Enrica Ciccarelli

Treatment of macroprolactinoma with cabergoline: a study of 85 patients

OBJECTIVE Cabergoline is now established as an effective and well‐tolerated treatment for prolactinoma. However, there are relatively few published data on the treatment of macro‐, as opposed to micro‐, prolactinoma. We have therefore reviewed the efficacy and safety of cabergoline in the treatment of patients with prolactin‐secreting macroadenomas treated on a compassionate basis.

Long-term treatment with cabergoline, a new long-lasting ergoline derivate, in idiopathic or tumorous hyperprolactinaemia and outcome of drug-induced pregnancy

Cabergoline (CAB), a new long-acting ergoline derivative, was shown to be very effective in reducing PRL levels in normal volunteers and in hyperprolactinemic patients. We evaluated the hormonal changes after discontinuation of long-term therapy with CAB as well as the safety of drug exposure during pregnancy both for mothers and babies. We therefore studied 48 patients (47 females and one male) with pathological hyperprolactinaemia (mean±SE, 117.2±15.2; median 73.2 µg/l), treated for 1–82 months (mean±SE, 28.3±3; median 18). After long-term treatment, CAB was withdrawn in 11 patients and PRL levels were persistently normal for almost 15 days and significantly lower (p <0.05) than basal at 30, 45, 60, 90, 120 days. Three patients had normal PRL levels still at 45 days after treatment discontinuation. Nine patients became pregnant after 1–37 months (mean 12.4) of therapy. In two patients the pregnancy was interrupted spontaneously in one case and voluntarily in the other. In all but one patients, after delivery or three-month breast feeding, PRL levels trended towards reduction. In two cases (one with microadenoma and one with idiopathic hyperprolactinaemia) PRL remained in the normal levels for 1–3 years after delivery. In conclusion CAB is able to inhibit plasma PRL levels for long time (up to 120 days) after withdrawal in patients with pathological hyperprolactinaemia treated with long-term therapy.

Prolactinomas resistant to standard doses of cabergoline: a multicenter study of 92 patients

BACKGROUND Dopamine agonist resistance in prolactinoma is an infrequent phenomenon. Doses of cabergoline (CAB) of up to 2.0 mg/week are usually effective in controlling prolactin (PRL) secretion and reducing tumor size in prolactinomas. The clinical presentation, management, and outcome of patients that are not well controlled by such commonly used doses of CAB-resistant patients are poorly understood. DESIGN AND METHODS A multicenter retrospective study was designed to collect a large series of resistant prolactinoma patients, defined by uncontrolled hyperprolactinemia on CAB ≥2.0 mg weekly. RESULTS Ninety-two patients (50 F, 42 M) were analyzed. At diagnosis, most had macroprolactinomas (82.6%); males were significantly older than females (P=0.0003) and presented with a more aggressive disease. A genetic basis was identified in 12 patients. Thirty-six patients (39.1%) received only medical therapy, most underwent surgery (60.9%, including multiple interventions in 10.9%), and 14.1% received postoperative radiotherapy. Eight patients developed late CAB resistance (8.7%). The median maximal weekly dose of CAB (CAB(max/w)) was 3.5 mg (2.0-10.5). Despite a higher CAB(max/w) in patients treated with multimodal therapy (P=0.003 vs exclusive pharmacological treatment), a debulking effect of surgery was shown in 14 patients, with a higher rate of PRL control (P=0.006) and a significant reduction in CAB(max/w) (P=0.001) postoperatively. At last follow-up (median 88 months), PRL normalization and tumor disappearance were achieved in 28 and 19.9% of the patients respectively, with no significant sex-related difference observed in CAB(max/w) or disease control. Mortality was 4.8%, with four patients developing aggressive tumors (4.3%) and three a pituitary carcinoma (3.3%). CONCLUSION CAB-resistant prolactinomas remain a serious concern. Surgical debulking, newer therapeutic strategies, and early diagnosis of genetic forms could help to improve their outcome.

