in the diagnosis of Cushing's disease. We studied 15 patients with pituitary-dependent Cushing's disease (10 with detected microadenoma and 5 with undetected microadenoma using magnetic resonance imaging). The diagnosis was confirmed during pituitary surgery. The control group included 15 subjects without Cushing's syndrome. Patients underwent tests with desmopressin, CRH and 8 mg overnight dexamethasone. A false negative response to CRH was present in 1 of 15 patients, a false negative response t dexamethasone was present in 1 of 15 patients and a false negative response to desmopressin in 2 of 15 patients. In other patients positive responses to CRH, desmopressin and dexamethasone were found. A positive response to desmopressin was present in 4 of 5 patients with undetected pituitary adenoma. In the control group a positive response to CRH and dexamethazone and a negative response to desmopressin was found in all patients. 1. The highest diagnostic accuracy in the diagnosis of some patients with Cushing's disease is achieved by using a desmopressin test with high-dose dexamethasone test and CRH-test. 2. The desmopressin test can be used to precisely identify healthy individuals.

Personality characteristics and quality of life in patients treated for Cushing's syndrome

Psychological distress does not always disappear upon proper endocrine treatment of Cushing's syndrome, and quality of life may still be compromised. Little is known on the personality correlates that may be involved. The aim of this study was to provide a controlled assessment of personality characteristics and quality of life in patients successfully treated for Cushing's syndrome. A single-centred, controlled, prospective study. Twenty-four consecutive outpatients who were in remission upon proper treatment of Cushing's syndrome for at least 1 year and no more than 3 years (20 with pituitary-dependent Cushing's disease and four with a cortisol-secreting adrenal adenoma; 5 M/19 F; mean age 34.5, SD = 10.6; range 18-57 years) were compared with 24 healthy control subjects matched for sociodemographic variables. Both patients and controls were administered two self-rating scales: (a) tridimensional personality questionnaire (TPQ), a 100-item inventory that yields three scales: novelty seeking, harm avoidance and reward dependence. (b) symptom rating test (SRT), a 46-item scale for assessing psychological distress and quality of life with six subscales (anxiety, depression, somatic symptoms, anger-hostility, cognitive symptoms, psychotic symptoms). There were no significant differences in personality dimensions, as measured by the TPQ, between patients and controls. The results did not change when the four patients with an adrenal adenoma were excluded and only the 20 with pituitary-dependent Cushing's disease were considered. As to the SRT scale, patients with Cushing's syndrome displayed significantly higher scores in anxiety (P= 0.046), depression (P= 0.013), and psychotic symptoms (P= 0.006), with a generalized compromised quality of life (P= 0.02). Again, no differences were found in evaluating the 20 patients with Cushing's disease separately. Even though personality traits other than those explored here may be involved, the results seem to exclude the presence of latent dysfunctional attitudes and beliefs contributing to long-standing psychological disturbances, even in the pituitary-dependent form of Cushing's syndrome. Data from larger populations might provide further insight in this field. The findings of a compromised quality of life are in agreement with the recent literature and have implications for the long-term management of patients.

The Role of Somatostatin Analogs in Cushing's Disease

Somatostatin (SRIF) has been proposed to be of therapeutic interest in the medical treatment of Cushing's disease. While in vitro data demonstrate the presence of SRIF-receptor subtype (sst) expression in corticotroph adenomas, the current clinically available SRIF-analog Octreotide, predominantly targeting sst(2), is ineffective in lowering ACTH levels in Cushing's disease and only appears to inhibit the release of ACTH in Nelson's syndrome. In the present review, current knowledge on the physiological role of SRIF in the regulation of ACTH secretion by the anterior pituitary gland, as well as by corticotroph tumor cells is summarized. In addition, the role of glucocorticoids in regulating sst-mediated inhibition of ACTH release by corticotroph adenoma cells is discussed. Recently, it was reported that the novel multiligand SRIF-analog SOM230 might have the potential to be of therapeutic interest for Cushing's disease. On the basis of the potent suppressive effects on ACTH release by SRIF-analogs with high binding affinity to sst(5) and the observation that sst(5) expression and action is relatively resistant to glucocorticoid treatment, including the recent observation that sst(5) is the predominant sst expressed in human corticotroph adenomas, it is hypothesized that sst(5) may be a new therapeutic target for the control of ACTH and cortisol hypersecretion in patients with pituitary dependent Cushing's disease.

Somatostatin receptors in pituitary function, diagnosis and therapy.

