Recurrence of hyperprolactinaemia following discontinuation of dopamine agonist therapy in patients with prolactinoma occurs commonly especially in macroprolactinoma

Context The optimal duration of dopamine agonist (DA) therapy in prolactinoma is unknown. There are concerns that despite low recurrence rates in highly selected groups, high recurrence rates after DA withdrawal may occur in routine practice. Objective To explore recurrence of hyperprolactinaemia and predictive factors following DA withdrawal in patients with microprolactinoma and macroprolactinoma. Design A retrospective study on adult patients with confirmed prolactinoma attending the Oxford Endocrine Department. Patients and Measurements We identified patients with macroprolactinoma (n = 15) and microprolactinoma (n = 45) treated with DA therapy for >3 years, with a trial off DA therapy. None had other treatments. Measurements included recurrence of hyperprolactinaemia following DA withdrawal, tumour size (macroprolactinomas), duration of DA therapy, prolactin levels (baseline, during DA therapy, recurrence) and time to recurrence. Data were reported as mean (range). Results During DA therapy, prolactin levels suppressed to normal range in all patients with macroprolactinoma and microprolactinoma, and most macroprolactinomas (n = 14) had substantial tumour shrinkage. Hyperprolactinaemia recurred in 93% of macroprolactinomas (n = 14) at 8·8 months (3–36) and 64% of microprolactinomas (n = 29) at 4·8 months (3–12). Duration of DA therapy was 7·5 years (4–15) for macroprolactinomas and 4·1 years (3–10) for microprolactinomas. Prolactin levels during DA therapy were 144 mU/l (7–336) for macroprolactinomas and 278 mU/l (30–629) for microprolactinomas. For microprolactinomas, prolactin levels during DA therapy were less suppressed in those with recurrence than in those without recurrence (P < 0·05). Conclusions In routine practice, hyperprolactinaemia recurs early in most macroprolactinomas (93%) and microprolactinomas (64%) following DA therapy discontinuation. For most macroprolactinomas, cessation of DA cannot be recommended even after 7 years of therapy.     

Primary medical therapy of micro- and macroprolactinomas in men

The presentation and long-term therapeutic responses of PRL-secreting pituitary tumors in men have been only partially studied. Gender-specific differences in tumor size at clinical presentation and possible differences in tumor biology in men compared to women make it important to determine treatment outcomes of male patients with prolactinomas. We performed a retrospective review of men with prolactinomas medically managed at Massachusetts General Hospital between 1980 and 1997. We identified 46 male patients with prolactinomas managed with medical therapy alone. Twelve patients had microadenomas, defined as a serum PRL level greater than 15 ng/mL and a normal pituitary scan or a tumor smaller than 1 cm. Thirty-four patients had macroprolactinomas, defined by a serum PRL greater than 200 ng/mL and pituitary adenoma larger than 1 cm. Bromocriptine, quinagolide, and/or cabergoline were administered as medical therapy. All patients had at least one follow-up visit, and the most recent serum PRL measurement after initiating dopamine agonist therapy was reported. Baseline clinical characteristics for patients with macroprolactinomas and microprolactinomas showed a larger proportion of patients with macroprolactinomas reporting a history of headache (74% vs. 0%), whereas the prevalence of sexual dysfunction and testosterone deficiency was similar between the two groups. Median serum PRL at presentation was 99 ng/mL (range, 16-385 ng/mL) vs. 1,415 ng/mL (range, 387-67,900 ng/mL), in the microprolactinoma and macroprolactinoma groups, respectively. A normal PRL level was achieved in a similar percentage of men with microprolactinomas vs. macroprolactinomas (83% vs. 79%, respectively). Although the majority of patients in both groups were treated with bromocriptine, a comparable number of patients with microprolactinomas vs. macroprolactinomas achieved a normal PRL level with cabergoline therapy. The response rates for bromocriptine and cabergoline were similar in both groups. No patient with a microprolactinoma required hormone replacement therapy, in contrast to patients with macroprolactinomas, who required thyroid, testosterone, and/or glucocorticoid replacement therapy. No patient had evidence of an increase in tumor size during therapy. In summary, we investigated the clinical presentation and treatment outcome in men with prolactinomas. We found that normalization of serum PRL levels occurs in approximately 80% of men with prolactinomas. Of importance, dopamine agonist administration yielded similar biochemical remission rates in men with microprolactinomas and macroprolactinomas.     

