Prostate Cancer & Hormones - Prolactin

Evolution has given hormones promiscuous roles in the body. A particular hormone may be involved in a number of unrelated functions.

Prolactin, as one might guess, is a hormone mostly associated with milk production, but it has various roles in the male body too. In addition, the prostate has prolactin receptors.

"In humans, prolactin is produced at least in the anterior pituitary, decidua, myometrium, breast, lymphocytes, leukocytes and prostate." [1] Which means that prostate cells have the means to produce prolactin, & also have the receptor for it. Thus, local activity is not dependent on the endocrine system (acting at a distance), but may occur entirely within the cell (autocrine) or between local cells (paracrine).

There are 463 PubMed hits for <prostate cancer prolactin>, stretching back to 1960.

[2] (2001 - Sweden)

"Prolactin, a pituitary peptide hormone with multiple effects, stimulates prostate growth in experimental models. In humans, prolactin receptors are present in the prostate and are particularly abundant in pre-cancerous lesions. This suggests that prolactin could also be involved in the development of prostate cancer. In this study, we tested the hypothesis that elevated levels of circulating prolactin are associated with an increase in prostate cancer risk. We conducted a case-control study nested within the Northern Sweden Health and Disease Cohort using plasma samples collected from 29,560 men at a health survey. We measured prolactin in plasma from 144 men who had a diagnosis of prostate cancer after a median follow-up time of 4 years after health survey and from 289 controls matched for age and date of recruitment. Risk was not associated with plasma prolactin levels ..."

Prior to this, circulating prolactin had often been included in a basket of tested hormones & almost never been implicated in PCa. But I'll continue with the reason it had been a suspect:

"In vitro, prolactin induces proliferation and antagonises apoptosis in prostate organ culture and in some tumour cell lines but not in others. In vivo studies have consistently shown that hyperprolactinaemia induces prostate proliferation ... in the rat prostate, and prolactin stimulated growth of the Dunning R3327 PAP tumour."

"In humans, receptors for prolactin are expressed in the prostate, and the expression is particularly elevated in high-grade prostate intra-epithelial cell neoplasia (PIN), a precursor of prostate cancer. Local production of prolactin has also been demonstrated in the prostate. Plasma prolactin rises sharply at puberty and continues to increase in parallel with the age-related increase seen in the incidence of benign prostatic hyperplasia and prostate cancer."

"Collectively, these experimental and chronobiological results suggest that increased levels of circulating prolactin induce prostate growth and possibly prostate tumour growth. However, epidemiological data concerning prolactin and prostate cancer are sparse and inconclusive: several small case-control studies and prospective cohort studies have not shown a consistent association between circulating prolactin concentrations and prostate cancer risk."

"The absence of an association between prostate cancer risk and circulating prolactin does not entirely rule out the possibility that prolactin may be involved in the pathogenesis of prostate cancer. The autocrine and paracrine effects of locally produced prolactin may be more important than the effects of circulating prolactin. Furthermore, although most studies indicate that prolactin stimulates prostate cell proliferation, this growth-promoting effect could be counteracted by the other inhibitory effects of prolactin. Prolactin 16K, a proteolytic fragment, is a potent inhibitor of angiogenesis, and the prostate gland has the highest capacity of all organs to form prolactin 16K fragments. It is tempting to speculate that prostate tumours could remain dormant due to inhibition of angiogenesis by prolactin 16K activity. Thus, several mainly experimental studies suggest that prolactin may be involved in the development of prostate cancer, but the effect of circulating and locally produced prolactin on tumour formation may be more complex than previously recognised."

[3] (2005 - Italy)

"... we have analyzed the PRL levels in a group of metastatic prostate cancer patients with hormone-dependent or hormone-resistant cancer. The study included 50 patients with metastatic prostate cancer, 15 of whom had hormone-resistant tumors."

"Abnormally high concentrations of PRL were found in 11/50 (22%) patients. Moreover, the percent of patients with cancer-related hyperprolactinemia was significantly higher in the hormone-resistant group than in the hormone-dependent group (8/15 vs 3/35, ...). This study confirms the possible existence of a hyperprolactinemic state in metastatic prostate cancer, as previously reported by other authors. Moreover, it appears to demonstrate that the occurrence of hyperprolactinemia is more frequent in hormone-resistant neoplasms, suggesting the possible involvement of PRL in hormone independence."

[4] (2007 - Czech Republic)

"In 250 men ... who underwent radical retropubic prostatectomy for histologically confirmed prostate cancer were analyzed serum samples for total testosterone, dehydroepiandrosterone sulfate, estradiol, progesterone, prolactin, cortisol, sex hormone-binding globulin, luteinizing hormone and follicle stimulating hormone. "

"Significant correlation was found between serum levels of ... estradiol and prolactin in patients with locally advanced prostate cancer ..."

[5] (2010 - U.S.)

Why not target the prolactin receptor?

"Breast and prostate cancers are hormone-sensitive malignancies that afflict millions of women and men. Although prolactin (PRL) is known as a survival factor that supports tumor growth and confers chemoresistance in both cancers, its precise role in these tumors has not been studied extensively. Growth hormone and placental lactogen also bind PRL receptor (PRLR) and mimic some of the actions of PRL. Blockade of the PRLR represents a novel treatment for patients with advanced breast or prostate cancer with limited therapeutic options."

