Long-Term Natural Course of Pituitary Tumors in Patients With MEN1

Long-Term Natural Course of Pituitary Tumors in Patients With MEN1: Results From the DutchMEN1 Study Group (DMSG)

Joanne M. de Laat, Olaf M. Dekkers, et al.
The Journal of Clinical Endocrinology & Metabolism 2015 100:9, 3288-3296;

Results:

...Ninety-one percent of the nonfunctioning PIT detected during screening (n = 35), did not require intervention during followup (median, 6.0 y). Three microadenomas showed limited growth but did not progress toward macroadenomas. Both screening-detected and prevalent prolactinomas ...responded well to treatment with dopamine agonists.

Conclusion:

Systematic presymptomatic screening for PIT in patients with MEN1 predominantly results in detection of nonfunctioning microadenomas. Prolactinoma in patients with MEN1 responded well to medical treatment. Microadenomas grew only occasionally and after many years without clinical consequences. Frequent magnetic resonance imaging followup of nonfunctioning microadenomas in the context of MEN1 and sporadically occurring PITs therefore seems debatable.

Diagnosis of MEN1 in a patient with back pain

Diagnosis Of Multiple Endocrine Neoplasia Type 1 In A Patient With Back Pain; Case Report And Review Of Literature
-G Cristina, L Cesar A, L Robert, M Vinuta. Diagnosis Of Multiple Endocrine Neoplasia Type 1 In A Patient With Back Pain; Case Report And Review Of Literature. The Internet Journal of Internal Medicine. 2008 Volume 8 Number 1.

• "Usually MEN1 patients are first diagnosed when they present with hypercalcemia. Our patient’s diagnosis was made only after he presented with back and flank pain, and imaging of his abdomen incidentally noted multiple abdominal tumors."
  

Men1 mouse studies claim pre-clinical proof-of-concept for gene replacement therapy in pituitary NETs.

Clinical and pre-clinical studies of neuroendocrine tumours (NETs) in multiple endocrine neoplasia type 1 (MEN1), and evaluation of MEN1 gene replacement therapy for MEN1-associated NETs.
-Gerard Walls, Paul Newey, et al.
Endocrine Abstracts (2013) 31 YEP1.1 | DOI:10.1530/endoabs.31.YEP1.1

MEN Syndrome and M.E.N. 1: Parathyroid, Pituitary, Pancreas, Thyroid Tumors and MEN type 1 Syndrome - Disorders of the Parathyroid, Pituitary, and Pancreas

MEN Syndrome and M.E.N. 1: Parathyroid, Pituitary, Pancreas, Thyroid Tumors and MEN type 1 Syndrome - Disorders of the Parathyroid, Pituitary, and Pancreas

An overview of MEN1, its treatment, and what patients can expect.

By James Norman MD, FACS, FACE
Norman Parathyroid Center
http://www.parathyroid.com/Parathyroid-Surgeon.htm

MEN1 gene replacement therapy reduces proliferation rates in a mouse model of pituitary adenomas

MEN1 gene replacement therapy reduces proliferation rates in a mouse model of pituitary adenomas
-G Walls, M Lemos, et al.
Journal of Cancer Research, OnlineFirst August 21, 2012; doi: 10.1158/0008-5472.CAN-12-1821

• "In this study, we conducted a preclinical evaluation of MEN1 gene therapy in pituitary tumors of Men1+/- mice, using a recombinant non-replicating adenoviral serotype 5 vector..."
  
• "Menin expression was higher in the Men1.rAd5-treated mice when compared to other groups. Daily proliferation rates assessed by BrdU incorporation were reduced significantly in Men1.rAd5-injected tumors relative to control treated tumors."
  
• "Our findings establish that MEN1 gene replacement therapy can generate menin expression in pituitary tumors, and significantly reduce tumor cell proliferation."
  

The Genetics of Pituitary Adenomas

The Genetics of Pituitary Adenomas
-Monica Fedele, Giovanna Maria Pierantoni and Alfredo Fusco (2011). The Genetics of Pituitary Adenomas, Contemporary Aspects of Endocrinology, Dr. Evanthia Diamanti-Kandarakis (Ed.), ISBN: 978-953-307-357-6, InTech, Available from: http://www.intechopen.com/books/contemporary-aspects-of-endocrinology/the-genetics-of-pituitary-adenomas

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas
-Casanueva F, et al. Clinical Endocrinology (2006) 65, 265–273

• "Doses [of cabergoline] over 3 mg per week are rarely necessary."

Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: Morphological findings

Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: Morphological findings
-Kovacs K, et al. Human Pathology Volume 38, Issue 1 , Pages 185-189, January 2007

• "Based on the clinical, laboratory, and morphological findings, we recommend temozolomide therapy in patients with pituitary tumors not responding adequately to other treatment options."

Transsphenoidal Surgery for Pituitary Tumors in the United States, 1996–2000: Mortality, Morbidity, and the Effects of Hospital and Surgeon Volume

Transsphenoidal Surgery for Pituitary Tumors in the United States, 1996–2000: Mortality, Morbidity, and the Effects of Hospital and Surgeon Volume
-Barker F, II, et al. Journal of Clinical Endocrinology & Metabolism 88(10):4709–4719, ©2003 by The Endocrine Society, doi: 10.1210/jc.2003-030461

• Results of transsphenoidal surgery for pituitary tumors, as a function of hospital volume, surgeon volume, and more.

Endoscopic endonasal transsphenoidal surgery for functional pituitary adenomas

Endoscopic endonasal transsphenoidal surgery for functional pituitary adenomas
-Hofstetter C, et al. Neurosurg Focus 30 (4):E10, 2011

• Description of endoscopic endonasal transsphenoidal surgery.
• Results from the resection of 86 functional pituitary adenomas at Weill Cornell Medical College, New York–Presbyterian Hospital, from 2004-2010.

Asymptomatic children with multiple endocrine neoplasia type 1 (MEN1) mutations harbour pancreatic and pituitary tumours

Asymptomatic children with multiple endocrine neoplasia type 1 (MEN1) mutations harbour pancreatic and pituitary tumours
-Newey P, et al. Endocrine Abstracts (2009) 19 P171

• "...These two cases highlight the importance of screening children with MEN1 mutations as early diagnosis and treatment is likely to reduce both morbidity and mortality."

Pituitary surgery for small prolactinomas as an alternative to treatment with dopamine agonists

Pituitary surgery for small prolactinomas as an alternative to treatment with dopamine agonists
-Babey M, et al. Pituitary Volume 14, Number 3 (2011), 222-230, DOI: 10.1007/s11102-010-0283-y

• "Ninety percent of symptomatic patients experienced significant improvement of their signs and symptoms upon surgery... [Among 34 patients] postoperative PRL levels (median 3.45 μg/l) returned to normal in 94% of patients with small prolactinomas. There was no mortality and no major morbidities."
• "Patients with small prolactinomas can safely consider pituitary surgery in a specialized centre with good chance of long-term remission as an alternative to long-term DA therapy."

MEN1 and pituitary adenomas

MEN1 and pituitary adenomas
-Delemer B. Service d’endocrinologie-diabète-nutrition

"MEN1 [pituitary] tumors seem more aggressive, invasive and resistant to treatment requiring a very careful long-life follow-up. Occurrence of these tumors can be described in the pediatric population and it can be the first and only manifestation of MEN1 for some years asking the question of the systematic screening for MEN1 gene mutation in pediatric population with pituitary adenoma."

Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study

Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study
-Verges, et al. Journal of Clinical Endocrinology & Metabolism 87(2):457–465, ©2002 by The Endocrine Society.

• Among the 85 prolactinomas [treated surgically, medically, or with radiotherapy] PRL levels were normalized in only 37 patients (44%).
• "Compared with pituitary adenomas in the non-MEN1 population, pituitary lesions in MEN1 are characterized by a higher frequency of macroadenomas and a worse response to treatment. This suggests that pituitary adenomas in MEN1 may be more aggressive than those occurring in the non-MEN1 patients."

The treatment of sporadic versus MEN1-related pituitary adenomas

The treatment of sporadic versus MEN1-related pituitary adenomas
-Beckers A, et al. Journal of Internal Medicine, 2003; 253: 599-605.

• MEN1-related adenomas [appear to be] more aggressive and less responsive to therapy than their sporadic counterparts."
• "...prolactinomas are over-represented in MEN1."
• [In non-invasive, sporadic cases, about] 92% of cases of prolactinoma or hyperprolactinemia were normalized with Cabergoline.
• 10-15% of patients are resistant to Bromocriptine. Cabergoline normalized PRL in more than 70% of patients intolerant or resistant to Bromocriptine.
• "In the future, somatostatin analogues with greater affinity to receptors subtype 5 (SSTR5) -frequently present at the cell surface of prolactinomas- may be tried.
• "Malignancy does not appear a characteristic of pituitary tumours in MEN1."
• "it appears therefore probable that MEN1 pituitary adenomas are more aggressive than the sporadic counterpart."
• In MEN1 patients with pituitary adenomas, "aggressive therapy is more frequently needed!"