Management of prolactinomas in Brazil: an electronic survey

Dopamine agonists are the treatment of choice for prolactinomas. However, there are still controversies concerning dose, treatment duration and criteria for drug withdrawal in different clinical situations. The aim of this study was to assess diagnostic and therapeutic approaches to prolactinomas among members of the Brazilian Society of Endocrinology and Metabolism (SBEM). SBEM members answered a questionnaire sent by e-mail that included 18 questions related to controversial issues about the management of prolactinomas. Among SBEM members, 721 (approximately 24% of total) answered the questionnaire. Concerning the diagnosis, 38% of the respondents stated that prolactin levels < 100 ng/ml would exclude the presence of a prolactinoma. Most of them favored the screening for macroprolactin in asymptomatic individuals instead of a routine screening (74% vs. 26%). Regarding the treatment, 70% of the respondents chose cabergoline as the drug of choice to treat macroprolactinomas whereas similar proportions advised cabergoline or bromocriptine as the best treatment for microprolactinomas (52% vs. 48%). Only 20% and 34% of respondents favored treatment withdrawal 2–3 years after prolactin normalization in patients with macroprolactinomas and microprolactinomas, respectively. In case of pregnancy, only 58 and 70% of respondents advocated discontinuation of treatment with dopamine agonists in patients with macroprolactinomas and microprolactinomas, respectively. Finally, only 36% would allow breast-feeding without restriction, 44% would restrict it to patients with microprolactinomas and 20% would not recommend it for women with prolactinomas There are several points of disagreement among SBEM members regarding the management of prolactinomas.     

Withdrawal of dopamine agonist therapy in prolactinomas: In which patients and when?

Purpose

The aim of the study was to assess the effect of dopamine agonist (DA) withdrawal, the current recurrence rate of hyperprolactinemia, and possible factors that predict recurrence in patients with prolactinoma.

Methods

We evaluated DA withdrawal in 67 patients with prolactinoma (50 female/17 male) who received DA treatment for at least 2 years and showed normalization of prolactin (PRL) levels and tumor disappearance or ≥50 % tumor shrinkage, retrospectively. Accordingly, patients were divided into two groups as remission and recurrence groups, and factors that predict recurrence were evaluated.

Results

The overall remission rate was 46 %; the remission ratios were 65 % in microprolactinomas and 36 % in macroprolactinomas. Remission rates were 39 % in the bromocriptine withdrawal group and 55 % in the cabergoline withdrawal group. The maximum tumor diameter and baseline PRL levels were significantly higher in the recurrence group (p = 0.001 and p = 0.003, respectively). The mean duration of DA therapy was significantly longer in the remission group (88.7 ± 48.1 and 66.7 ± 30.4 months, respectively, p = 0.026).The mean time to recurrence was 5.3 ± 3.2 months. The mean PRL levels at recurrence time were significantly lower than baseline PRL levels (p = 0.001).

Conclusion

The most important predictors of recurrence were maximum tumor diameter and baseline PRL levels in this study. The remission rate in our study group was higher, which was thought to be associated with the longer duration of DA treatment and that our patients were selected according to certain criteria. Despite these positive results, close monitoring is necessary for detection of early and late recurrence, especially within the first year after DA withdrawal.

     

Secondary resistance to cabergoline therapy in a macroprolactinoma: a case report and literature review

Primary resistance to dopamine agonists occurs in 10–15% of prolactinomas but secondary resistance following initial biochemical and anti-proliferative response is very rare and has only been hitherto described in four previous cases, two with bromocriptine and two with cabergoline. We describe a case of a 57-year-old woman who presented with a large macroprolactinoma with suprasellar extension. She was initially treated with bromocriptine therapy with a resolution of symptoms, marked reduction in prolactin concentration and complete tumour shrinkage; a response which was subsequently maintained on cabergoline. After 8 years of dopamine agonist therapy, her prolactin concentration began to rise and there was symptomatic recurrence of her tumour despite escalating doses of cabergoline up to 6 mg weekly. Non-compliance was outruled by observed inpatient drug administration. The patient underwent surgical debulking followed by radiotherapy with good response. This case adds to the previous two cases of secondary resistance to cabergoline therapy in prolactinomas a marked initial response. While the mechanism of secondary resistance remains unknown and not possible to predict, close observation of prolactinoma patients on treatment is necessary.     

