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."
  

Hyperprolactinemia and Macroprolactinemia

Hyperprolactinemia due to big big prolactin is differently detected by commercially available immunoassays.
-B Cavaco, S Prazeres, et al.
J Endocrinol Invest. 1999 Mar;22(3):203-8.

"Macroprolactinemia, i.e. sustained hyperprolactinemia where the predominant circulating form of prolactin (PRL) is of large molecular weight, is a common phenomenon comprising up to one-fourth of all cases of hyperprolactinemia."

"we suggest that the routine measurement of PRL should be done with methods that are only minimally affected by the presence of macroprolactin."

Hyperprolactinemia or pseudohyperprolactinemia?

Reporting of Post–PEG Prolactin Concentrations: Time to Change
-T Smith, M Fahie-Wilson
Clinical Chemistry March 2010 vol. 56 no. 3 484-485

Measurement of serum prolactin levels can be exagerated by the presence of biologically inactive "big prolactin" or "macroprolactin", aka "big big prolactin".

"The polyethylene glycol (PEG) precipitation test is widely used to detect pseudohyperprolactinemia caused by big prolactin and/or macroprolactin. Current best practice recommends that all sera with increased total prolactin concentrations be subfractionated by PEG precipitation to measure the bioactive monomeric prolactin concentration, a more clinically meaningful variable."

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!"

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?
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⁽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