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.

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 Parkinson's 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.

Quality of life in women with microprolactinoma treated with dopamine agonists.

OBJECTIVES: To evaluate QOL in women with microprolactinomas treated with dopamine agonists, comparing the patients with normal versus those with elevated prolactin levels, and to identify clinical and biochemical influences on patients' QOL. MATERIAL AND METHODS: A cross-sectional evaluation was performed in two University referral centers. Fifty women with microprolactinoma answered the SF-36 questionnaire by the time of their clinical evaluation. Their biochemical analysis included PRL, estradiol, testosterone, and SHBG. Fifty women of similar age distribution served as controls. RESULTS: Patients had lower scores than controls in all SF-36 categories: physical functioning, physical role, pain, general health, vitality, social functioning, emotional aspect, and mental health. Within the patients' group, the ones with normal PRL levels had higher scores than those with high PRL levels in all categories but the physical role. The physical functioning score correlated with the free androgen index, while the pain, vitality, social functioning, emotional aspect, and mental health scores were associated with the prolactin levels obtained at study entry. CONCLUSIONS: QOL is impaired in women with microprolactinoma treated with dopamine agonists, and was inversely associated with the PRL levels. This latter finding reinforces the importance of providing adequate disease control for these patients in order to avoid the adverse consequences of hyperprolactinemia on QOL.

Circulating IGF-I levels are associated with increased biventricular contractility in top-level rowers.

BACKGROUND: The intensive physical activity is often associated with cardiac changes. OBJECTIVES: (i) To evaluate the IGF-I system and myocardial structure and function by standard Doppler echocardiography and Tissue Doppler in athletes and sedentary controls; and (ii) to determine any relationship between IGF-I system and echocardiographic parameters. METHODS: Nineteen male top-level rowers and 19 age-matched healthy sedentary male controls underwent blood determination of fasting serum IGF-I, IGFBP-3 and acid-labile subunit levels and standard Doppler echocardiography combined with pulsed Tissue Doppler of posterior septal wall, left ventricular (LV) lateral mitral annulus and right ventricular (RV) tricuspid annulus. Myocardial presystolic (PS(m)), systolic (S(m)), the ratio of early diastolic (E(m)) to atrial (A(m)) velocities as well as myocardial time intervals were calculated. RESULTS: Rowers had higher serum IGF-I levels (P = 0.04), higher biventricular cavity dimensions and wall thicknesses compared to controls. They also had better LV and RV myocardial function than controls. In the rowers, IGF-I was associated with LV ejection fraction (r = 0.50, P = 0.03), RV PS(m) velocity (r = 0.55, P = 0.01) and with RV myocardial precontraction time (r = -0.57, P = 0.01). These associations remained significant after adjusting for age and heart rate. CONCLUSIONS: Top-level athletes showed higher IGF-I levels and a better myocardial performance than controls, particularly for the RV systolic activity. The independent correlations between IGF-I and systolic parameters of the left (ejection fraction) and right (PS(m) velocity and precontraction time) ventricles may possibly indicate a role of IGF-I system in the modulation of myocardial inotropism in athletes. Further studies are needed to confirm this hypothesis.

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. OBJECTIVE: To report the estimated recurrence rate at 24-96 months after CAB withdrawal and indicate predictors of disease remission. DESIGN: Observational, analytical, prospective. PATIENTS: Of 381 previously untreated de novo patients with hyperprolactinaemia, 221 (58%) (173 women, 48 men; 27 with NTH, 115 with micro-, and 79 with macroprolactinoma) were studied. MEASUREMENTS: Using multiple regression analysis the diagnostic accuracy of nadir PRL levels (t = 7.6, P < 0.0001) and nadir maximal tumour diameter at CAB withdrawal (t = 3.9, P < 0.001) was analysed using receiver operating characteristic (ROC) curves. RESULTS: The recurrence of hyperprolactinaemia was 25.9, 33.9 and 53.1% in patients with NTH, micro- or macroprolactinoma, respectively. To predict the last PRL level after withdrawal, the optimum cut-off of nadir PRL levels at withdrawal was 162 mU/l (5.4 microg/l) [sensitivity (95% CI) 76% (67-84%), specificity 65% (51-77%)] and that of nadir maximal tumour diameter was 3.1 mm [sensitivity 52% (41-63%), specificity 86% (79-91%)]. The patients achieving both nadir PRL levels

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.

The treatment with cabergoline for 24 month normalizes the quality of seminal fluid in hyperprolactinaemic males.