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. DESIGN: Multicentre, prospective, randomized, placebo controlled and double blind. PATIENTS: One hundred and eighty-eight women with hyperprolactinaemia secondary to microprolactinoma (n = 113), idiopathic disease (n = 67), empty sella syndrome (n = 7) or following failed surgery for a macroprolactinoma (n = 1). MEASUREMENTS: Weekly assessment of adverse symptoms, blood pressure and pulse, serum PRL, blood count, liver and renal function. RESULTS: Patients received either placebo (n = 20) or cabergoline 0.125 (n = 43), 0.5 (n = 42), 0.75 (n = 42) or 1.0 mg (n = 41) twice weekly for 4 weeks. The five treatment groups were comparable in age (mean 31.8, range 16-46 years), diagnosis, previous therapy, and pretreatment serum PRL. PRL was suppressed to below half the pretreatment level in 5, 60, 90, 95 and 98% and normalized in 0, 30, 74, 74 and 95% of patients taking placebo or cabergoline 0.125, 0.5, 0.75 or 1.0 mg twice weekly respectively (Armitage's test, chi 2 = 39.3, P < 0.01). Cabergoline therapy (all doses) restored menses in 82% of the amenorrhoeic women not previously treated with dopamine agonists. Adverse events were recorded in 45% of patients in the placebo group and in 44, 50, 50 and 58% of those taking 0.125, 0.5, 0.75 and 1.0 mg cabergoline twice weekly (Armitage's test, P > 0.05). Over 95% of reported symptoms were relatively trivial, most frequently transient nausea, headache, dizziness, fatigue and constipation. More severe adverse events, interfering significantly with the patients' lifestyle, occurred in 13 (7.7%) patients taking cabergoline; treatment withdrawal was necessary in only one case. No adverse effects were detected on blood pressure or haematological or biochemical parameters. CONCLUSIONS: We have shown a linear dose-response relationship for cabergoline in the treatment of hyperprolactinaemia in the range 0.125-1.0 mg twice weekly, with normalization of PRL in up to 95% of cases and acceptable tolerability throughout the dose range.     

Prolactinoma and pregnancy: From the wish of conception to lactation

Prolactinoma is a common cause of infertility in young women and treatment with dopamine agonists (DA) allows restoration of fertility in over 90% of the cases. Both bromocriptine and cabergoline have shown a good safety profile when administered during early pregnancy. In particular, data on exposure of the fetus or embryo to cabergoline during the first weeks of pregnancy have now been reported in more than 900 cases, and do indicate that cabergoline is safe in this context. There is no increase in the frequency of spontaneous miscarriage, premature delivery, multiple births or neonatal malformations, and follow-up studies of the children for up to 12 years after fetal exposure to cabergoline did not show any physical or developmental abnormalities. These women should therefore continue DA treatment until pregnancy has been initiated. Treatment discontinuation is recommended at that time in women with microprolactinoma or non-compressive macroprolactinoma. For microprolactinomas, the risk of symptomatic tumour enlargement during pregnancy is very low (2–3%). It is higher for macroprolactinomas (20–30%) and careful follow-up is advised, including MRI without contrast injection if symptoms or visual disturbances develop. If a symptomatic tumour enlargement does occur, reinitiation of the dopamine agonist (BRC or CAB) is indicated rather than surgery. Breast-feeding has no harmful effect on tumour growth and DA treatment, if still needed, may be postponed as long as breast-feeding is desired. Finally, about 40% of women with a microprolactinoma or an intermediate size macroprolactinoma may be in prolonged remission after one or more pregnancies.     

