Giant prolactinomas are rare tumours, representing only 2–3% of all prolactin (PRL)-secreting tumours and raising special diagnostic and therapeutic challenges. Based on several considerations developed in this review, their definition should be restricted to pituitary adenomas with a diameter of 40 mm or more, significant extrasellar extension, very high PRL concentrations (usually above 1000 μg/l) and no concomitant GH or ACTH secretion. Giant prolactinomas are much more frequent in young to middle-aged men than in women, with a male to female ratio of about 9:1. Endocrine symptoms are often present but overlooked for a long period of time, and diagnosis is eventually made when neurologic complications arise from massive extension into the surrounding structures, leading to cranial nerve palsies, hydrocephalus, temporal epilepsy or exophthalmos. PRL concentrations are usually in the range of 1000–100 000 μg/l, but may be underestimated by the so-called ‘high-dose hook effect’. As in every prolactinoma, dopamine agonists are the first-line treatment allowing rapid alleviation of neurologic symptoms in the majority of the cases, a significant reduction in tumour size in three-fourths of the patients and PRL normalization in 60–70%. These extensive tumours are usually not completely resectable and neurosurgery has significant morbidity and mortality. It should therefore be restricted to acute complications such as apoplexy or leakage of cerebrospinal fluid (often induced by medical treatment) or to patients with insufficient tumoural response or progression. Irradiation and temozolomide are useful adjuvant therapies in a subset of patients with aggressive/invasive tumours, which are not controlled despite combined medical and surgical treatments. Because of these various challenges, we advocate a multidisciplinary management of these giant tumours in expert centres.
Dominique Maiter and Etienne Delgrange
Virginie Atquet, Orsalia Alexopoulou, and Dominique Maiter
Objectives: We aimed to investigate the clinical, biochemical, histological and radiological characteristics as well as the response to somatostatin analogs (SSA) in a large cohort of acromegaly patients with a paradoxical GH response (PR) to oral glucose tolerance test (OGTT).
Design: retrospective study.
Methods: Of 110 patients with acromegaly included in our study, 30 (PR+; 27%) had a paradoxical GH increase of more than 25% relative to basal GH levels during OGTT.
Results : At diagnosis, PR+ patients were older than PR- patients (52 ± 16 vs 44 ± 14 years, p<0.05) and had smaller pituitary tumours (40% microadenomas vs 19%, p<0.05), which were less often invasive (17 vs 35%, p<0.05), overall more secreting (IGF-1/tumoural surface: 2.35 ULN/cm² [0.28-9.06] vs 1.08 [0.17- 7.87], p=0.011), and more often hypointense on T2-weighted MRI (92 vs 48%, p=0.001). While the rate of remission after surgery was similar in the two groups (69%), a better response to SSA treatment was observed in PR+ patients, either before (IGF-1 reduction of > 50% after 3-6 months in 77 vs 49%, p=0.023) or after surgery (normalization of IGF-1 in 100 vs 44%, p=0.011).
Conclusions: Our study demonstrates that in acromegaly, a paradoxical GH increase during OGTT is associated with particular features of somatotroph adenomas and with a better prognosis in terms of response to somatostatin analogs.
Etienne Delgrange, Dominique Maiter, and Julian Donckier
Delgrange E, Maiter D, Donckier J. Effects of the dopamine agonist cabergoline in patients with prolactinoma intolerant or resistant to bromocriptine. Eur J Endocrinol 1996;134:454–6. ISSN 0804–4643
Cabergoline is a new long-acting ergoline derivative used to treat hyperprolactinaemia. Its effect was assessed in 10 patients (eight women and two men) with prolactinoma who were intolerant (group I; N = 7) or resistant (group II; N = 3) to bromocriptine. In group I, no side effect was observed on cabergoline therapy; two patients became pregnant and normoprolactinaemia was achieved in the five others. In group II, cabergoline was active and well-tolerated in two out of the three patients: one woman had three consecutive pregnancies; in another patient normoprolactinaemia was restored and the tumour shrank by 60%; in the third patient cabergoline was discontinued because of side effects and inefficacy. Thus, cabergoline appears to be an alternative of choice as treatment of hyper-prolactinaemic patients who are intolerant or resistant to bromocriptine.
Julian Donckier, Internal Medicine and Endocrinology, University Hospital UCL of Mont-Godinne, B-5530 Yvoir, Belgium
Vanessa Primeau, Christian Raftopoulos, and Dominique Maiter
Few studies have recently re-examined the efficacy of neurosurgery in prolactinoma patients operated for various indications.
To analyze outcomes of patients with a prolactinoma treated by transsphenoidal surgery, to identify factors associated with remission and relapse, and to evaluate if surgical debulking allows for better hormonal control in patients with preoperative resistance to dopamine agonists (DAs).
Patients and methods
This was a retrospective review of patients with a benign prolactinoma followed preoperatively and postoperatively in our department and treated by transsphenoidal surgery (n=63; 45 women; mean age: 31±14 years).
