September 2009

Mal's Musings

Malcolm A Traill

                                                                      First 8/9/2009

Lithium, Heparanase and Gynaecomastia


Probably, during the early stages of his Lithium Rx, patient PC noted a small, tender lump in both breasts. This was gynaecomastia, and is quite a common occurrence during male adolescence. At the time, it was assumed to be some age-related sex hormone effect, possibly accentuated by the Lithium Rx and, accordingly, was not well documented.  Sadly, the exact date of this development is not known with great accuracy, but was considered to follow the start of the Lithium Rx, and before the prostatectomy. The condition abated post operatively.

With the presentation and examination of the documented bone[1] and probable human bone marrow effects[2] that have been attributed to cancer-produced Heparanase (HPSE) from distant sites, the possibility of a human HPSE-derived gynaecomastia takes on new interest. This is because :

a)      HPSE is normally produced by the placenta, as well as (generally) lymphoid, inflammatory and endothelial cells, and keratinocytes[3]

b)      Placental production may contribute to mammary gland proliferation during pregnancy

c)    When human HPSE (65 kDa < 50 kDa, chiefly cytoplasmic) is overproduced in transgenic mice[4],  duct diameters are increased, with more side branchings and alveolar structures to the mammary glands, the stroma having increased vascularization and there is fragmentation of the basement membranes. These are presumed local effects, with the HPSE produced by the juxtaposed gland epithelium itself

d)      The development of gynaecomastia during the Lithium Rx treatment of a HPSE-producing condition, such as cancer or, possibly, active Rheumatoid arthritis or Lupus erythematosus, may provide a clinical indication, firstly, that HPSE is being produced and secondly, that its metabolic processing had been impeded in or near the point of production.
In the context of the Lithium Rx[5], the structure and function of Heparan may be disturbed, and this may disturb the HPSE metabolic pathway; in particular, impede the cellular uptake of the inactive proenzyme into the cancer (or other) cells, leaving this proenzyme form to enter the circulation.
Accordingly, those involved in any Lithium Rx treatment should be on the alert to look for the possible development of gynaecomastia (males), because it may be a simple clinical indicator. (Females may note breast enlargement and firmness, with tenderness.)

In the murine model, when HPSE is produced to excess (globally), it induces a mammary duct proliferation. In noting this, a number of aspects arrise : -

i.         The HPSE receptor mechanisms involved in the  murine mammary model (see above), the human gynaecomastia (patient PC) and the bone marrow responses as revealed by the lymphocyte and NK cell count changes (patient PC), when treated with the Lithium may be similar.

ii.       Those with breast cancer may show HPSE-induced changes in the more normal parts of the affected breast, and in the other breast.

iii.      There may be concern that such stimulation may cause the breast cancer to grow faster and have greater vascularization[6]. This overlooks the postulated operating mechanism, whereby the HPSE proenzyme (65 kDa) is diverted away from the breast cancer that has produced it, and the HPSE is, accordingly, greatly diluted by extracellular fluids. Whilst the breast with the cancer may show some response in the "normal" areas, the concentration of both enzymatically active HPSE (50 kDa) and enzymatically inactive HPSE (65 kDa) there would be expected to be a fraction of what would probably occur in and around the relatively smaller volume of the cancer, where it would have greater intimacy with the cancer cells

iv.     At least two breast cancer patients are recalled that received Lithium, though not having the Lithium Rx protocol that has been described : -

1.     One patient took Lithium for only days. Through a dosing misunderstanding, she developed Lithium toxicity and the treatment was stopped. However, she went on to do unexpectedly well.

2.    Another had 750 mg Lithium carbonate as a bolus dosage on 5 days a week for 3 weeks, concomitant with a UHF treatment course[7]. Examination of her skin biopsy, taken 6 weeks later, revealed cancer cells with nuclei smaller and with more apoptotic forms than in the skin biopsy taken earlier, as though there was less cellular activity (see Photomicrographs below):




The sections are of skin secondary carcinoma deposits from a patient who received UHF and Lithium treatments (see text). The section on the left is a pre-treatment specimen; that on the right is post-treatment. The nuclei on the left are large and there are occasional apoptotic (degenerating) forms. The specimen on the right has smaller nuclei, with more apoptotic forms. That on the right also shows some degree of gland differentiation.


 The view was that these changes were probably largely Lithium-induced effects (the reasons for this conclusion were not strong).

Both these cases are hardly convincing, however, there was no clear evidence of appreciable worsening associated with the Lithium use.




There is a possibility that Lithium Rx (as used) for HPSE-producing conditions, may result in gynaecomastia.  If this occurs (and it needs confirmation) it could be due to an excessive production of HPSE that has its normal processing blocked by the effect of Lithium upon the formation of normal Heparan sulphate. The HPSE is then diverted, reaching other, more remote sites, where it may produce effects, such as breast duct proliferation, lymphocyte and NK cell production and bone changes.
Malcolm Adams Traill;
Copyright MA Traill, 8th September 2009


[1] Kelly T Suva LJ et al. Cancer Res. 2005; 65(13):5778-84


[3] Vlodavsky I & Friedmann Y. J. Clin. Invest. 2001; 108:341-347

[4] Zcharia E Metzger S et al. FASEB J. 2004; 18:252-63


[6] Elkin M Cohen I et al. Cancer Res. 2003; 63:8821-6