Quinagolide--a valuable treatment option for hyperprolactinaemia

Hyperprolactinaemia is characterised by gonadal dysfunction, including infertility and reduced libido and, if left untreated, is associated with an increased risk of long-term complications, such as osteoporosis. The first-line therapy for patients with hyperprolactinaemia is pharmacological intervention with a dopamine agonist. Currently, there are three dopamine agonists available for hyperprolactinaemia therapy: bromocriptine, quinagolide and cabergoline. Bromocriptine has a long history of use; however, a range of 5-18% of patients are reported to show bromocriptine resistance, with only partial lowering of plasma prolactin levels and an absence of tumour shrinkage. The newer dopamine agonists, quinagolide and cabergoline, offer improved efficacy over bromocriptine, with a lower incidence of adverse events. Quinagolide and cabergoline have also demonstrated efficacy in many patients intolerant or resistant to bromocriptine. Thus, the selection of dopamine agonists available provides more than one option for pharmacological intervention of hyperprolactinaemia. This review discusses the clinical use of quinagolide in comparison to other dopamine agonists for hyperprolactinaemia therapy. Quinagolide may improve patient compliance to treatment owing to its reduced side effect profile, simple and rapid titration over just 7 days, once-daily dosing regimen and easy to use starter pack (available in some countries). Quinagolide offers an additional benefit for patients wishing to become pregnant, as it can be used until the point of confirmation of pregnancy. Therefore, as a well tolerated and effective therapy, with a simple dosing regimen, quinagolide should be considered as a first-line therapy in the treatment of hyperprolactinaemia.     

Aortic valve calcification and mild tricuspid regurgitation but no clinical heart disease after 8 years of dopamine agonist therapy for prolactinoma

Objective: Treatment with ergot-derived dopamine agonists, pergolide, and cabergoline has been associated with an increased frequency of valvular heart disease in Parkinson's disease. The aim of the present study was to assess the prevalence of valvular heart disease in patients treated with dopamine agonists for prolactinomas. Design: This was a cross-sectional study. Patients: We performed two-dimensional and Doppler echocardiography in 78 consecutive patients with prolactinoma (mean age 47 +/- 1.4 yr, 26% male, 31% macroprolactinoma) treated with dopamine agonists for at least 1 yr (mean 8 +/- 0.6 yr) and 78 control subjects. Patients were classified according to treatment: patients treated with cabergoline (group 1: n = 47) and patients not treated with cabergoline (group 2: n = 31). Results: Clinically relevant valvular heart disease was present in 12% of patients (nine of 78) vs. 17% of controls (13 of 78) (P = 0.141) and 17% (eight of 47) of patients treated with cabergoline vs. 3% (one of 31) of patients not treated with cabergoline (P = 0.062). Mild tricuspid regurgitation was present in 41% of patients vs. 26% of controls (P = 0.042), and aortic valve calcification was present in 40% of patients, compared with 18% of controls (P = 0.003). There was no relation between the cumulative dose of cabergoline and the presence of mild, moderate, or severe valve regurgitation. Conclusion: Several years of dopamine agonist treatment in patients with prolactinomas is associated with increased prevalence of aortic valve calcification and mild tricuspid regurgitation but not with clinically relevant valvular heart disease. Therefore, additional studies on the adverse cardiac effects of dopaminergic drugs in prolactinoma are warranted, especially in patients with much longer use of these drugs.     

Clinical management of prolactinomas.

Prolactinomas are benign, sporadic pituitary tumours that typically present with amenorrhoea and galactorrhoea in women, and hypogonadism and space-occupying effects in men. Hyperprolactinaemic hypogonadism in either sex is associated with reduced bone mineral density, which may be progressive and only partially reversible. For most microprolactinomas, dopamine agonists are the treatment of choice, achieving normoprolactinaemia and restoring gonadal function in 80-90% of cases. Trans-sphenoidal surgery is curative in 60%, but may be complicated by hypopituitarism and is usually reserved for patients with dopamine agonist intolerance or resistance. A subgroup of patients with small tumours, mild symptoms and normal gonadal function may be monitored without specific treatment--the risk of tumour expansion is small. Macroprolactinomas should be treated medically, dopamine agonists controlling prolactin secretion and achieving significant tumour shrinkage in 80% of cases, whereas surgery is curative in only a quarter. Cabergoline is the dopamine agonist of choice in most situations, being better tolerated and more effective than bromocriptine. Quinagolide is an effective alternative. Dopamine agonist withdrawal or dose reduction should be considered after 2-5 years therapy. Oestrogens may be used with caution in women with prolactinomas.     

