ergoline and Cushing-Syndrome

Dopamine (DA) is a catecholamine with a wide range of functions and whose five subtype receptors are found in different organs where they exert a mainly inhibitory action. Since this action may also appear in a number of secretory tumors in various locations, DA agonists have elicited some interest as a medical treatment for hypercorticism. Non-iatrogenic Cushing's syndromes are due in 70% of the cases to a pituitary adrenocorticotropic hormone (ACTH)-producing adenoma, and, less frequently, to an adrenal adenoma or an ectopic ACTH secretion by a neuroendocrine tumor. First-line treatment in Cushing's syndrome consists of the surgical removal of the secreting tumor. However, surgery may not achieve a complete cure in a number of cases, hence emphasizing the potential benefit of a medical complementary treatment, which could also benefit patients as an alternative approach, either when waiting for, or when the patient is not eligible for surgery. Studies of corticotropic adenomas have shown that 80% of these tumors express D2 receptors. Clinical trials of DA agonists in Cushing's disease have shown an inhibitory effect of these drugs with an inhibition of ACTH secretion and/or a decrease of tumor size. There are only a few cases of documented use of DA agonists in ectopic ACTH secretion, but when the tumor expresses DA receptors, DA agonists may represent a useful complementary treatment. DA receptors are also expressed in normal and tumoral adrenals, suggesting a potential use of DA agonists in Cushing's syndrome secondary to adrenal tumors. However, clinical data regarding this specific situation are very scarce, maybe due to the relatively high rate of surgical cure of adrenal adenomas. In conclusion, DA agonists represent a potential preparatory or complementary treatment for endogenous Cushing's syndrome, especially in Cushing's disease. These compounds may be underused as suggested by the scarce number of publication and case reports in the literature. In the future, association of these drugs with somatostatin analogs may also prove beneficial.

Topics: Cabergoline; Cushing Syndrome; Dopamine Agonists; Ergolines; Humans

Cushing's syndrome is a complex endocrine condition with potential serious complications if untreated or inadequately treated. Transsphenoidal surgery with resection of a pituitary adenoma is successful in 75 - 80% of patients, but approximately 20 - 25% show persistence of Cushing's, and a similar proportion may experience recurrence within 2 - 4 years post-op. When surgery fails, medical treatment can temporarily suppress excessive cortisol production and ameliorate its clinical manifestations while more definitive therapy becomes effective. We describe pharmacological approaches to the treatment of Cushing's syndrome. Drugs used to suppress cortisol secretion are mostly inhibitors of steroidogenesis. Ketoconazole, fluconazole aminoglutethimide, metyrapone, mitotane and etomidate are in that category. Ketoconazole is in current use while other drugs, although mostly available in the past, continue to have a potential role either alone or in combination. Drugs that suppress adrenocorticotropic hormone (ACTH) secretion are less popular as standard treatment and include cyproheptadine, valproic acid, cabergoline, somatostatin analogs, PPAR-gamma agonists, vasopressin antagonists. Some of these drugs have been tested in limited clinical trials but there is potential therapeutic benefit in analogs with better specificity for the class of receptors present in ACTH-secreting tumors. A third category of drugs is glucocorticoid receptor antagonists. Mifepristone is currently being tested in clinical trials in patients with persistent or recurrent Cushing's disease and in patients with metastatic adrenal cortical carcinoma or ectopic ACTH syndrome not amenable to surgery. We also review replacement therapy after surgery and non-specific drugs to treat complications in patients with severe hypercortisol. The review provides a complete survey of the drugs used in the medical treatment of Cushing's, and new advances in the development of pituitary-active drugs as well as receptor blockers of glucocorticoid action. It also provides avenues for exploration of new drugs active on somatostatin, dopamine and vasopressin receptors. There are effective pharmacological agents capable of chronically reversing biochemical and clinical manifestations of hypercortisolemia in Cushing's syndrome but new drugs are needed with action at the pituitary level.

Topics: Adrenal Cortex Neoplasms; Adrenocorticotropic Hormone; Antiparkinson Agents; Cabergoline; Cushing Syndrome; Ergolines; Human Growth Hormone; Humans; Hydrocortisone; Ketoconazole; Metyrapone; Pituitary Hormones; Pituitary Neoplasms

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 37 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.