Recent studies have demonstrated that human pituitary adenomas express multiple somatostatin receptor (sst) subtypes. The expression of sst subtypes in human pituitary adenomas is highly variable. This variability in sst subtype expression may explain the variable responsiveness of patients with pituitary adenomas to medical treatment with the sst2-preferring SS-analogs octreotide and lanreotide. In human GH-secreting pituitary adenomas, both sst2 and sst5 are involved in the regulation of GH secretion. In prolactinomas, sst5 receptors are the key receptors in regulating responsiveness to SS. The low abundance of sst2 in prolactinomas explains the lack of efficacy of octreotide in lowering the elevated PRL levels in prolactinoma patients. Octreotide and lanreotide successfully suppress TSH levels, including normalization of thyroid hormone levels in the large majority of patients with TSH-secreting pituitary adenomas, probably due to the high level of sst2, expression in the adenomas. Although sst2 receptors are expressed by a significant proportion of gonadotroph and clinically non-functioning pituitary adenomas, the overall efficacy of sst2-preferring SS-analogs seems low in this type of patients. Finally, corticotroph adenomas may express multiple sst subtypes as well. Octapeptide SS-analogs do not lower circulating ACTH levels in patients with untreated pituitary-dependent Cushing's disease, whereas SS and the SS-analog octreotide suppress pathological ACTH release in some patients with Nelson's syndrome. This review discusses the expression and potential role of sst subtypes in the different types of human pituitary adenomas.

Circadian variation in Cushing's disease and pseudo-Cushing states by analysis of F and ACTH pulsatility.

Distinguishing pituitary-dependent Cushing's disease from pseudo-Cushing's states can present a diagnostic challenge. Although many studies potentially discriminate between the 2, only the dexamethasone-suppressed corticotropin-releasing hormone (CRF) stimulation test at 15 minutes is 100% sensitive or specific. We measured baseline profiles of F and ACTH in 31 Cushing's disease patients, 11 with pseudo-Cushing's and 17 controls. Venous blood was collected at 30 minute intervals for 24-h. Subjects also had CRF stimulation tests and 2.0 mg/day dexamethasone suppression tests. F and ACTH profiles were analyzed for circadian rhythmicity, variability, and pulsatility. Relative circadian amplitude was decreased in Cushing's disease compared to both pseudo-Cushing's and normal states. Relative pulse amplitude was reduced in Cushing's disease. Because of this dampening of circadian and pulsatile variations, the overall variability of F and ACTH levels around their mean levels as quantified by the intra-series coefficient of variation (CV), was also decreased in Cushing's disease compared to pseudo-Cushing's and normal states. A F 24-h CV<40% was able to distinguish Cushing's disease from pseudo-Cushing's with 100% sensitivity (95% confidence interval (CI), 88-100%) and specificity (CI, 71-100%). An ACTH CV<40% had 97% sensitivity (CI, 83-100%) and 100% specificity (CI, 71-100%). An overnight 8-h F CV <40% also distinguished Cushing's disease from pseudo-Cushing's with 100% sensitivity (CI, 88-100%) and specificity (CI, 71-100%). These data show that a simple index of total temporal variability (the intra-series CV) derived from the analysis of basal F profiles, provides a useful method to distinguish Cushing's disease from pseudo-Cushing's. A F or ACTH CV <40% discriminates Cushing's disease from pseudo-Cushing's and reflects reduced circadian and pulsatile variations.

Medical Treatment of Canine Pituitary-Dependent Hyperadrenocorticism (Cushing's Disease)

Pituitary-dependent hyperadrenocorticism (Cushing's disease) is a relatively common endocrine disorder of middle- to old-age dogs. Three treatments commonly used in the management of pituitary-dependent Cushing's disease in dogs include mitotane, ketoconazole, and L-deprenyl. These medications are associated with the potential of different side effects and expense, but all can produce satisfactory results in dogs with this disease. The choice of treatment for a given dog depends on the severity of the dog's disease, as well as clinician and client preferences. This article reviews the indications and adverse effects associated with each of these three drugs, as well as the treatment protocols commonly used in treating dogs with hyperadrenocorticism.

Growth hormone and prolactin are secreted more irregularly in patients with Cushing's disease.