BACKGROUND: Alterations of sperm number and motility are found in hyperprolactinaemic men. Cabergoline treatment reverses alterations in semen. No information is currently available on the quality of seminal tests in hyperprolactinemia in response to cabergoline treatment. OBJECTIVE: To further investigate the effect of hyperprolactinaemia and its treatment with cabergoline on semen quality. PATIENTS: Forty-three men with hyperprolactinaemia (32 macro- and 11 micro-prolactinomas); 60 healthy men served as control. METHODS: Live spermatozoa count, sperm membrane function, kinetic index, nuclear DNA integrity, sperm curvilinear and linear velocity and amplitude of lateral movement of the sperm head were investigated before and after 6 and 24 months of treatment with cabergoline. STUDY DESIGN: Open prospective. RESULTS: At study entry, semen functional tests were severely and similarly impaired both in patients with macro- and micro-prolactinomas compared to controls. After 6 and 12 months of treatment there was a significant improvement of semen quality in patients achieving normalization of prolactin levels, although most of the parameters remained lower than in controls. After 24 months of treatment, seminal fluid characteristics were similar to the controls except for live spermatozoa count, sperm membrane function, sperm kinetic index and sperm nuclear DNA integrity, which remained abnormal in 9.3-53% of the patients. CONCLUSIONS: Twenty-four months of cabergoline treatment restored gonadal function in 66.7% of men with hyperprolactinaemia.

Hypertension in acromegaly and in the normal population: prevalence and determinants.

BACKGROUND: The GH/IGF-I axis has a relevant role to play in the cardiovascular system but its implication in the pathogenesis of hypertension in the normal population and in acromegaly is not yet clear. PATIENTS AND MEASUREMENTS: The aim of this retrospective and controlled study was to evaluate the prevalence and determinants of hypertension in 200 patients with acromegaly and 200 nonacromegalic subjects, matched for sex, age, body mass index (BMI) and smoking habits. RESULTS: Hypertension was found in 46% of patients and in 25% of controls (P < 0.0001), without any difference between men and women. Family history of hypertension occurred in 30% of hypertensive acromegalic patients and in 62% of hypertensive controls (P < 0.0001). In both groups, hypertensive subjects were older than normotensive subjects. Systolic (SBP) and diastolic blood pressures (DBP) in hypertensive acromegalic patients were lower and higher, respectively, than in hypertensive controls. The risk of hypertension increased with age and was higher in the patients than in the controls [hazard ratio (HR) 1.9; P = 0.0002]. Independent predictors of SBP were age and glucose in the acromegalic population, and BMI, age and glucose levels in the controls. Independent predictors of DBP were age and glucose in the patients, and BMI, age and IGF-I in the controls. CONCLUSIONS: In acromegaly, hypertension is more frequent than in the general population, involves predominantly DBP, and occurs earlier, is not related to gender, and is less frequently related to family history of hypertension and IGF-I levels. IGF-I may have a protective role for DBP in the general population.

PRL secreting adenomas in male patients.

Prolactinomas are the most frequent pituitary tumors and their frequency varies with age and sex, occurring most frequently in females between 20-50 yr-old. In men, hyperprolactinaemia is often present for many years without symptoms, as generally the most important symptoms are the decrease in libido and/or sexual potency both underestimated by the majority of the patients. Prolactin (PRL) plays a role in the process of spermatogenesis, and normal serum PRL levels are required for normal testicular function. On the other hand, hyperprolactinaemia has multiple negative effects on the gonadal axis. As a consequences hyperprolactinemic males show alteration of sexual potency and seminal fluid quality. Cabergoline treatments is able to induce normalization of PRL levels and a reduction of tumor mass in the majority of patients and consequently restoring the normal semen quality and ameliorating the quality of life of men with pituitary PRL-secreting adenoma.

Prolactin and prostate hypertrophy: a pilot observational, prospective, case-control study in men with prolactinoma.

In experimental models, prolactin (PRL) displays independent hypertrophic effects on the prostate. To investigate whether hyperprolactinemia is associated with prostate enlargement in humans, we designed this open, prospective, case-control study enrolling 20 men with prolactinoma (aged 34 +/- 10 yr) and 20 age-matched healthy men. The endocrine profile and prostate transrectal ultrasonography were performed before and after 12 and 24 months of cabergoline treatment in the patients and at study entry and after 24 months in the controls. The patients had lower serum testosterone, dihydrotestosterone (DHT), and IGF-I levels and prostate volume (15.4 +/- 3.5 vs. 19.6 +/- 5.1 ml; P < 0.001) and higher PRL levels and prostate-specific antigen density than controls. There was no difference in prostate and transitional zone volumes between patients with normoandrogenemia (n = 8) or hypoandrogenemia (n = 12). After 12 and 24 months of treatment, PRL, testosterone, and DHT levels were normal in all cases, as were IGF-I and IGF-binding protein-3 levels. After 24 months, prostate volume was comparable to that in controls (21.7 +/- 4.5 vs. 22.5 +/- 4.7 ml). There were no changes in prostate structure throughout the study period in either the patients or the controls. In conclusion, in young men with prolactinoma PRL excess is unlikely to have effects on the prostate per se, because it is accompanied by low testosterone and DHT levels that produce the major effects.