The assessment of cabergoline efficacy and tolerability in patients with pituitary prolactinoma type

Prolactinoma is the most frequent type of secreting pituitary tumours. In the treatment, pharmacotherapy with dopamine agonists is considered the first-line option. For many years bromocriptine, a D1 and D2 dopamine receptor agonist, has been the standard medicine for hyperprolactinemic patients. However, the treatment is frequently associated with intolerance or resistance. Recently cabergoline, a long acting, ergoline-derived, selective D2 agonist has become available and has been promoted as the initial treatment. Therefore the object of four studies was to assess the efficacy and tolerability of cabergoline in patients with prolactin-secreting pituitary adenomas. 17 patients, 13 women at the age of 21-55 years (average 37.1) and 4 men at the age of 29-45 years (average 36.3), with pathological hyperprolactinemia due to pituitary tumours were involved in the study. In all patients the increased pretreatment concentration of PRL was observed, ranging from 1047 to 1678 mlU/ml (mean 1369 mlU/ml). MRI scans revealed microprolactinomas in 11 (64.7%) cases and macroadenomas in 6 (35.3%) cases. None of the patients had previously undergone pituitary surgery and all of them were newly diagnosed, previously untreated. The patients were treated with cabergoline for 6 months. Cabergoline therapy was started at a dose of 0.5 mg twice a week for the first two months, then the dose was decreased to a 0.25 mg twice a week and finally maintained at 0.25 mg a week. After 6 months of the therapy, the normalization of serum PRL concentrations (from mean 1358 mlU/ml to mean 420 mlU/ml; p < 0.001) was achieved in 13 (76.5%) patients (8 with microprolactinoma and 5 with macroprolactinoma). In the remaining 4 patients PRL levels remained elevated but were decreased from mean 1403 mIU/ml to mean 812 mIU/ml. There were no differences, regarding CAB efficacy in lowering PRL levels, between patients with micro- and macroadenomas (p > 0.05). About 90% women resumed menstrual cycles in our study. All the other clinical pretreatment symptoms disappear in the course of the therapy. The tumour shrinkage, confirmed by control MRI was noted in 2 patients (33%) with macroprolactinoma. Cabergoline was tolerated satisfactorily by all our patients. The results have confirmed a high efficacy and a very good tolerability of CAB in the treatment of patients with pituitary adenomas. Together with a very convenient administration, such therapy can provide a very good patient compliance thus should be considered the first line option in patients with prolactinomas.     

CSF rhinorrhoea following treatment with dopamine agonists for massive invasive prolactinomas

OBJECTIVE: The management of CSF rhinorrhoea following dopamine agonist (DA) treatment for invasive prolactinomas is difficult and there is no clear consensus for its treatment. Our objective was therefore to investigate the different treatments for this condition. DESIGN AND PATIENTS: We examined the case notes of five patients with invasive prolactinomas and CSF rhinorrhoea following DA treatment. The different ways in which this complication had been managed is detailed along with a review of the literature. RESULTS: Five patients aged 24-67 years (3 male) with massive invasive prolactinomas (serum prolactin 95000-500000 mU/l) eroding the skull base were treated with dopamine agonists (3 bromocriptine, 1 cabergoline and 1 both). CSF rhinorrhoea developed in all patients between 1 week and 4 months after commencing dopamine agonist treatment. In two patients (cases 1 and 4), CSF rhinorrhoea ceased within a few days of stopping bromocriptine but restarted when treatment was resumed. One of these (case 4), a 67-year-old woman had no further treatment and CSF leakage stopped completely. She died of unrelated medical problems 3 years later. In one patient staphylococcus aureus meningitis and pneumocephalus developed as a complication of CSF rhinorrhoea. Three patients had endoscopic nasal surgery to repair the fistula using muscle grafts, and to decompress the pituitary tumour, with success in two. One patient had intracranial surgery and dural repair, which was successful in sealing the leak. CONCLUSIONS: We suggest that surgery as soon as is feasible is the treatment of choice for the repair of a CSF leak following dopamine agonist treatment. An additional strategy is the withdrawal of dopamine agonist to allow tumour re-growth to stop the leak.     

Megavoltage pituitary irradiation in the management of prolactinomas: long-term follow-up

