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.

Research shows how medicine for the brain can be absorbed through the nose

Research shows how medicine for the brain can be absorbed through the nose
-University of Southern Denmark. "Research shows how medicine for the brain can be absorbed through the nose." Medical News Today. MediLexicon, Intl., 27 Sep. 2013. Web. 27 Sep. 2013.

Editor's notes:
There may be a wonderful use for nasal administration in the treatment of medically resistant pituitary prolactinomas.  These are commonly treated medically by oral administration of the dopamine agonists cabergoline (CAB) or bromocriptine (BRO).  But in some patients normalization of PRL (prolactin) levels is not achieved with even unusually high doses of CAB or BRO. If CAB or BRO can be delivered effectively to the brain via nasal administration, it may be possible to produce higher therapeutic levels of the drug at the pituitary tumor while avoiding the undesired increased exposure to other systems which may be affected: such as the kidneys, pancreas, and immune system.

Cref: Dopamine -Wikipedia

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."

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."