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Table of Contents    
Year : 2011  |  Volume : 59  |  Issue : 4  |  Page : 501-503

Management of prolactinomas: The fine print between the lines!

Department of Neurosurgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

Date of Submission20-Jun-2011
Date of Decision21-Jun-2011
Date of Acceptance29-Jun-2011
Date of Web Publication30-Aug-2011

Correspondence Address:
Sanjay Behari
Department of Neurosurgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.84326

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How to cite this article:
Behari S. Management of prolactinomas: The fine print between the lines!. Neurol India 2011;59:501-3

How to cite this URL:
Behari S. Management of prolactinomas: The fine print between the lines!. Neurol India [serial online] 2011 [cited 2023 Dec 1];59:501-3. Available from:

Prolactinomas are the commonest of the functioning pituitary adenomas. Management involves controlling hyperprolactinemia, decreasing tumor mass, and normalizing pituitary functions. [1] Medical management forms the mainstay of treatment. Prolactin secretion is inhibited mainly by dopamine but also by gamma-aminobutyric acid and cholinergic pathways and is mildly stimulated by TSH-releasing hormone, serotonin, estrogens, endogenous opiates, and vasoactive intestinal polypeptide. Pharmacological agents to treat hyperprolactinemia are dopamine agonists (ergot derivatives, including bromocriptine, cabergoline, pergolide, lisuride, and terguride, and the non-ergot octahydro benzo (g) quinoline derivative, quinagolide) as well as the serotonin antagonist metergoline. These agents cause cell volume reduction (via an early secretory inhibition and a late gene transcription and prolactin synthesis inhibition), perivascular fibrosis, antimitotic activity, and cell necrosis. [1] Withdrawal of these agents, however, usually leads to recurrence of tumor and hyperprolactinemia. The potential side effects of these agents include postural hypotension, nausea/vomiting, dry mouth, dyspepsia, constipation, headache, drowsiness, psychiatric symptoms, and drug resistance. Other adverse effects include painless digital vasospasm, causing cold-induced extremity blanching, leg cramps, flushing, and nasal congestion. In high doses, pergolide may cause organ fibrosis, including cardiac valve fibrosis. [1],[2]

In this issue of Neurology India, Sinha et al. [3] have aptly focused on patients with prolactinomas who respond better to surgery than to protracted medical therapy. The surgical indications included noncompliance and intolerable side effects of pharmacotherapy; failure to achieve prolactin normalization; tumor enlargement despite prolactin reduction; pregnancy, with enlarging prolactinomas; unstable ophthalmological symptoms; personal choice; and the presence of cystic tumors, apoplexy, or cerebrospinal fluid rhinorrhea. [4]

Some interesting facts in this study require elaboration. The majority of patients (59%; median age: 32 years) were male. This varies from the usual trend (female: male ratio of 10:1; age range: 20-50 years) and may represent a referral bias. After the fifth decade, however, the frequency of prolactinomas is similar in both the genders. Invasive prolactinomas have a much higher frequency in men. In children, although infrequent, they still represent half of the adenomas detected. The higher frequency of prolactinomas in women may be due to their earlier detection when they manifest with amenorrhea/galactorrhea/infertility. In men, decreased libido and impotence often go unreported until late, when visual symptoms, hypopituitarism, or raised intracranial pressure develop. [1] In this study, hormonal assessment and immunohistochemistry revealed positivity to prolactin and growth hormone (GH) in 28 (16%) patients even in the absence of clinical features of acromegaly or gigantism. Historical reviews validate this close association between GH and prolactin during hormonal detection. It was in fact impossible to separate the two hormones (so much so that the very existence of prolactin was being questioned!) using conventional methods until 1970, when Frantz and Kleinberg developed a bioassay containing antibodies against GH. This led to detection of measurable amounts of prolactin levels in women with galactorrhea but not in most normal men. [5] In patients with macroprolactinomas and hypopituitarism requiring hormonal replacement, GH-replacement therapy should be delayed until surgery/pharmacotherapy/radiotherapy achieves normoprolactinemia and resolves the hypopituitarism. This cautious approach is warranted due to the possibility of a GH/growth factor-induced tumor enlargement. [1]

The surgical results in this series were analyzed by tumor classification into microadenoma (<1 cm; 9%), macroadenoma (>1 cm; 66%), and giant prolactinoma (>4 cm; 25%). This has special therapeutic implications. The natural history of microprolactinomas rarely reveals significant tumor enlargement (<7% patients). [6] Thus, periodic magnetic resonance imaging (MRI) and serum prolactin level assessment may be the only measures needed for microadenomas occurring in eugonadal women with non-troublesome galactorrhea. Hypogonadal women with microprolactinomas may be treated for hypogonadism with oral contraceptives. [1],[7] Women with a microadenoma and amenorrhea and anovulation desirous of pregnancy, however, definitely require treatment. Macroadenomas, especially the invasive ones that cause chiasmal-pituitary-hypothalamic compromise, will also require treatment. Surgery via a trans-sphenoidal/endoscopic endonasal approach is to be preferred except in tumors with large parasellar, subfrontal, temporal, cavernous sinus, or prepontine extensions, or when tumor consistency is very firm. [8] In the latter situations, transcranial approaches are preferred.