OBJECTIVE To determine the long-term effects of external beam megavoltage radiotherapy (RT: 4500 cGy via three portals at 180 cGy or less total daily dose) on endocrine function in prolactinomas. DESIGN Longitudinal study following radiotherapy with periodic re-assessment at regular intervals, at least 2 months off dopamine agonist therapy. PATIENTS Thirty-six female patients, age range 19-50 years, with either macroprolactinomas (12 patients) or microprolactinomas (24 patients), but without significant suprasellar extensions. MEASUREMENTS Clinical appraisal, and anterior and posterior pituitary assessment: basal levels at yearly intervals or less, with dynamic screening with TRH, LHRH and hypoglycaemic stimulation every 2-3 years. RESULTS Before RT, serum prolactin (PRL) levels ranged from 1150 to 34,000 mU/l; after RT (mean 8.5 years, range 3-14), serum PRL fell to normal (i.e. less than 360 mU/l) in 18 of the 36 patients (50%), and to just above the normal range (378-780 mU/l) in a further 10 (28%). Two patients had PRL levels at their last follow-up higher than those at presentation, with one patient showing evidence of tumour recurrence on CT scan. A total of eight of the 36 patients (23%) developed post-RT gonadal deficiency by the end of follow-up at 8 +/- 3.1 years (+/- SD, range 3-11), but six were aged over 40 years at that time. GH deficiency was frequent, occurring in 94% of patients, usually from 2 to 3 years post-RT, while TSH deficiency and reduced ACTH reserve was uncommon (each 14%), and occurred later. In the subgroup of 12 patients with macroprolactinomas, results were broadly comparable. CONCLUSIONS Megavoltage RT produces a progressive fall in serum prolactin in the great majority of patients with prolactinomas, with a relatively low incidence of TSH or ACTH deficiency. As it is now clear that dopamine agonist therapy alone provides sufficient management for microprolactinomas, RT may be used for the long-term control of macroprolactinomas, together with interim dopamine agonist therapy. It allows pregnancy to be safely undertaken but, in view of the delayed onset of gonadal deficiency, its administration should be timed with respect to the desired onset of conception in women.     

Factors determining the remission of microprolactinomas after dopamine agonist withdrawal

Background Withdrawal of dopamine agonist (DA) therapy in the management of microprolactinoma is common practice, but it is unclear which patients are likely to attain long‐term remission. Objective To identify predictive factors for long‐term remission. Design Prospective cohort study. Patients Forty subjects (39 female, aged 24–60 years) with microprolactinoma; all had been normoprolactinaemic on DA therapy for at least 2 years [mean duration of therapy 9 years (range 2–27)]. Measurements A pituitary magnetic resonance imaging (MRI) was performed on 36 (90%) subjects before DA withdrawal. Relapse was defined as prolactin greater than 480 mIU/l (22·8 μg/l) on two occasions. Results Nine out of 40 (22·5%) subjects were normoprolactinaemic 12 months after DA withdrawal. Amongst the relapse group, 24 of 31 subjects (79·4%) had already relapsed at 3 months. Normalization of MRI prior to DA withdrawal (P = 0·0006) and longer duration of DA treatment (P = 0·032) were significant predictors of remission. Age, pre‐treatment prolactin, nadir prolactin, previous failure of DA withdrawal, pregnancy, dose and type of DA were not significant predictors of remission. The nine patients who were in remission at 12 months were then followed up for 58·0 ± 5·8 months; all remained in remission. Conclusions As many as 22·5% of subjects with microprolactinoma remained normoprolactinaemic 12 months after DA withdrawal and these subjects stayed in remission for up to 5 years. Significant predictive factors were normalization of MRI prior to discontinuation, and duration of DA treatment. Our findings support intermittent DA withdrawal after a period of normoprolactinaemia, particularly where MRI appearances have normalized.     

Management of prolactinomas: a survey of physicians from the Middle East and North Africa

Background

Prolactinomas are the commonest functional tumors of the pituitary gland. There are still controversies regarding medical therapy in specific clinical situations. Patients may be managed by different specialists in the Middle East and North Africa (MENA) region and no data exist on patterns of clinical management.

Objectives

To ascertain the diagnostic and therapeutic approaches to prolactinomas among relevant professionals from the MENA region.

Methods

An online survey of a large sample of physicians was conducted. The questionnaire covered various aspects of diagnosis and treatment of prolactinomas. 468 respondents were included; 36 % were endocrinologists; 49 % worked in public facilities and 81 % graduated more than 10 years. 40 and 30 % would have seen 1–5 and more than 5 suspected or confirmed prolactinomas over a 6 months period, respectively.