Bone mineral density in acromegaly: the effect of gender, disease activity and gonadal status

objective Data on bone mineral density (BMD) in acromegaly are conflicting as most previous studies collectively evaluated eugonadal and hypogonadal patients of both sexes, with or without active disease. We have evaluated BMD in 152 acromegalic patients of both sexes with varying disease activity and gonadal status.

Screening of Cushing's Syndrome in Outpatients with Type 2 Diabetes: Results of a Prospective Multicentric Study in Italy

CONTEXT Cushings syndrome may remain unrecognized among patients referred for metabolic syndrome; thus, a proactive screening has been suggested in certain patient populations with features of the disorder. However, conflicting data have been reported on the prevalence of Cushings syndrome in patients with type 2 diabetes. OBJECTIVE Our aim was to evaluate the prevalence of unsuspected Cushings syndrome among outpatients with type 2 diabetes. DESIGN AND SETTING This was a cross-sectional prospective study in 24 diabetes clinics across Italy. PATIENTS Between June 2006 and April 2008, 813 patients with known type 2 diabetes without clinically overt hypercortisolism were evaluated. Follow-up of the study was closed in September 2010. Patients were not selected for characteristics conferring a higher pretest probability of hypercortisolism. Patients underwent a first screening step with the 1-mg overnight dexamethasone suppression test. RESULTS Forty patients failed to suppress serum cortisol less than 5.0 μg/dl (138 nmol/liter) and underwent a standard 2-d, 2-mg dexamethasone suppression test, after which six patients (0.6% of the overall series) failed to suppress cortisol less than 1.8 μg/dl (50 nmol/liter), receiving a definitive diagnosis of Cushings syndrome that was adrenal dependent in five patients. Four patients were cured, being able to discontinue, or reduce, the glucose-lowering agents. CONCLUSIONS The present data do not support widespread screening of patients with type 2 diabetes for Cushings syndrome; however, the disorder is less rare than previously thought when considering epidemiology of type 2 diabetes. Our results support a case-finding approach in patients with uncontrolled diabetes and hypertension despite appropriate treatment.

The efficacy and tolerability of long‐term cabergoline therapy in hyperprolactinaemic disorders: an open, uncontrolled, multicentre study

OBJECTIVE We assessed the efficacy and safety of the new, long‐acting dopamine agonist drug cabergoline during long‐term therapy of hyperprolactinaemia.

Dose‐dependent suppression of serum prolactin by cabergoline in hyperprolactinaemia: a placebo controlled, double blind, multicentre study

OBJECTIVE Dopamine agonists have a well established place in the treatment of hyperprolactinaemic disorders but their use is associated with a high incidence of adverse effects. We have investigated the biochemical efficacy and side‐effect profile of a range of doses of the novel, long‐acting dopamine agonist, cabergoline, in suppressing prolactin (PRL) in hyperprolactinaemic women.