Postoperative remission was obtained in 63% of microprolactinomas, 60% of noninvasive macroprolactinomas, and none of the invasive macroprolactinomas. Better remission rate was independently predicted by lower diagnostic prolactin (PRL) levels and by the lack of abnormal postoperative residual tissue (P<0.05). A recurrence of hyperprolactinemia was observed in 34% of patients after a median follow-up period of 36 (7–164) months. In patients with preoperative DA resistance treated again after surgery, there was a significant reduction in PRL levels postoperatively (26 (6–687) ng/ml) vs preoperatively (70 (22–1514) ng/ml; P<0.01) under a lower DA dose, and about half of the patients had PRL normalization.
Recurrence of hyperprolactinemia is observed in one-third of prolactinoma patients after surgical remission and may occur as late as 13 years after surgery. Resistance to DA can be considered as a good surgical indication, as partial tumor resection allows for better hormonal control with a lower dose of DAs.
Etienne Delgrange, Tania Daems, Johan Verhelst, Roger Abs, and Dominique Maiter
Macroprolactinomas poorly responsive to dopamine-agonists are often more aggressive and are usually termed ‘resistant’ but this clinical concept has always been defined empirically.
To define resistance to cabergoline (CAB) on the basis of a dose–response relationship established in a large series of macroprolactinoma patients and to assess the influence of gender and tumor invasiveness on the response to treatment.
One hundred and twenty-two patients (72 women and 50 men) primarily treated with CAB for at least 1 year were included. Main outcome measures were serum prolactin (PRL) and tumor size.
Normalization of PRL was obtained in 115 out of the 122 patients (94%). The majority of patients (96/115, 83%) were controlled with a CAB dose ≤1.5 mg/week. Most of the other patients (19/26) had only a partial resistance, responding to a further increase of the CAB dose. Beyond the dose of 3.5 mg/week, there was no clear advantage in further increasing the dose instead of continuing the treatment at the same dose. Most tumors (98/119 assessable cases, 82%) showed a significant shrinkage during CAB treatment. It was more likely to occur in cases of PRL normalization. Both cavernous sinus invasion and male gender were significantly and independently associated with partial or complete resistance to treatment.
Most macroprolactinomas primarily treated with CAB are adequately controlled with doses ≤1.5 mg/week. About 20% of patients, mainly men and/or those with invasive tumors will require a higher dose of CAB. We suggest defining such patients as resistant to CAB.
Pascale Abrams, Orsalia Alexopoulou, Roger Abs, Dominique Maiter, and Johan Verhelst
Lanreotide-Autogel is a depot formulation of the somatostatin analog lanreotide used in the treatment of acromegaly. We investigated whether prolonging or shortening the interval between injections would offer any benefit.
Subjects and methods
The interval was prolonged from once every 4 weeks to once every 6 weeks when patients (n=9) had normal IGF-I and GH concentrations. When patients (n=12) had still elevated IGF-I or GH on the maximal dose of 120 mg every 4 weeks, the interval was shortened to once every 3 weeks. Serum IGF-I and GH were measured after 12 and 24 weeks to allow for dose adaptation. Symptoms and tumor volume were evaluated at baseline and after 36 weeks.
In seven of the nine subjects with normal IGF-I and GH, the interval could be extended to 6 weeks without loosing efficacy on IGF-I (195 vs 213 μg/l; not significant, NS) and GH concentrations (1.4 vs 1.3 μg/l; NS). The weekly dose could significantly be reduced (from 23.3 to 17.8 mg; P=0.002). In only 1 of the 12 not-controlled patients, reducing the interval to once every 3 weeks induced normalization of IGF-I and GH.
In subjects whose acromegaly is well controlled using lanreotide-Autogel, prolonging the time interval between injections can often be increased 4 to 6 weeks without loss of efficacy, thereby improving the subject's comfort and reducing the cost of treatment. On the other hand, in subjects whose acromegaly is not controlled on a dose of 120 mg every 4 weeks, reducing the interval to every 3 weeks is rarely beneficial.
Marie Bex, Roger Abs, Guy T’Sjoen, Jean Mockel, Brigitte Velkeniers, Katja Muermans, and Dominique Maiter
Objectives: To constitute a registry on acromegaly, AcroBel, to evaluate the epidemiology and quality of care of acromegaly in Belgium and Luxembourg.
Design: A nationwide survey from June 2003 till September 2004 aiming to collect data from all patients with acromegaly who had visited the participating endocrine clinics after 1 January 2000.
Methods: Retrospective data collection coupled to a visit within the survey period, allowing sampling of metabolic parameters and centralised determination of GH and IGF-I.
Results: Four hundred and eighteen patients (51% men) were included, of which 96 were new cases, giving a mean incidence of 1.9 cases per million (c.p.m.) per year. The global prevalence was 41 c.p.m. but varied between 21 and 61 among different areas. Twenty-eight deaths were reported at a median age of 68 years in men and 74 years in women. The standardised mortality rate was significantly increased only in irradiated patients (2.70; confidence interval 1.60–4.55). Central measurements were available in 316 (75%) patients. Mean GH was ≤ 2 μg/l in 65% and IGF-I was normal for age in 56%, while both criteria were fulfilled in 49%. Multimodal treatment was more effective than primary medical therapy, since 56.5% were controlled versus 24.3% (P < 0.0001).