Pituitary tumors in patients with MEN1 syndrome

Pituitary tumors in patients with MEN1 syndrome
-Syro LV, et al. Copyright © 2012 Hospital das Clínicas da FMUSP

• "pituitary tumors in MEN1 ...are more often resistant to medical therapy."
• "...normalization of pituitary hypersecretion was much less frequent in MEN1 patients than in non-MEN1 subjects (42% vs. 90%)."

Epigenetic and Posttranscriptional Alterations of Tumor Suppressor Genes in Sporadic Pituitary Adenomas

Epigenetic and Posttranscriptional Alterations of Tumor Suppressor Genes in Sporadic Pituitary Adenomas
-Henriett Butz, et al. InTech, February 2012, ISBN 978-953-307-879-3.

Endoscopic Removal of Pituitary Tumors

Endoscopic transphenoidal resection of pituitary tumors at UCLA.

Drug-resistant hyperprolactinemia

MEN1 frequently involves pituitary disease. One study found pituitary disease occurred in 42% of MEN1 patients.⁽¹⁾ Depending on the specific type of pituitary disorder, treatment may include the surgical removal of an adenoma, the use of hormones or drugs to normalize pituitary function, or radiotherapy.

A prolactinoma, for example, is a non-cancerous pituitary tumor that produces the hormone prolactin; it's the most common form of pituitary tumor.⁽²⁾ Prolactinomas tend to cause hyperprolactinemia, abnormally high blood levels of prolactin. This can cause a variety of symptoms, including interfering with normal ovulatory function in women.

Normally, prolactin-producing cells are down-regulated, or inhibited, by dopamine signals from the hypothalamus.⁽³⁾ Therefore, hyperprolactinemia often is treated by dopamine agonists, usually Cabergoline or Bromocriptine.

Cabergoline usually is more effective than Bromocriptine at normalizing prolactin levels and restoring gonadal function.⁽⁴⁾ Yet it is not always successful in lowering prolactin to normal levels.

One particular patient, "P", was found to have hyperprolactinemia which then prompted an MRI scan and diagnosis of a pituitary adenoma. Treatment with Cabergoline was started. Within four months, the adenoma shrank and was no longer detectable via MRI, and P's prolactin level dropped to normal levels. But not for long. The prolactin level began to rise, and P's doctor responded with increasing dosage of Cabergoline. This went on for eight years, with Caborgoline dosage of up to 2.5mg/wk and prolactin levels typically about 50-100 mg/dL. When Cabergoline was discontinued, the prolactin would shoot up to about 180, and when Cabergoline was resumed, prolactin would reduce but not normalize. Periodic MRIs suggested possible empty sella syndrome and no sign of adenoma.

P's treatment subsequently was switched to Bromocriptine for a year, but her prolactin did not respond as well as it did to Cabergoline, and so Cabergoline was resumed.

What is there to do for a patient whose hyperprolactinemia does not respond sufficiently to dopamine agonist therapy, and who does not exhibit an operable adenoma?
__________

⁽¹⁾ Bruno Vergès, et al. Pituitary Disease in MEN Type 1 (MEN1): Data from the France-Belgium MEN1 Multicenter Study. The Journal of Clinical Endocrinology & Metabolism February 1, 2002 vol. 87 no. 2, 457-465.
⁽²⁾ http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001377/
⁽³⁾ http://en.wikipedia.org/wiki/Dopamine#Regulating_prolactin_secretion
⁽⁴⁾ Webster, et al. A Comparison of Cabergoline and Bromocriptine in the Treatment of Hyperprolactinemic Amenorrhea. N Engl J Med 1994; 331:904-909

What is MEN1?

Multiple Endocrine Neoplasia Type 1 is a genetic disorder that greatly increases the risk of developing multiple cancerous and noncancerous tumors in glands such as the parathyroid, pituitary, and pancreas. These endocrine tumors may produce excessive levels of hormones that lead to secondary disease.

Individuals with MEN1 are born with one mutated copy of the MEN1 tumor suppressor gene in each cell. Cells that later develop a mutation in the remaining copy of the MEN1 gene then are left unable to produce menin, an important tumor suppressor protein. With no functional MEN1 gene, such cells may divide uncontrollably, resulting in the development of tumors.

MEN1 is also known as: MEN Type 1, MEN-1, Multiple Endocrine Adenomatosis Type 1, MEA Type 1, MEA 1, Wermer's syndrome.

references:
http://www.mayoclinic.org/men1/
http://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia_type_1