Diagnosis and Drug Therapy of Prolactinoma

SummaryA prolactin-secreting pituitary tumour is the most frequent cause of hyperprolactinaemia that commonly occurs in clinical practice. Prolactinomas occur more frequently in women than in men and may differ in size, invasive growth and secretory activity. At presentation, macroadenomas are more frequently diagnosed in men. Specific immunohistochemical stains are necessary to prove the presence of prolactin in the tumour cells. The main investigations in the diagnosis of a prolactin-secreting adenoma are hormonal and radiological. As prolactin is a pulsatile hormone, it is a general rule to obtain several blood samples by taking a single sample on 3 separate days or 3 sequential samples (every 30 minutes) in restful conditions. Prolactin levels of 100 to 200 μg/L are commonly considered diagnostic for the presence of a prolactinoma; however, prolactinoma cannot be excluded in the presence of lower levels, and prolactin levels >100 μg/L are present in some patients with idiopathic hyperprolactinaemia.Several dynamic function tests have been proposed to differentiate idiopathic from tumorous hyperprolactinaemia. Although they could be used for group discrimination, these tests cannot be used for individual patients. To differentiate between a prolactinoma and a pseudoprolactinoma, thyrotrophin response to a dopamine receptor antagonist may be used, as only prolactinomas may have an increased response. A short course of dopaminergic drugs may also be of some help, as in macroprolactinomas only a shrinkage may be observed. After hyperprolactinaemia is confirmed, imaging with computerised tomography (CT) and magnetic resonance imaging (MRI) are necessary to define the presence of a lesion compatible with a pituitary tumour.There is now a general agreement that medical therapy is of first choice in patients with prolactinomas. Bromocriptine, the most common drug used in this condition, is a semisynthetic ergot alkaloid that directly stimulates specific pituitary cell membrane dopamine D2 receptors and inhibits prolactin synthesis and secretion. In most patients, a reduction or normalisation of prolactin levels is usually observed, together with the disappearance or improvement of clinical symptoms. The sensitivity to bromocriptine is variable and patients may need different doses of the drug. Bromocriptine is also able to shrink the tumour in most patients; however, a few reports of disease progression during therapy have been described. The need for close follow-up, including prolactin levels and CT or MRI studies, is therefore emphasised. Bromocriptine is conventionally given in 2 or 3 daily doses; however, a single evening dose has been shown to be equally effective. Bromocriptine is usually well tolerated by the majority of patients; some adverse effects (nausea, vomiting, postural hypotension) may be initially present, but they usually wear off in time. To prevent such adverse effects it is advisable to start treatment with a low dose during the evening meal and gradually increase the dose over days or weeks. A few patients are unable to tolerate oral bromocriptine, so different formulations of bromocriptine or alternative dopamine agonist drugs (lisuride, terguride, metergoline, dihydroergocryptine, quinagolide, cabergoline, pergolide) have been proposed. Of particular clinical relevance because of their good tolerability and sustained activity are cabergoline and quinagolide.Particular attention should be paid to pregnancy in prolactinoma patients, as tumour enlargement has been reported. As the risk for this occurrence is low in patients with microprolactinoma, there is a general agreement that the drug can be stopped once pregnancy is diagnosed. In patients with macroprolactinoma the risk of tumour enlargement is higher. Therefore, primary therapy with bromocriptine until the tumour has shrank is suggested before pregnancy is attempted. Bromocriptine should be stopped as soon as pregnancy is confirmed, but reinstated in case of neurological complication during pregnancy.

Hexarelin, a synthetic growth hormone releasing peptide, stimulates prolactin secretion in acromegalic but not in hyperprolactinaemic patients

OBJECTIVE In man, new synthetic peptides such as hexarelin have been shown to have a potent and dose dependent GH releasing activity. Furthermore, a significant PRL releasing activity has also been demonstrated, but this has been investigated in less detail. We have therefore evaluated the effect of hexarelin on PRL and GH secretion in patients with active acromegaly or pathological hyperprolactinaemia.

VERTEBRAL BONE DENSITY IN NON‐AMENORRHOEIC HYPERPROLACTINAEMIC WOMEN

Recently, a decrease in bone mineral content (BMC) in hyperprolactinaemic women with long‐lasting amenorrhoea has been reported, and attributed either to a direct effect of PRL on bone or secondary to the oestrogen deficiency. To verify if PRL by itself has a direct effect on bone, we have studied BMC at the lumbar level by double‐photon absorptiometry in 22 patients with hyperprolac‐tinaemia, selected on the basis of normal or near‐normal oestradiol levels. The results were compared with those obtained in 28 healthy closely‐matched women, and seven hyperprolactinaemic patients with long‐lasting amenorrhoea and oestrogen deficiency. No significant difference in BMC was observed between hyperprolactinaemic patients with normal oestrogen levels (mean ± SEM = 3.87 ± 0.10 gHA/cm) and normal subjects (mean ± SEM = 3.76±0.10 gHA/cm). Moreover, no significant change was observed during a 6 month follow‐up in 13 patients. On the other hand, a significant difference (P < 0.05) was detected in BMC between the hyperprolactinaemic patients with normal oestradiol levels and those with long‐lasting amenorrhoea and oestrogen deficiency (mean ± SEM = 3.39 ± 0.18). These results suggest that hyperprolac‐tinaemia by itself is not a risk factor for the development of osteoporosis.