Conclusions: AcroBel provides an excellent tool to analyse the prevalence, incidence, treatment modalities and outcome of acromegaly in Belgium. This real-life survey reveals that only half of acromegalic patients received an adequate therapy resulting in cure or disease control when stringent biochemical criteria are used.
Guy T’Sjoen, Marie Bex, Dominique Maiter, Brigitte Velkeniers, and Roger Abs
Objective: To assess the impairment of quality of life (QoL), evaluated by the acromegaly QoL (AcroQoL) questionnaire, in patients with controlled and uncontrolled acromegaly.
Design: Cross-sectional evaluation of AcroBel, a national observational registry of acromegalic patients newly diagnosed or in follow-up.
Methods: Disease perception by the patients was evaluated by the disease-specific signs and symptoms score (SSS) and QoL was assessed by the AcroQoL questionnaire. Hormonal status was determined by central measurements of GH and IGF-I.
Results: Patients (n = 291) had a median GH of 1.43 μg/l (0.65–3.03; IQR), a median IGF-I of 231 μg/l (150–367), and a mean IGF-I z-score of +1.91 (s.d. 2.21). The AcroQoL total score in the whole group was 67.1 (51.1–78.4), with a score of 65.6 (43.8–78.1) for the physical dimension, 67.9 (53.6–80.4) for the psychological dimension, 78.6 (64.3–89.3) for personal relations and 57.1 (39.3–75) for appearance. The median SSS was 3 (–). There was a negative correlation between both questionnaires (r = −0.478; P < 0.001). There was no correlation between AcroQoL score and biochemical markers of disease activity. When subdividing patients into groups of biochemical control according to GH and IGF-I levels, no difference could be established for either SSS or AcroQoL scores.
Conclusions: The AcroQoL results from the AcroBel registry confirm the marked impairment of the patients’ QoL, especially in relation with appearance. A negative correlation between AcroQoL and SSS was confirmed. There was, however, no correlation between AcroQoL and biochemical markers of disease activity.
Sophie Lefebvre, Lutgarde De Paepe, Roger Abs, Jacques Rahier, Philippe Selvais, and Dominique Maiter
Lefebvre S, De Paepe L, Abs R, Rahier J, Selvais P, Maiter D. Subcutaneous octreotide treatment of a growth hormone-releasing hormone-secreting bronchial carcinoid: superiority of continuous versus intermittent administration to control hormonal secretion. Eur J Endocrinol 1995;133:320–4. ISSN 0804–4643
Diagnosis of ectopic acromegaly was made in a 21-year-old female patient who 3 years before had undergone a right pneumectomy for a disseminated bronchial carcinoid. Plasma growth hormonereleasing hormone (GHRH) concentrations were markedly elevated (6440 ng/l; normal value <100 ng/l), as were serum GH (187 μg/l; normal <5 μg/l) and plasma insulin-like growth factor I (IGF-I) levels (6.7 U/ml; normal <2 U/ml). Retrospective immunohistochemical examination of the carcinoid tumor was positive for GHRH and the tumoral content of GHRH was 2130 ng/g wet weight. Subcutaneous treatment with octreotide was begun and first resulted in a profound inhibition of GH hypersecretion, normalization of plasma IGF-I and only partial reduction of GHRH concentrations. However, the initial dose of 3 × 100 μg had to be increased gradually to 4 × 750 μg because of a progressive deterioration of the hormonal control. After 15 months of intermittent therapy, octreotide was administered by continuous sc infusion. This treatment improved compliance, allowed the daily dose of octreotide to be reduced to 1500 μg and normalized serum GH levels. A near-normalization of the plasma IGF-I concentrations was also obtained, whereas the suppression of plasma GHRH concentrations remained incomplete. Despite favorable evolution of the endocrine parameters, intramedullar metastases were diagnosed and required radiation therapy. This observation emphasizes the superiority of continuous over intermittent administration of octreotide in the treatment of ectopic acromegaly. It also shows that the somatostatin analog acts more at the pituitary level to inhibit GH secretion than at the site of the neuroendocrine tumor.
S Lefebvre, Division of Rheumatology, Clinique du Refuge, Rue du Couvent 39, B-7700 Mouscron, Belgium
Dorota Tomalik-Scharte, Dominique Maiter, Julia Kirchheiner, Hannah E Ivison, Uwe Fuhr, and Wiebke Arlt
Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drug-metabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied.
We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer.
Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes. We also performed genotyping for variant CYP alleles known to affect drug metabolism.
Though CYP enzyme genotyping predicted normal or high enzymatic activities in both subjects, in vivo assessment showed subnormal activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in the patient and of CYP1A2 and CYP2C9 in her mother.
Our results provide in vivo evidence for an important role of POR in regulating drug metabolism and detoxification. In patients with ORD, in vivo assessment of drug-metabolizing activities with subsequent tailoring of drug therapy and steroid replacement should be considered.