"The significance of the PRL/PRLR axis in prostate cancer."

"Epidemiological data have not shown an association between circulating PRL levels and prostate cancer, whereas increasing evidence indicates a strong role for locally-produced PRL. As a proof of concept, transgenic mice overexpressing PRL in their prostates developed a dramatic enlargement of the gland with diminished apoptosis. As depicted in Table 2, both PRL and the PRLR are expressed in normal and malignant human prostates. An autocrine loop for PRL was revealed by the reduced cell viability in response to hPRL antagonists in the androgen-independent 22Rv1 cells, and the androgen-sensitive LnCaP cells ..."

"... analysis of prostate cancer samples showed a strong link between PRL and its signaling and prostate cancer pathology. For example, 50% of 183 hormone-insensitive prostate cancer specimens, and 63% of prostate cancer metastases, stained for PRL. The PRL-positive tumors showed a correlation with activated STAT5 and a high Gleason score (high grade, hormone refractory and metastatic disease), which portends a much greater mortality than those with a low score. A recent gene expression array study found a 6.7-fold increase in PRLR mRNA in ductal vs acinar prostate carcinomas; ductal adenocarcinoma presents a more aggressive clinical picture than acinar carcinoma."

"The strongest evidence linking the PRL pathway to prostate cancer comes from studies on STAT5, which was found to be constitutively active in human prostate cancer and a prognosticator of early disease recurrence. Indeed, STAT5 promotes metastatic behavior of human prostate cancer cells in vitro and is essential for growth of human prostate cancer xenografts in nude mice. Indeed, inhibition of STAT5 by siRNA induced a massive death of human prostate cancer cells in vitro and in nude mice."

...

[6] "The most common type of pituitary tumor is a prolactinoma, a tumor that hypersecretes prolactin." "Dopamine agonists that are approved for the treatment of hyperprolactinemia are bromocriptine and cabergoline."

[7] (2000 - Italy)

"Efficacy of bromocriptine in the treatment of metastatic breast cancer- and prostate cancer-related hyperprolactinemia."

"The study included 10 women affected by metastatic breast cancer and 10 men with metastatic prostate cancer, showing persistent hyperprolactinemia."

"Bromocriptine induced a normalization of PRL levels in both groups of patients with breast and prostate cancers. Moreover, mean levels of PRL persisted significantly lower than those found before therapy during the whole 24-hour circadian period."

"This preliminary study shows that low-dose bromocriptine is sufficient to acutely normalize PRL secretion in both metastatic breast cancer and prostate carcinoma patients, irrespectively of the mechanisms involved in inducing cancer-related hyperprolactinemia."

But would bromocriptine reduce local production in PCa cells?

Regardless, it seems prudent to address elevated prolactin in the blood.

...

Here's a weird study. L-Dopa is supposed to lower prolactin, but in 4 of 10 men it actually increased it. Casodex brought levels back down. No indication that prolactin regulation would occur in the absence of L-Dopa.

[8] (2002 - Italy)

"Before therapy, a paradoxical increase in PRL levels after L-dopa occurred in 4 patients, 3 of them showed basal concentrations of PRL within the normal range. Moreover, bicalutamide therapy significantly reduced PRL increase in response to L-dopa."

...

Unfortunately, there are no studies showing that my favorite polyphenols can inhibit prolactin. However, prolactin is associated with STAT5 activation, & silibinin (from milk thistle) may inhibit STAT5:

[9] (2009 - U.S. - mouse study)

"A marked inhibitory effect of silibinin on Signal Transducers and Activators of Transcription (STAT) 1 (Tyr(701)), STAT1 (Ser(727)), STAT3 (Tyr(705)), STAT3 (Ser(727)), and STAT5 (Tyr(794)) ... {was} ... observed."

-Patrick

[1] en.wikipedia.org/wiki/Prola...

[2] onlinelibrary.wiley.com/doi...

[3] ncbi.nlm.nih.gov/pubmed/282...

[4] ncbi.nlm.nih.gov/pubmed/172...

[5] ncbi.nlm.nih.gov/pmc/articl...

[6] courses.washington.edu/conj...

[7] ncbi.nlm.nih.gov/pubmed/114...

[8] ncbi.nlm.nih.gov/pubmed/118...

[9] ncbi.nlm.nih.gov/pubmed/191...

4 Replies

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  • Patrick, I had my prolactin level tested Thursday. I don't expect it to be high, since I am taking Casodex. If it is high do you think Milk Tistle is the best way to go?

    Rich

  • Milk THistle is a liver supplement that can cause prolactin levels to rise so DO NOT TAKE MILK THISTLE FOR HIGH PROLACTIN IT WILL MAKE IT WORSE. Dostinex is the drug for high prolactin, always see a Dr. about changing meds. forums.phoenixrising.me/ind...

  • Dan59,

    Thank you for the link. I read the articles you directed me to.

    A menber of the Reluctant Brotherhood.

    Rich

  • Great Post Patrick! I remember Myers and Strumm wanting to test prolactin levels while on hormone therapy, especially in the old days of estrogens

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