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Arquivos Brasileiros de Endocrinologia & Metabologia

On-line version ISSN 1677-9487

Arq Bras Endocrinol Metab vol.52 no.7 São Paulo Oct. 2008 



Severe hyperprolactinemia associated with internal carotid artery aneurysm: differential diagnosis between prolactinoma and hypothalamic-pituitary disconnection


Hiperprolactinemia severa associada a aneurisma interno da artéria carótida: diagnóstico diferencial entre prolactinoma e desconexão hipotálamo-hipofisária



Felipe Henning Gaia DuarteI, II; Marcio Carlos MachadoI, II; Joilma Rodrigues de LimaI; Luiz Roberto SalgadoII

IEndocrine Service, Hospital do Câncer A.C. Camargo, Fundação Antonio Prudente, São Paulo, SP, Brazil
IINeuroendocrine Unit, Division of Endocrinology and Metabolism, University of São Paulo School of Medicine, São Paulo, SP, Brazil

Correspondence to




Sellar and parasellar masses blocking inhibitory hypothalamic dopaminergic tonus can produce hyperprolactinemia. One of these conditions, seldom reported, is internal carotid artery aneurysm causing pituitary stalk compression and hyperprolactinemia, the majority of which is related to small increases in serum prolactin levels. The aim of this study is to report the case of a patient with an internal carotid aneurysm and severe hiperprolactinemia. A 72 years old female patient, on oncology follow-up for clinically controlled cervical carcinoma, was evaluated due to worsening chronic headaches. During the investigation, computed tomography and magnetic resonance imaging (MRI) showed a sellar mass associated with high prolactin level (1.403 µg/L) that initially was considered a macroprolactinoma, and treated with bromocriptine. However, subsequent pituitary MRI suggested an internal carotid aneurysm, which was confirmed by an angioresonance imaging of cerebral vessels. On low bromocriptine dose (1.25 mg/day), there was a prompt normalization of prolactin levels with a great increase (> 600 µg/L) after withdrawal, which was confirmed several times, suggesting HPD. We report a patient with internal carotid artery aneurysm with severe hyperprolactinemia never reported before in patients with HPD, and the need for a differential diagnosis with macroprolactinomas even considering high prolactin levels.

Keywords: Hyperprolactinemia; Internal carotid artery aneurysm; Hypothalamic-pituitary disconnection; Prolactinoma; Differential diagnosis of pituitary tumor


Massas selares e parasselares podem produzir hiperprolactinemia por bloquear o tônus inibitório hipotalâmico de dopamina. Uma destas condições, raramente reportada, é o aneurisma de artéria carótida interna causando compressão da haste hipofisária e hiperprolactinemia, a maioria com pequenas elevações da prolactina. O objetivo deste estudo é descrever o caso de uma paciente com aneurisma de carótida interna e grave hiperprolactinemia. Paciente feminina, 72 anos, em acompanhamento oncológico por carcinoma de colo de útero clinicamente controlado, avaliada por causa da piora de cefaléia crônica. Durante investigação, tomografia computadorizada e ressonância magnética (RM) de hipófise mostraram massa selar associada com altos níveis de prolactina (1.403 µg/L), sendo avaliado como macroprolactinoma e tratado com bromocriptina. Entretanto, RM subseqüente sugeriu aneurisma de carótida interna que foi confirmado por angiorressonância de vasos cerebrais. Em uso de baixas doses de bromocriptina (1,25 mg/dia), houve pronta normalização da prolactina com grande elevação (> 600 µg/L) após a retirada do medicamento, sendo confirmado por várias vezes sugerindo DHH. Reporta-se uma paciente com aneurisma de artéria carótida interna com grave hiperprolactinemia, nunca descrita anteriormente em pacientes com DHH, e a necessidade do diagnóstico diferencial com macroprolactinoma, mesmo considerando altos níveis de prolactina.

