Antonella Di Sarno

Increased prevalence of tricuspid regurgitation in patients with prolactinomas chronically treated with cabergoline.

BACKGROUND Cabergoline, a dopamine receptor-2 agonist used to treat prolactinomas, was associated with increased risk of cardiac valve disease in Parkinsons disease. OBJECTIVE Our objective was to evaluate prevalence of cardiac valve regurgitation in cabergoline-treated patients with prolactinomas. DESIGN AND SETTING An observational, case-control study was conducted at a university hospital. PATIENTS Fifty treated patients (44 women and six men) and 50 sex- and age-matched control subjects participated; 20 de novo patients were also studied. INTERVENTION In the treated patients, the last cabergoline dose was 1.3 +/- 1.3 mg/wk (<1 mg/wk in 44%, 1-3 mg/wk in 46%, and >3 mg/wk in 10%). Treatment duration was 12-60 months in 32% and more than 60 months in 68%. The cumulative (milligrams x months of treatment) dose of cabergoline ranged from 32-1938 mg (median 280 mg). MEASUREMENTS Valve regurgitation was assessed according to the recommendations of the American Society of Echocardiography. RESULTS In de novo patients, treated patients, and controls, the prevalence of mild regurgitation of mitral (35, 22, and 12%, P = 0.085), aortic (0, 4, and 2%, P = 0.59), tricuspid (55, 30, and 42%, P = 0.13) or pulmonic (20, 12, and 6%, P = 0.22) valves was similar. Conversely, the prevalence of moderate tricuspid regurgitation was higher in the treated patients (54%) than in de novo patients (0%) and controls (18%, P < 0.0001). Moderate tricuspid regurgitation was more frequent in patients receiving a cumulative dose above the median (72%) than in those receiving a lower dose (36%, P = 0.023). A higher systolic (P = 0.03) and diastolic blood pressure (P < 0.0001) was found in patients with than in those without moderate tricuspid regurgitation. CONCLUSION Moderate tricuspid regurgitation is more frequent in patients taking cabergoline (at higher cumulative doses) than in de novo patients and control subjects, but the clinical significance of this finding has not been established. A complete echocardiographic assessment is indicated in patients treated long term with cabergoline, particularly in those requiring elevated doses.

The effect of quinagolide and cabergoline, two selective dopamine receptor type 2 agonists, in the treatment of prolactinomas

To compare effectiveness and tolerability of quinagolide (CV 205–502) and cabergoline (CAB) treatments in 39 patients with prolactinoma.

Prolactinomas in adolescents: persistent bone loss after 2 years of prolactin normalization

To evaluate the effect of hyperprolactinaemia and its treatment with dopamine‐agonists on bone mass and turnover in adolescent patients compared to adults.

Hyperprolactinemia in men: clinical and biochemical features and response to treatment.

Hyperprolactinemia induces hypogonadism by inhibiting gonadotropin-releasing hormone pulsatile secretion and, consequently, follicle-stimulating hormone, luteinizing hormone, and testosterone pulsatility. This leads to spermatogenic arrest, impaired motility, and sperm quality and results in morphologic alterations of the testes similar to those observed in prepubertal testes. Men with hyperprolactinemia present more frequently with a macroadenoma than a microadenoma. Symptoms directly related to hypogonadism are prevalent. In men hypogonadism leads to impaired libido, erectile dysfunction, diminished ejaculate volume, and oligospermia. It is present in 16% of patients with erectile dysfunction and in approx 11% of men with oligospermia. Treatment with bromocriptine or cabergoline (CAB) is effective in men with prolactinomas, with a response that is in general comparable to treatment in women. Seminal fluid abnormalities rapidly improve with CAB treatment, while other dopaminergic compounds require longer periods of treatment. Moreover, to improve gonadal function in men, the integrity of the hypothalamic-pituitary-gonadal axis is necessary. New promising data indicate that a substantial proportion of patients with either micro- or macroprolactinoma do not present hyperprolactinemia after long-term withdrawal from CAB. Whether this corresponds to a definitive cure is still unknown, but treat-ment withdrawal should be attempted in patients achieving normalization of prolactin levels and disappearance of tumor mass to investigate this issue.

Predictors of remission of hyperprolactinaemia after long‐term withdrawal of cabergoline therapy

Background  Remission rates of 76, 69·5 and 64·3% have been reported in patients with nontumoural hyperprolactinaemia (NTH), microprolactinoma and macroprolactinoma, respectively, 2–5 years after cabergoline (CAB) withdrawal.