To investigate whether the spontaneous secretion of growth hormone and prolactin in adult patients with pituitary-dependent Cushing's disease is decreased. Fourteen adult patients (9 women, 5 men; age: 34 +/- 3.4 years, mean +/- SEM) with pituitary-dependent Cushing's disease and 14 controls matched for age, gender and body mass index were studied. Blood samples were withdrawn at 10 minutes intervals starting at 0900 h for 24 h. GH and PRL release were quantified with deconvolution methods. The regularity of GH and PRL release was measured with approximate entropy statistics. The number of GH secretory events per 24 h was higher in patients than in controls: 19 +/- 1.3 vs. 14 +/- 1.5 peaks per 24 h, respectively (P = 0.020). GH secretion rate was about one quarter lower in patients (ns), and the 24 h secretion of PRL was unchanged. Total GH production correlated negatively with the urinary excretion of free cortisol (R = 0.729, P = 0.005) and with the plasma cortisol production rate (R = 0.613; P = 0.026). The orderliness of GH and PRL secretion was appraised with the approximate entropy statistic (ApEn). For GH secretion ApEn(1,20%) in patients was 0.952 +/- 0.084 vs. 0.404 +/- 0.047 in controls, P = 1.17 x 10-4, pointing to a markedly disordered secretion in patients. Similar results were obtained for PRL secretion: patients: 1.586 +/- 0.063 vs. 1.003 +/- 0.068 in controls, P = 3.67 x 10-5. No statistically significant differences in secretory dynamics were demonstrated between the 10 patients with a microadenoma and the four with a macroadenoma. The amount of GH released spontaneously into the circulation in adult patients with pituitary-dependent Cushing's disease is inversely related to the degree of cortisol hypersecretion. However, except for severe hypercortisolism, GH secretion is relatively preserved. In addition, secretion of GH and PRL is remarkably disordered in patients with Cushing's disease. Since we could not detect differences in GH and/or PRL secretory dynamics between patients with a microadenoma and those harboring a macroadenoma, we speculate that an intrapituitary paracrine mechanism and/or elevated cortisol feedback effects may be responsible for the evident disruption of GH and PRL secretion patterns.

Effect of the serotonin antagonists ritanserin and ketanserin in Cushing's disease.

Central serotonergic regulation could have a role in the course of pituitary-dependent Cushing's disease. We studied the effects of ritanserin and ketanserin, two related selective 5HT2 receptor antagonists, in 11 patients with Cushing's disease. Treatment lasted from 1 month to 1 year (up to 4 years in one patient). Daily doses were 10-15 mg for ritanserin, and 40-80 mg for ketanserin. Since the two drugs share the same mechanism of action and no qualitative or quantitative differences in response to their administration were observed, the results were pooled together. Patients were assessed by clinical and hormonal evaluation. Urinary cortisol and ACTH were considered the parameters of interest. Short-term response: after 1 month, there was a significant decrease of urinary cortisol from 781 (160) to 331 (215) nmol/d (P < 0.02) while ACTH was 9.8 (1.5) pmol/L baseline and again 8.8 (2.2) pmol/L at 1 month (P = NS). For 9 patients, hormonal parameters were available after 1 week of treatment. In this case, also ACTH levels were significantly decreased (from 9.6 (1.7) to 5.2 (1.3) pmol/L; P < 0.01) together with urinary cortisol (from 781 (194) to 372 (165) nmol/d; P < 0.01). Long-term response: in 3 patients, hormonal parameters failed to respond to serotonin receptor antagonists, which were thus discontinued. An improvement was recorded in the remaining 8 patients, that was prolonged in 3, and transient in 5. In 3 of these latter patients, a marked increase of ACTH was observed before treatment discontinuation. Ketanserin was given to 2 patients with Nelson's syndrome, with only transient ACTH decrease in one, and no changes in ACTH response to CRH after 1 month treatment in both cases. An inhibitory effect of ritanserin and ketanserin on ACTH and cortisol production in Cushing's disease appeared to be limited both in terms of duration of response and number of patients with a satisfactory outcome. However, the results may provide a better understanding of serotonergic modulation in Cushing's disease and lead to therapeutic developments.

MEDICAL THERAPY FOR CUSHING'S DISEASE

Various drugs have been employed in the management of pituitary-dependent Cushing's disease. The neuromodulatory compounds used thus far have demonstrated true clinical efficacy only occasionally when employed as sole treatment. Steroid synthesis inhibitors are effective in the majority of cases in a dose-dependent manner. By their ability to correct hypercortisolism and its severe complications quickly, they are suitable for critical cases and in preparation for surgery. The clinical experience with the only glucocorticoid receptor antagonist that can be administered to humans is still too limited to assess its therapeutic validity. No medical strategy can be standardized for this complex condition. Different therapeutic tools should be selected according to the form of disease to be treated (hypothalamic/pituitary) and the peculiar clinical situation of each patient. Combined treatments may achieve better therapeutic efficacy.