Descritores: Hiperprolactinemia; Aneurisma de artéria carótida interna; Desconexão hipotálamo-hipofisária; Prolactinoma; Diagnóstico diferencial de tumor hipofisário



Prolactin differs from other pituitary hormones as its secretion is regulated mainly through an inhibitory dopamine tonus, produced by neurons located in the hypothalamus (1). In addition to dopamine, other hypothalamic factors (TRH, oxytocin, VIP, angiotensin II, NPY and galanin) or even steroid hormones (estrogen) modulate the secretion of prolactin (2). The hypothalamic dopamine reaches the pituitary through the pituitary stalk and interacts with the dopamine receptor (D2), located in the cell membrane of lactotropes via protein Gi. After its binding, dopamine exerts an inhibitory effect on prolactin gene causing a reduction in secretion and hormone production (1).

Sellar and parasellar masses may hinder transportation of hypothalamic dopamine to the pituitary, leading to secondary hyperprolactinemia due to an absence of its inhibitory action on normal lactotropes (3). This process has been called hypothalamic-pituitary disconnection (HPD) and is classically associated to small or moderate serum prolactin increases, usually less than 100 µg/L.

We report the case of a patient with sellar and suprasellar mass associated with a very high serum prolactin levels (1.403 µg/L) initially considered as a macroprolactinoma. This is an atypical case of severe hyperprolactinemia due to HPD, and it should be stressed that prolactin levels as high as in this case has never been reported before. The aim of this paper is to discuss the importance of the differential diagnosis between internal carotid aneurysm and macroprolactinoma.



A female patient, age 72 years, was evaluated in 1987 for cervical carcinoma and submitted to radiotherapy treatment with clinical remission. After three years, she presented worse chronic headaches, nausea and arterial hypertention. A cranial computed tomography (CT) revealed the presence of a sellar and suprasellar mass with a 20 mm diameter, which was confirmed by pituitary MRI. The patient had no complaints of decreased libido, abnormal visual fields or galactorrhea. Initial laboratory analysis excluded hematological, renal and hepatic abnormalities. Patient denied having taking medications that could lead to hyperprolactinemia. Hormonal assessment showed a prolactin level of 1403 µg/L (NV 2-15 µg/L) (Table 1) and panhypopituitarism (T4L 0.69 ng/dL, NV: 1.0-1.8 ng/dL; TSH 0.06 mUI/L, NV: 0.3-4.2 mUI/L; serum cortisol < 1.0 µg/dL, NV: 5-25 µg/dL; and IGF1 74 µg/L, NV: 96-502 µg/L). Screening for macroprolactinemia was negative as well. The patient was treated with replacement therapy of prednisone 5 mg/day and thyroxine 100 µg/day. As the high prolactin levels suggested a macroprolactinoma, she also received bromocriptine (BRC) starting with 1.25 mg/day. A new pituitary MRI confirmed a sellar and suprasellar mass of similar dimensions of the previous one, but with heterogeneous content, which raised suspicion of a giant aneurysm of the internal carotid artery with a thrombus inside (Figure 1). This was confirmed by an angioresonance imaging of cerebral vessels (Figure 1). On BRC (1.25 mg/day), a dramatic reduction of prolactin levels was observed and the dosage was increased to 2.5 mg/day when serum prolactin levels became almost undetectable (0.6 µg/L) (Table 1). After multi-disciplinary discussion, a conservative approach was chosen instead of surgery.



The patient continued BRC use for approximately one year when it was discontinued. Shortly after hyperprolactinemia as high as 657 and 437 µg/L was observed, bromocriptin was restarted with a dose of 2.5 mg/day with prolactin returning to normal values (Table 1). The drug was then gradually reduced to 0.625 mg/day, keeping serum prolactin in normal range levels (8.5 µg/L). During imaging assessment, the aneurysm remained with the same diameter as in the initial exam, and the patient was kept in full replacement for hypopituitarism.

The Research Projects and Graduate Studies Commission and the Ethics Commission of our institutions approved the study, and the patient provided informed consent.

Hormonal assay

Serum prolactin was measured by commercial immunoassay (Bayer Advia Centaur, Indiana, USA).