Topics: Adult; Cabergoline; Cushing Syndrome; Dopamine Agonists; Ergolines; Female; Humans; Ketoconazole; Pregnancy; Pregnancy Complications; Pregnancy Outcome

Topics: Adrenocorticotropic Hormone; Amenorrhea; Blood Glucose; Cushing Syndrome; Erectile Dysfunction; Ergolines; Female; Galactorrhea; Gonadotropins; Growth Hormone; Hormones; Humans; Lactation; Luteinizing Hormone; Male; Metergoline; Pancreatic Hormones; Pimozide; Pituitary Gland; Postpartum Period; Pregnancy; Prolactin; Receptors, Dopamine; Serotonin Antagonists; Thyrotropin

Topics: 14-alpha Demethylase Inhibitors; Adenoma; Cabergoline; Cushing Syndrome; Dopamine Agonists; Ergolines; Female; Humans; Hypokalemia; Ketoconazole; Middle Aged; Pituitary ACTH Hypersecretion; Pituitary Neoplasms

A 23-year-old man presenting with florid Cushing's syndrome was found to have high plasma ACTH and very high serum prolactin. Pituitary MRI showed a large invasive macroadenoma. Low-dose cabergoline promptly suppressed both ACTH and prolactin levels within 2 weeks, with unexpected clinical and biochemical hypocortisolism requiring hydrocortisone replacement. Secondary hypogonadism was reversed. Clinical and biochemical remission of his Cushing's syndrome together with significant shrinkage of his macroadenoma has been maintained for 1 year on cabergoline 0.5 mg twice weekly. Reduction in pituitary tumour volume and brisk fall in serum prolactin in response to low-dose cabergoline is regularly observed in patients with macroprolactinomas, but the concurrent fall in the plasma ACTH level and hypocortisolism was a pleasant surprise. We assume that he most likely has a single bihormonal adenoma that is enriched with dopamine-2 receptors.

Topics: ACTH-Secreting Pituitary Adenoma; Adenoma; Antineoplastic Agents; Cabergoline; Cushing Syndrome; Ergolines; Humans; Male; Pituitary Neoplasms; Prolactinoma; Young Adult

Cushing's disease is the result of chronic overproduction of ACTH by a pituitary tumor. Although the optimal treatment is surgical removal of the adenoma, medical treatment might be an option in selected cases. A 40-year old woman with Cushing's disease was treated with cabergoline, a neuromodulatory drug, for a corticotrophic macroadenoma. Treatment was initiated at a weekly dose of 0.5 mg and then, on the basis of the evolution of UFC values, adjusted until it reached 6 mg/week. With cabergoline treatment the patient was asymptomatic, the pituitary adenoma showed a significant shrinkage on MRI and urinary cortisol excretion remained within the normal range during 7 years. We show the effectiveness of cabergoline in maintaining long-term biochemical control of hypercortisolism with significant reduction and stabilization of macroadenoma volume in a patient with Cushing's disease.

Topics: Adult; Cabergoline; Cushing Syndrome; Ergolines; Female; Humans; Magnetic Resonance Imaging; Pituitary ACTH Hypersecretion

Cushing syndrome is associated with significant morbidity and mortality if left untreated because of associated metabolic and cardiovascular complications. An extremely ill patient with Cushing's syndrome caused by adrenocorticotropic hormone producing pituitary macro adenoma responded dramatically to ketoconazole and cabergoline treatment. His 4 month long medical treatment resulted in improvement of hypercotisolism clinically and biochemically and in complete disappearance of pituitary macro adenoma without any surgical intervention.

