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."
  

The Cabergoline-Resistant Prolactinoma Patient: New Challenges

The Cabergoline-Resistant Prolactinoma Patient: New Challenges
-Molitch M. The Journal of Clinical Endocrinology & Metabolism December 1, 2008 vol. 93 no. 12 4643-4645, doi: 10.1210/jc.2008-2244

• "11 of 60 previously untreated patients (18.3%) required more than 2 mg/wk cabergoline to normalize PRL levels. Of these, four required 3 mg/wk, two required 6 mg/wk, four required 9 mg/wk, and one required 11 mg/wk to normalize PRL levels."
  
• "Of 150 patients, normalization of PRL was eventually achieved in all but one, but doses had to be raised to high levels in many."

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."

Cabergoline Resistance in Pediatric Prolactinomas

Cabergoline Resistance in Pediatric Prolactinomas
-Spinks J, et al. Journal of Pediatric Hematology/Oncology May 2009 - Volume 31 - Issue 5 - pp 377-379 doi: 10.1097/MPH.0b013e31819b71eb

• "We report 3 cases of cabergoline resistance in adolescents with prolactinomas. All patients failed to respond to conventional doses of cabergoline."

Dopamine agonist-resistant prolactinomas

Dopamine agonist-resistant prolactinomas
-Oh MC, Aghi MK Journal of Neurosurgery 2011 May;114(5):1369-79. published online January 7, 2011; DOI: 10.3171/2010.11.JNS101369.

• "Dopamine agonist-resistant prolactinomas exhibit aggressive behavior and tend to be large, invasive, hyperangiogenic tumors with high mitotic indices, which makes their management via surgery, radiosurgery, or alternative medical therapies challenging, thus underscoring the need for novel medical therapies or treatment regimens that target these lesions."
  
• "...slightly less than 10% of patients with prolactinomas do not experience normalization of their prolactin levels in response to dopamine agonists, and harbor tumors that are resistant to dopamine agonist therapy."
  
• "...a minimum pharmacological definition of dopamine agonist resistance would seem to require a failure to respond to 3 months of treatment with up to 3.5 mg of cabergoline per week."
  
• "Although very rare, secondary or acquired resistance to dopamine agonist therapy has also been described, in which patients who were initially responsive to... either bromocriptine or cabergoline, later develop dopamine agonist resistance, with elevated prolactin levels and sometimes an enlarging tumor volume several years after beginning treatment... According to a recent report... there have been only 5 reported instances of patients who demonstrated secondary resistance to dopamine agonist therapy (2 to bromocriptine and 3 to cabergoline).
  
• DARPs (dopamine agonist resistant prolactinomas) are more likely to exhibit cavernous sinus invasion... [71% vs 10% for dopamine agonist-responsive prolactinomas]."
  
• "DARPs typically do not metastatize."
  
• "Transsphenoidal surgery is recommended for prolactinomas instead of medical treatment if
  • ...2) inadequate prolactin reduction despite high cabergoline doses...
    
  • 3) a female patient desires fertility, which may not occur while on dopamine agonists...
    
  • 5) the patient cannot tolerate dopamine agonist therapy due to side effects.
• transsphenoidal surgery:
  • prolactin was normalized in 36% of patients with DARPs in one study.
    
  • prolactin was normalized in 75% of patients with DARPs that were microprolactinomas.
    
  • "Temozolomide... has been used to treat 3 patients with cabergoline-resistant DARPs... with good results in all 3 cases."

Prolactinomas: Diagnosis and Treatment: Management

Prolactinomas: Diagnosis and Treatment: Management
-Nassiri F, et al. Medscape Education CME Released: 02/29/2012.

• "Despite the effectiveness of [dopamine agonists]... some [patients] do not respond at therapeutic levels or higher. Such patients are considered to be DA resistant. The mechanism of resistance seems to be mediated by a decreased number of D2 receptors without a decreased affinity for DA agonists, and an altered signal transduction mechanism."
• "In resistant patients, treatment options include switching DA agonists, increasing DA agonist dosage beyond convention and surgery and/or radiotherapy."
• "Although doses of 2 mg/week exceed recommended package levels for cabergoline, some patients may require up to 3 mg/day for normalization of PRL levels."
• "Temozolomide therapy has even reduced tumor volume and normalized PRL levels in a resistant macroprolactinoma suggesting a possible role for temozolomide in resistant prolactinomas."

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."

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!"