The differential diagnosis of hyperprolactinemia includes a large number of clinical physiological situations (pregnancy, lactation, stress, sleep, exercise, maxillary stimulation) or pathological conditions (1). Among the pathological causes, the two most common etiologies are prolactinomas and use of anti-dopamine drugs. Other pathologic conditions such as polycystic ovary syndrome, hypothyroidism, adrenal failure, hepatic cirrhosis, chronic kidney failure, brain trauma injuries and clinically non-functioning pituitary adenomas are known causes of hyperprolactinemia (3). Furthermore, other lesions of the hypothalamic-pituitary region also can cause increased secretion of prolactin due to HPD. In addition to HPD, the rise in intrasellar pressure caused by pituitary masses can also lead to increased levels of serum prolactin (4). However, both increases of intrasellar pressure and suprasellar masses causing HPD are usually associated with moderated increases of serum prolactin levels (4-6).

Classically, serum levels of prolactin higher than 200 µg/L are related to macroprolactinomas, but those levels should not exclude other etiologies or even use of anti-dopamine drugs as been reported in literature (7). Therefore, any sellar masses among craniopharyngiomas, optical gliomas, secondary metastatic implants, chordomas and internal carotid aneurysms can be associated with moderated increases of serum prolactin levels and should be differentiated from prolactinomas (8,9).

It should be mentioned that co-existence of aneurysm of internal carotid and hyperprolactinemia is usually iatrogenic (10), and descriptions of its primary association is rare (11). Another considered possibility was the presence of a co-existing prolactinoma. Although rare, few reports described this association (12-15), however in all cases the macroadenoma was evident in the images obtained, a situation that was ruled out in our case. The first published case of internal carotid aneurysm and primary hyperprolactinemia was reported by Verbalis et al.(5), in 1982, in a 59 years old patient with hypopituitarism and prolactin serum levels of 177 µg/L related to internal carotid aneurysm. After the aneurism surgical decompression serum prolactin levels returned to normal. Thereafter, a number of new cases were reported over the subsequent years (6,8,9,15-21).

An important clinical aspect of these reported cases is the female prevalence and age ranged between 42 and 76 years, exceptions being a case reported by Kayath et al. (18-year-old male patient) and two other patients reported by Fonseca et al.(17), both males, age 57 and 68 years. Serum prolactin levels ranged between 4 and 182 µg/L (5,6,8,9,16,17,19-21) associated with hypopituitarism. Clinically, the most common complaints were headaches and blurred vision attributed to the mass effect.

In only two reported cases, serum prolactin levels were higher than 200 µg/L. The first was reported by Fernandez-Real et al.(18), who described a case of a 52-year-old women with a giant aneurysm associated with subarachnoid hemorrhage and serum prolactin levels of 1.093 µg/L who presented sudden headaches, a decline in consciousness, hemiparesis and signs, and symptoms relate to hypopituitarism. In the second case, published by Kahn et al.(15), a 42 years old patient presented galactorrhea, headaches, abnormal visual fields and serum prolactin levels of 365 µg/L.

In the case reported, the patient presented higher serum prolactin levels, associated with internal carotid aneurysm (1.403 µg/L), than reported in the literature to date. Our case was noticed to be similar to that case reported by Kahn et al. (15) where there were no other factors besides the internal carotid aneurysm that could cause compression leading to HPD and hyperprolactinemia. It should be stressed that there is no histological proof excluding a macroprolactinoma extremely sensitive to dopamine agonist. However, the absence of imaging suggestive of pituitary adenoma, an angioresonance confirming a giant aneurysm of internal carotid artery and the extreme sensibility to the BRC presented by the patient, strongly suggest hyperprolactinemia secondary to the HPD.

In conclusion, we reported a case of a patient with severe hyperprolactinemia due to HPD caused by internal carotid artery aneurysm, stressing the need for a more critical evaluation in the differential diagnosis, when considering the presence of sellar masses. A test with low dose of dopamine agonist, independent of serum prolactin levels, could be a clue to the diagnosis of HPD.



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Correspondence to:
Luiz Roberto Salgado
Av. Dr. Eneas de Carvalho Aguiar #155, 8th floor, Cerqueira Cesar
University of São Paulo School of Medicine
05403-060 São Paulo, SP - Brazil

Recebido em 31/3/2008
Aceito em 22/7/2008

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