Topics: 14-alpha Demethylase Inhibitors; Adenoma; Adult; Antineoplastic Agents; Cabergoline; Cushing Syndrome; Diagnosis, Differential; Drug Therapy, Combination; Ergolines; Humans; Ketoconazole; Magnetic Resonance Imaging; Male; Pituitary Neoplasms; Severity of Illness Index; Tomography, X-Ray Computed

Topics: Adolescent; Cabergoline; Cushing Syndrome; Dopamine Agonists; Ergolines; Female; Humans; Kidney Neoplasms; Paraneoplastic Syndromes; Wilms Tumor

Topics: ACTH Syndrome, Ectopic; Adult; Cabergoline; Carcinoid Tumor; Cushing Syndrome; Drug Therapy, Combination; Ergolines; Humans; Lung Neoplasms; Male; Peptides, Cyclic; Somatostatin

Multiple pituitary hormone hypersecretions have already been described, but the co-occurrence of PRL and ACTH excess is very rare. To our knowledge, medical treatment with cabergoline only, avoiding pituitary surgery and radiotherapy in this type of tumor has never been reported before. This case report deals with a 31-yr-old man affected with a macroprolactinoma associated with a florid clinical image of Cushing's disease. Normalization of the prolactin levels and the disappearance of clinical and biochemical features of Cushing's disease were obtained after administration of medical treatment only.

Topics: Adrenocorticotropic Hormone; Adult; Antineoplastic Agents; Cabergoline; Cushing Syndrome; Dexamethasone; Ergolines; Glucocorticoids; Humans; Hydrocortisone; Magnetic Resonance Imaging; Male; Pituitary Neoplasms; Prolactin; Prolactinoma; Thyrotropin-Releasing Hormone; Treatment Outcome

In this case report we demonstrated that treatment with the long-acting D2 receptor agonist cabergoline for 1 year induced normalization of plasma ACTH levels and disappearance of the pituitary tumor in a patient with Nelson's syndrome. A young man underwent bilateral adrenalectomy and subsequent pituitary irradiation for Cushing's disease after unsuccessful neurosurgical treatment. Thereafter, he was given cortisone acetate replacement at the dose of 62.5 mg a day. Fifteen months after pituitary irradiation, he developed Nelson's syndrome, having skin hyperpigmentation, high plasma ACTH levels (376 ng/l) and a pituitary microadenoma (5 mm) documented at magnetic resonance imaging (MRI) of the pituitary region. After 6 months of cabergoline treatment, given at the dose of 1 mg a week, plasma ACTH levels were significantly decreased (from 376 to 113 ng/l) but they were not normalized. Cabergoline dose was then increased up to 2 mg a week. Six months later plasma ACTH levels were normalized (22 ng/l) and MRI demonstrated the disappearance of the pituitary adenoma. In order to investigate on the direct effect played by cabergoline treatment on the remission of Nelson's syndrome, the treatment was withdrawn. Plasma ACTH levels significantly increased (119 ng/l) after 3 months of treatment withdrawal. At the last follow-up, during cabergoline treatment at the dose of 2 mg/week plasma ACTH levels were normalized (40.4 ng/l). This case demonstrated that cabergoline treatment is able to induce the remission of Nelson's syndrome and may be a valid therapeutic alternative in this syndrome.

Topics: Adenoma; Adrenalectomy; Adrenocorticotropic Hormone; Adult; Antineoplastic Agents; Cabergoline; Cushing Syndrome; Dopamine Agonists; Ergolines; Humans; Magnetic Resonance Imaging; Male; Nelson Syndrome; Pituitary Neoplasms; Remission Induction

To define the role of dopaminergic drugs on pituitary ACTH secretion, we studied the effect of a dopamine-agonist, lisuride, on a group of 9 patients with pituitary dependent Cushing's syndrome. Lisuride (0.4-0.6 mg/day) was administered for two days: in only two out of eight cases the ACTH levels, sampled every 30 min for 6 h (08:00-14:00 h), showed some reduction when compared with the control day. Two of the nonresponders (R.P.; B.F.) and one untested patient (L.E.) were then treated chronically with a similar amount of lisuride per day for 20 days (L.E.) and for 4 months (B.F.; R.P.). One patient (L.E.) showed a clear decrease in urinary free cortisol without clinical improvement; while in the other two cases, followed for a longer period of time, a clinical improvement was observed together with a decrease of the hormonal parameters. In conclusion, lisuride may occasionally reduce ACTH secretion in patients with pituitary dependent Cushing's syndrome, but the acute test fails to identify the patients who would benefit from this treatment.