Results

Regarding the diagnosis, 30 % of the respondents considered that prolactin levels <100 ng/ml exclude the presence of a prolactinoma. 21 % of respondents considered prolactin levels >250 ng/ml compatible with macroprolactinomas only, whereas others accepted this to be compatible also with microprolactinomas, macroprolactinaemia and drug-induced hyperprolactinemia (50, 42 and 36 % respectively). 71 % of respondents favored the screening for macroprolactin in asymptomatic individuals with hyperprolactinemia. Regarding the treatment, 84 % of respondents would treat microprolactinomas even in the absence of symptoms whereas 72 % of the respondents would treat microprolactinomas only if symptoms exist. 60 and 49 % of the respondents chose cabergoline as the drug of choice to treat macroprolactinomas and microprolactinomas respectively. Similar proportions had no preference of either cabergoline or bromocriptine as the best treatment for macroprolactinoma (27 %) and microprolactinomas (32 %). 46 and 75 % of respondents favored treatment withdrawal 2–3 years after prolactin normalization in patients with macroprolactinomas and microprolactinomas, respectively whereas 10 % of respondents withdraw treatment after menopause in either case. 94 % of respondents considered medical therapy as the primary treatment for microprolactinomas. In case of pregnancy, 49 % considered bromocriptine as the drug of choice for women who wish to become pregnant. 65 and 38 % of respondents advocated discontinuation of treatment with dopamine agonists in patients with microprolactinomas and macroprolactinomas, respectively. Finally, 48 % would allow breast-feeding without restriction, 28 % would restrict it to patients with microprolactinomas and 25 % would not recommend it for women with prolactinomas.

Conclusions

This is the first study of the clinical management of prolactinomas in the MENA region. Some of the practices are not in line with the latest Endocrine and Pituitary Societies guidelines. These warrant further discussions of contemporary guidelines in regional forums.

     

Cabergoline Therapy of Growth Hormone & Growth Hormone/Prolactin Secreting Pituitary Tumors

Dopamine agonists have been used as adjunctive therapy for acromegaly for many years, but relatively few studies have assessed the efficacy of a newer agonist, cabergoline. Some data suggest that cabergoline may be more effective than bromocriptine, in particular for those patients whose tumors secrete both growth hormone and prolactin. In order to assess this possibility further, we have evaluated the biochemical response to cabergoline therapy in patients with acromegaly at our center. We describe first an unusual patient who presented with a pituitary macroadenoma secreting both GH and prolactin. At presentation he had elevated levels of growth hormone 6.0 microg/L, IGF-I, 722 ng/ml, and prolactin, 6000 ng/ml. Cabergoline therapy alone was highly effective in this patient and normalized his levels of all three hormones and his gonadal function as well as produced significant shrinkage of his pituitary tumor. Fourteen other patients with more typical, active postoperative acromegaly were administered cabergoline in a 6-month, open label, dose-escalation study. Mean baseline GH was 1.3 +/- .23 ng/ml and fell to a nadir of 0.85 +/- .18 ng/ml on cabergoline therapy (p = 0.03). Mean baseline IGF-I was 520 +/- 45.2 ng/ml and fell to a mean nadir during cabergoline therapy of 368 +/- 29.8 ng/ml (p = 0.0013). At the completion of the cabergoline therapy study period, however, mean IGF-I was 453 +/- 46 ng/ml, not significantly lower than the baseline value (p = 0.11). No changes in tumor sizes occurred on cabergoline therapy. Eight of 14 patients achieved a normal IGF-I at some point during the 24 weeks study period, but the efficacy of cabergoline waned with time as only 3 of 14 (21%) of patients had a persistently normal IGF-I with up to 18 months of cabergoline therapy. Six patients had modest hyperprolactinemia at diagnosis (26-142 ng/ml) and 5 patients had positive immunohistochemical staining of their tumor for prolactin, but in neither of these small groups was cabergoline therapy more effective at normalizing IGF-I than in those patients with apparently pure GH secreting tumors. Three of 14 patients (21%) had side effects that limited therapy. A trial of cabergoline as adjunctive therapy may be considered in select patients with mild disease and small tumor residuals, but the expectation for biochemical control in these patients needs to be kept low, even for tumors that co-secrete GH and prolactin.     