New Medical Approaches in Pituitary Adenomas

Recently, the medical approach to patients with secreting and clinically non-functioning pituitary adenomas has received great impulse thanks to the availability of new, selective and long-lasting compounds with dopaminergic activity, such as cabergoline, and of somatostatin analogues provided in slow-release formulations, such as lanreotide and octreotide long acting release (LAR). In particular, the use of cabergoline has induced control of hyperprolactinaemia and tumour shrinkage in the great majority of patients with micro- and macroprolactinomas. Cabergoline treatment restores fertility both in women and men, and partially improves osteoporosis, one of the major complications of hyperprolactinaemia. In acromegaly, disease control (growth hormone [GH] <2.5–1.0 μg/l as a fasting or glucose-suppressed value, respectively, together with age-normalised insulin-like growth factor [IGF]-I) is achievable in more than half of patients receiving treatment with lanreotide or octreotide-LAR. Improvement in cardiomyopathy, sleep apnoea and arthropathy has been reported during GH/IGF-I suppression after pharmacotherapy. A synthetic GH analogue, B2036-PEG, that antagonises endogenous GH binding to its receptor-binding sites and a GH-releasing hormone antagonist that blocks the effect of this releasing factor on the hypothalamus and pituitary are presently under investigation in acromegaly. Preliminary studies have clearly demonstrated the effectiveness of the GH receptor antagonist in suppressing IGF-I levels in acromegalic patients previously unresponsive to somatostatin analogues. Beneficial effects of subcutaneous octreotide and lanreotide have also been reported in adenomas secreting thyroid-stimulating hormone, while the results of treatment with dopamine agonists or somatostatin analogues remain disappointing in patients with clinically non-functioning adenomas. In these patients the possibility of visualising in vivo the expression of D2 receptors using specific radiotracers such as 123I-methoxybenzamide has allowed selection of patients likely to respond to cabergoline. Scant effects of pharmacotherapy have also been reported in patients with adenomas secreting adrenocorticotropic hormone. However, some preliminary data suggest a potential use of cabergoline in combination with ketoconazole, or alone, in selected cases of Cushing’s disease or Nelson’s syndrome.

Severe impairment of bone mass and turnover in Cushing's disease: comparison between childhood-onset and adulthood-onset disease.

background Osteoporosis is an important, frequently unrecognized consequence of hypercortisolism.

Hormone levels and tumour size response to quinagolide and cabergoline in patients with prolactin‐secreting and clinically non‐functioning pituitary adenomas: predictive value of pituitary scintigraphy with 123I‐methoxybenzamide

BACKGROUND Dopamine agonists are indicated as primary therapy for PRL‐secreting pituitary adenomas, while controversial results have been reported in nonfunctioning adenomas (NFA).

Drug Insight: cabergoline and bromocriptine in the treatment of hyperprolactinemia in men and women

Prolactinoma is the most frequent pituitary tumor histotype. Men generally have macroadenomas whereas women generally have microadenomas. The major objectives of treating prolactinomas are to suppress excessive hormone secretion and its clinical consequences, to remove the tumor mass while preserving the residual pituitary function, and possibly to prevent disease recurrence or progression. Primary therapy of prolactinomas is based on use of dopamine-receptor agonists. Bromocriptine induces normalization of prolactin levels in 80–90% of patients with microprolactinomas and approximately 70% of those with macroprolactinomas. Tumor-mass shrinkage and improvement of visual-field defects are found in the majority of treated macroprolactinomas, but bromocriptine often causes side effects. Cabergoline is very effective and well tolerated in more than 90% of patients with either microprolactinomas or macroprolactinomas. Cabergoline treatment also induces tumor shrinkage in the majority of patients with macroprolactinomas. Tumor shrinkage is more evident if patients have not previously been treated with other dopamine agonists. Fewer results are available for men than for women, but there is no evidence that men are less responsive to dopamine agonists than are women.

Results of a Single-Center Observational 10-Year Survey Study on Recurrence of Hyperprolactinemia after Pregnancy and Lactation

CONTEXT The current survey study investigated the recurrence rate of hyperprolactinemia after cabergoline (CAB)-induced pregnancy and after lactation as well as safety of CAB exposure during early gestation. PATIENTS AND METHODS From 1997-2008, 143 pregnancies were recorded in 91 patients with hyperprolactinemia (age 30.4 ± 4.7 yr, 76 microadenomas, 10 macroadenomas, and five nontumoral hyperprolactinemia). CAB therapy was discontinued within wk 6 of gestation in all. Pregnancies were monitored until delivery or termination, during and after lactation, twice yearly up to 60 months. The incidence of abortions, premature delivery, and fetal malformations was also analyzed. RESULTS Pregnancies resulted in 13 (9.1%) spontaneous abortions and 126 (88.1%) live births. No neonatal malformations and/or abnormalities were recorded. In 29 of 91 patients (three with macroadenomas), treatment with CAB had to be restarted within 6 months after lactation because of hyperprolactinemia recurrence, whereas in 68% of cases, no additional therapy was required up to 60 months. No tumor mass enlargement was observed. All patients but three were breastfeeding, 35 (38.5%) for less than 2 months and 56 (61.5%) for 2-6 months. Three months after cessation of lactation and 60 months after pregnancy, no difference in prolactin levels was found between patients nursing for less than 2 months and 2-6 months. CONCLUSIONS Fetal exposure to CAB at conception does not induce any increased risk of miscarriage or malformations. Pregnancy is associated with normalization of prolactin levels in 68% of patients. Breastfeeding does not increase the recurrence rate of hyperprolactinemia.