Prolactin Receptor in Primary Hyperparathyroidism

PLOS ONE: Prolactin Receptor in Primary Hyperparathyroidism – Expression, Functionality and Clinical Correlations

Conclusions:

We demonstrate that the prolactin receptor is highly abundant in human parathyroid tissues and that PRLr isoforms expression and PRLr subcellular localisation are altered in parathyroid tumours. Responsiveness of PRLr to physiological levels of prolactin was observed in the form of increased PTH secretion and altered gene transcription with significant increase of RIG-I like receptor, JAK-STAT and Type II interferon signalling pathways. These data suggest a role of the prolactin receptor in parathyroid adenomas.

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."

Prolactin produced in the breast may play a role in breast cancer

http://www.medicalnewstoday.com/releases/250906.php

• "...prolactin has long been thought to play a role in human breast cancer, however this has typically been assumed to be due to circulating prolactin produced by the pituitary. Since the PI3K-Akt signaling pathway is commonly activated in human cancers, this new finding suggests the important possibility that prolactin produced by the breast itself may play a role in breast cancer."
  
• "Since the PI3K-Akt pathway is one of the most commonly activated oncogenic pathways in human cancer, its identification as an upstream regulator of prolactin production in the mammary gland has intriguing potential implications for understanding the pathology of human breast cancer and as well as improving its treatment..."
  

-Medical News Today, October 2, 2012

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."

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."

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 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."