Randomized pilot study of cabergoline, a dopamine receptor agonist: effects on body weight and glucose tolerance in obese adults

Aim: Dopaminergic hypofunction and hyperprolactinaemia have been implicated in the pathogenesis of obesity and glucose intolerance. The aim of this pilot study was to determine the efficacy of cabergoline, a dopamine receptor agonist, on body weight and glucose tolerance in obese non‐diabetic persons with normal plasma prolactin levels. Methods: This 16‐week double blind, placebo‐controlled pilot study randomized non‐diabetic obese adults (body mass index 30–42 kg/m²) to placebo or cabergoline (0.25 mg twice weekly for 4 weeks followed by 0.5 mg twice weekly for the next 12 weeks). Of 40 subjects enrolled, 29 completed 16 weeks: 16 randomized to placebo and 13 to cabergoline. All subjects were counselled on a 500 kcal/day calorie deficit diet. A 75‐g oral glucose tolerance test was performed at baseline and at 16 weeks. Results: As expected, prolactin levels decreased after cabergoline (p < 0.001). Weight loss was similar after placebo compared with cabergoline treatment: 1.0 vs. 1.2% body weight, respectively. Fasting glucose levels did not differ between groups after treatment, however, 90‐min postprandial glucose and insulin decreased in the cabergoline group only (p = 0.029). HOMA‐IR (homeostasis model of assessment) increased by 40% after placebo and 1.5% after cabergoline treatment. Conclusions: This pilot study suggests that cabergoline therapy may improve glucose tolerance independent of weight loss, however, a larger, longer term study of dopamine receptor agonist therapy in obese individuals is warranted to confirm this finding.     

Cardiac valve disease and low‐dose dopamine agonist therapy: an artefact of reporting bias?

Introduction Chronic low‐dose cabergoline treatment for microprolactinoma may cause cardiac valve pathology, but the evidence is contradictory. We investigated whether the expectation of the echocardiographer could influence the report. Methods Transthoracic echocardiograms from 40 patients aged 49·3 ± 9·6 (mean ± SD) years (Men:Women 7:33) on long‐term cabergoline and bromocriptine therapy (duration 9·94 ± 4·5 years) were randomly assigned to two groups of echocardiographers so that each echocardiogram was reported twice. One group was told that ‘the patients were control subjects’ (Group A) and the other that ‘the patients were on dopamine agonist therapy which is known to cause valve disease’ (Group B). An observer who was blind to the group scored the reports for regurgitation at each valve (scores 0–4; max 16 per case). Results Mean total regurgitation score was significantly higher in Group B (1·43 ± 1·28; P = 0·014) than in Group A (0·73 ± 1·30). The difference was mainly from reporting trivial regurgitation: (mitral 16 vs 5, P = 0·005; tricuspid 17 vs 6, P = 0·007 and pulmonary 8 vs 1, P = 0·013). Mild regurgitation was uncommon (mitral 1 vs 1 and tricuspid 3 vs 6). Moderate regurgitation occurred in only one case and was associated with restriction of the leaflets consistent with the effects of cabergoline. Valve thickening was not reported in Group A, but in 9 (23%) mitral and 4 (10%) aortic valves in Group B. Conclusion Long‐term, low‐dose dopamine agonist therapy rarely causes cardiac valve disease, but operator bias can lead to over‐reporting of both valve thickening and trivial regurgitation.     

催乳素瘤治疗的研究进展

催乳素瘤是最常见的一种垂体瘤。药物治疗可使超过90%的患者血催乳素水平正常,但需要长期服药。溴隐亭、卡麦角林和喹高利特等都有降低血催乳素水平和缩小瘤体的作用。卡麦角林被认为比溴隐亭更有效且耐受性好。因已证明在孕期溴隐亭具有安全性而被推荐用于孕期治疗。手术一般用于药物治疗无效或不耐受者。放射治疗仅用于手术不能切除肿瘤及术后肿瘤复发或药物治疗失败的患者。     

Prolactinoma in pregnancy

Prolactinomas commonly cause infertility and treatment usually restores ovulation and fertility. The dopamine agonists are the preferred mode of treatment, with cabergoline generally being preferred to bromocriptine because of its higher therapeutic ratio. Experience with both drugs shows no increase in spontaneous abortions, preterm deliveries, multiple births, or congenital malformations, compared to what is expected in the normal population but the experience with bromocriptine is approximately 10-fold greater than with cabergoline. Clinically significant tumor growth may occur in 2.7% of those with microadenomas, 22.9% in those with macroadenomas without prior ablative treatment and 4.8% of those with macroadenomas with prior ablative treatment. Patients with macroadenomas should have visual fields assessed periodically during gestation. Should symptomatic tumor growth occur, reinstitution of the dopamine agonist is usually successful in shrinking the tumor but delivery if the pregnancy is sufficiently advanced is also an option and transsphenoidal debulking is rarely necessary.