Topics: Adrenocorticotropic Hormone; Cushing Syndrome; Dopamine; Ergolines; Humans; Hydrocortisone; Lisuride; Prolactin; Time Factors

39 patients with hyperprolactinaemia (32 adenomas of the pituitary gland, 7 idiopathic hyperprolactinaemias) were treated with the ergot derivative Lisurid. In 3 patients side-effects appeared which did not allow an increase to the therapy-effective dose. In all other patients with a dose of 0.075 to 6 mg Lisurid a day a normalisation of the prolactinaemia was achieved. A pregnancy appeared in 15 of 16 women who wished a child. In 4 men with normal gonadotropic reserve libido, potency and plasma testosterone normalised after the treatment with Lisurid. In addition of Lisurid also other ergot derivatives with prolactin-inhibiting effect, such as dironyl, deprenone and propyldeprenone were tested. Here dironyl has an advantage showing less side-effects and no changes of blood pressure. The ergot derivatives may be used also in the treatment of acromegaly. In 7 of 21 patients with acromegaly who were treated a longer time we succeeded in reducing the level of the growth hormone below 50%, in 2 patients the condition completely normalised. On the other hand, a normalisation of the somatomedin level appeared only in 11 of 21 patients. Patients with central Cushing's disease only exceptionally react to the treatment with ergot derivatives.

Topics: Acromegaly; Adult; Aged; Cushing Syndrome; Ergolines; Ergotamines; Female; Humans; Lisuride; Male; Middle Aged; Pregnancy; Prolactin

Topics: 17-Hydroxycorticosteroids; 17-Ketosteroids; Adrenocorticotropic Hormone; Cushing Syndrome; Cyproheptadine; Dexamethasone; Dopamine; Ergolines; Hydrocortisone; Metergoline; Pituitary Gland; Serotonin

Topics: Adrenocorticotropic Hormone; Adult; Bromocriptine; Cushing Syndrome; Dexamethasone; Ergolines; Humans; Hydrocortisone; Male

Topics: Adrenalectomy; Adrenocorticotropic Hormone; Adult; Bromocriptine; Cushing Syndrome; Ergolines; Female; Humans; Male; Postoperative Complications; Prolactin; Syndrome

The effect of metergoline, a specific antiserotoninergic drug, on ACTH secretion was investigated in 29 normal volunteers and in 4 patients with increased ACTH production (3 with Addison's disease, 1 with Cushing's disease). In 15 normal subjects, a 4-day treatment with 10 mg daily of metergoline significantly blunted the ACTH response to insulin hypoglycemia. Mean peak ACTH values before and after treatment were, respectively, 333 +/- 39.2 (SE) and 235 +/- 38.8 pg/ml (P less than 0.05). The corresponding values of plasma cortisol were 29.6 +/- 2.96 and 20.5 +/- 2.67 mug/100 ml (P less than 0.05). In contrast, metergoline failed to affect the ACTH response to lysine-vasopressin (LVP) administered iv (8 subjects studied) and im (6 subjects studied). In 3 patients suffering from Addison's disease, an appreciable although not statistically significant lowering of the plasma ACTH levels was noted during metergoline administration. The mean pre- and post-treatment values of plasma ACTH in these patients were, respectively, 1116 +/- 192.2 and 666 +/- 100.8 pg/ml, 4240 +/- 50.0 and 3398 +/- 368.0 pg/ml, and 431 +/- 44.0 and 352 +/- 23.9 pg/ml. In one patient with Cushing's disease caused by a pituitary adenoma, metergoline did not appreciably modify plasma ACTH levels. Taken together, these results lend support to the concept of a physiological stimulating effect of serotonin on ACTH secretion. Moreover, they are compatible with the view that serotonin exerts its action chiefly at the hypothalamic level while LVP promotes ACTH release by a primary action on the pituitary.

Topics: Addison Disease; Adrenocorticotropic Hormone; Adult; Cushing Syndrome; Ergolines; Female; Humans; Hydrocortisone; Hypoglycemia; Hypothalamo-Hypophyseal System; Insulin; Lypressin; Male; Metergoline; Middle Aged; Serotonin; Serotonin Antagonists; Vasopressins

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Bromocriptine; Cushing Syndrome; Ergolines; Female; Humans; Hydrocortisone; Male; Middle Aged