The intraoperative assessment of tumor extent may be facilitated by C-arm image intensifier, neuronavigation, or intraoperative MRI or ultrasound. Neuronavigation uses preoperative radiological images and cannot predict in real time the actual extent of tumor removal. An intraoperative MRI will be of limited use in resecting purely sellar microadenomas but readily assesses the adequacy of suprasellar and parasellar tumor excision. Intraoperative MR images may be updated on the neuronavigation console using ethernet to compensate for tumor shift following surgical decompression. An ultrasonographic image gives real-time feedback during open surgery for macroadenoma excision; the image, however, does not provide absolute anatomical delineation. Its quality is often operator dependent and compromised by tumor-bed hemorrhage and proximity to bony surfaces. [9]

In the present series, at the last follow-up, overall final hormonal remission was 44% (83% for microadenomas, 48% for macroadenomas, and only 16% for giant adenomas). The overall cure rate reported in the literature has been approximately 61% for microadenomas and 26% for macroadenomas (with prolactin levels normalizing to <200 ng/ml 1-2 weeks following surgery). A postoperative prolactin level above 200 ng/ml has been identified as a risk factor for poor surgical outcome, independent of the size of the tumor; giant and invasive prolactinomas, especially those with cavernous sinus involvement, rarely attain surgical cure. [1] In 92% of patients in this series, the dopamine agonists were stopped 6 weeks before surgery, presumably to circumvent the fibrosis that renders subsequent tumor excision difficult. However, a high drop-out rate of 50% at follow-up in this study inevitably leaves the lingering doubt that the cure rates may have been worse than what the authors have projected, assuming that many of those patients who were lost to follow-up were actually nonresponders to the therapeutic intervention and sought further treatment elsewhere. [3]

Radiotherapy was given as an adjunctive therapy in 33 patients who did not attain remission of prolactin levels. This was in the form of stereotactic radiotherapy (n=18) or gamma knife therapy (n=15). Radiotherapy has a role for those patients who do not respond to dopamine agonists and who also cannot be cured by surgery. Conventional radiotherapy works best for larger tumors. In small residual tumors, especially those involving the cavernous sinus, stereotactic radiotherapy may be a better option. Review of literature reveals that prolactin normalization following this adjunctive therapy occurs in 25%-35% of patients. The incidence of long-term morbidity of radiotherapy, hypopituitarism (occurring in approximately 50% patients at 10-20 years), optic nerve damage, neurological dysfunction, cognitive disturbances, and intracranial malignancies are issues that should have been addressed in this study. [1],[10]

At follow-up (range: 1-62 months, mean: 38.6 months), 68 (56%) patients could not achieve hormonal remission and were treated with dopamine agonist (n=35) or radiotherapy (n=33). In the literature, recurrence rates after the initial remission of prolactin levels have been fairly uniform both for microadenomas and macroadenomas (approximately 18%-22%). [1] This figure is unfortunately missing in the present study. Gonadotropic as well as other hormonal functions are often restored following attainment of postoperative normoprolactinemia (normal luteinizing hormone pulsatility restored by day 8). With macroadenomas, the postoperative pituitary functions may improve in one-third of the patients and become worse in one-third; besides, pan-hypopituitarism often does not improve following surgery. The authors have failed to mention the degree of postoperative normalization of pituitary hormonal functions (especially gonatotrophic hormones). Furthermore, 35 nonresponders to all forms of therapeutic interventions again responded to dopamine agonists. This does make one wonder why they were chosen for the surgical/radiotherapeutic intervention in the first place. In this subset of patients, it is possible that there was a periodicity of pharmacological response; that these patients would have initially responded to newer and more potent pharmacological agents; and perhaps surgery/radiotherapy took care of the nonresponding cells, rendering the rest of the adenoma vulnerable to pharmacotherapy.

To conclude, the authors have effectively highlighted the role of surgery and adjunctive radiotherapy in the management of prolactinomas. With a systematic methodology and well-defined protocols, they have, in a purely indigenous setup, attained a therapeutic response that compares favorably with the statistics available in the international literature emanating from several high-output centers.

 » References Top

1.Gillam MP, Molitch ME, Lombardi G, Colao A. Advances in the treatment of prolactinomas. Endocr Rev 2006;27:485-534.  Back to cited text no. 1
2.Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, et al. Endocrine Society. Diagnosis and treatment of hyperprolactinemia: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:273-88.  Back to cited text no. 2
3.Sinha S, Sharma BS, Mahapatra AK. Microsurgical management of prolactinomas-Clinical and hormonal outcome in a series of 172 patients. Neurol India 2011;59:327-9.  Back to cited text no. 3
4.Klibanski A. Clinical practice. Prolactinomas. N Engl J Med 2010;362:1219-26.  Back to cited text no. 4
5.Frantz AG, Kleinberg DL. Prolactin: Evidence that it is separate from growth hormone in human blood. Science 1970;170:745-7.  Back to cited text no. 5
6.Weiss MH, Teal J, Gott P, Wycoff R, Yadley R, Apuzzo ML, et al. 1983 Natural history of microprolactinomas: Six-year follow-up. Neurosurgery 1983;12:180-3.  Back to cited text no. 6
7.Fahy UM, Foster PA, Torode HW, Hartog M, Hull MG. The effect of combined estrogen/progestogen treatment in women with hyperprolactinemic amenorrhea. Gynecol Endocrinol 1992;6:183-8.  Back to cited text no. 7
8.Kawamata T, Iseki H, Ishizaki R, Hori T. Minimally invasive endoscope-assisted endonasal trans-sphenoidal microsurgery for pituitary tumors: Experience with 215 cases comparing with sublabial trans-sphenoidal approach. Neurol Res 2002;24:259-65.  Back to cited text no. 8
9.Ganslandt O, Behari S, Gralla J, Fahlbusch R, Nimsky C. Neuronavigation: concept, techniques and applications. Neurol India 2002;50:244-55.  Back to cited text no. 9
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10.Laws ER, Sheehan JP, Sheehan JM, Jagnathan J, Jane Jr JA, Oskouian R. Stereotactic radiosurgery for pituitary adenomas: a review of the literature. J Neurooncol 2004;69:257-72.  Back to cited text no. 10

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