Autoimmune Disorders & An Effect On The Immune System

I. Lupus & Lupron:

In 1994, Fritzler reported that “a number of drugs recently have been implicated in a syndrome that resembles systemic lupus erythematous.”(8) “New drugs most frequently implicated in a syndrome resembling lupus systemic erythematous (SLE), are recombinant protein molecules now undergoing use in the treatment of malignancies.” (8) Lupron is currently approved by the FDA for the palliative treatment of advanced prostate cancer. In the article, “Table I” is entitled “Drugs recently associated with lupus syndromes.” (8) Leuprolide Acetate (Lupron) is one of the 15 drugs listed. (8)

II. Lupron: An Effect On The Immune System

GnRH agonists are known to exert effects on the immune system.(1) In 1994, Grau et al reported a case of a women who developed leukopenia* while on Lupron depot for a fibroid.(2) Grau claimed that this was the first reported case in a woman taking Lupron for fibroids. He stated that previously leukopenia had only been noted occassionally in patients who were given Lupron for ovarian cancer and that the leukopenia was due to the other chemotherapies that they were given. This was initially reported by Miller who was doing a Phase II trial of Leuprolide Acetate in patients with advanced epithelial ovarian carcinoma funded in part by the manufacturer; an indication that has not gained approval by the US Food and Drug Administration to date.(3) However, we found numerous sources including the NDA (New Drug Application) for Lupron which stated the following:

  1. According to the NDA for Lupron for fibroids, “decreases in total WBC [White Blood Cell] count and neutrophils, were observed.” (4)
  2. According to the NDA for Lupron for endometriosis (1990), “white blood cell count fell with Lupron. Slight leukopenia has been noted with other analogues.” (5)

* Leukopenia – any situation in which the total number of leukocytes (White Blood Cells) in the circulating blood is less than normal.
* Leukocytes – (White Blood Cells) – includes: Lymphocytes, Monocytes and Granulocytes (Neutrophils, Eosinophils,and Basophils).

READ:  Endometriosis

In 1994, Rao et al investigated the effect of Lupron on sequential changes in peripheral blood leukocyte subpopulations in women with endometriosis and/or uterine fibroids. He concluded that “GnRH agonist [Lupron] alters circulating lymphocyte and granulocyte subpopulations.” In earlier work, Rao et al investigated the sequential changes in functional lymphocyte subpopulations in primary (thymus and bone marrow) and secondary (peripheral blood, spleen and lymph nodes) lymphoid tissues of prepubertal female mice following in vivo administration of Lupron depot. Rao et al stated that “significant effects on both primary and secondary lymphoid tissues were observed upon the administration of GnRH agonist [Lupron] in depot formulation. These effects appear to be unrelated to plasma estradiol levels, since estradiol did not change significantly over the course of GnRH [Lupron] treatment. This suggests that factors other than steroid hormones may have a role in this effect.” “Decreased bone marrow B-cells and thymocyte counts were observed in the primary lymphoid tissue of prepubertal female mice following GnRH agonist [Lupron] treatment.” “Secondary lymphoid tissues in these same mice also suggested decreased levels of lymphocytes and neutrophils in peripheral blood and reduced splenic and blood B-cells in Lupron-treated mice. These results indicate a general suppression of lymphocyte maturation and suggests a potential effect of GnRH agonists [Lupron] at an early stem cell stage of leukocyte [White Blood Cell] development. Suppression of the lymphoid immune system following GnRH agonist [Lupron] treatment is supported by the functional studies reported here. Assessment of in vivo cell-mediated immune function measured by contact hypersensitivity showed 33% suppression following GnRH agonist [Lupron] administration. Thus, GnRH agonist [Lupron] appears to have immunomodulatory effects in prepubertal female mice in vivo which results in suppressed immune responses.”

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A. EFFECTS OF LUPRON ON PRIMARY LYMPHOID ORGANS (Bone Marrow and Thymus)

1. Effect of Lupron on bone marrow lymphocyte subpopulations
“The percentage of bone marrow B cells was also significantly decreased at the 2nd and 3rd weeks following agonist [Lupron] administration.(7)

2. Effects of Lupron on thymic lymphocyte subpopulations over 6 weeks.
“Absolute levels of thymic T cells, CD8 positive cells, immature cells expressing both CD4 and CD8, and immature subsets differentiating toward CD4 were significantly reduced 2 weeks after agonist [Lupron] treatment.” (7)

“The absolute numbers of interleukin-2 receptor positive cells in the experimental group were also decreased significantly on the 3rd week after Lupron administration.” (7)

3. Effects of Lupron agonist on thymus weight and thymocyte counts.
“Single i.m.injection of agonist [Lupron] significantly decreased both absolute and relative thymic weights and absolute thymocyte counts.” (7)

B. EFFECTS OF LUPRON ON SECONDARY LYMPHOID TISSUES (Peripheral Blood, Spleen, Lymph Nodes)

1. Effects of Lupron on peripheral blood lymphocyte subpopulations over 6 weeks

  • “Following agonist [Lupron] administration, white blood cells counts decreased significantly with decreases in both granulocytes and lymphocyte counts.” (1)
  • “Blood T-cell and B-cell subsets were also reduced although B cells decreased more markedly.”
  • “Both the absolute number of T helper and T suppressor/cytotoxic cells were also decreased significantly in the 3rd and 4th week in the experimental group.” (1)
  • “Interleukin-2 receptor positive cells in the experimental group were also decreased significantly on the 3rd week after Lupron administration.” (1)

2. Effects of Lupron on splenic lymphocyte subpopulations over 6 weeks

  • “The absolute counts on splenic lymphocytes decreased significantly in the 4th and 6th week.” (1)
  • A “significant decrease was observed in all T and T-cell subsets” on the 6 th week. (1)
  • “The absolute splenic B lymphocytes were significantly decreased from the 2nd through the 6th week and more drastically in the 4th and 6th week over controls.” (1)
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3. Effects of Lupron on lymph node lymphocyte subpopulations over 6 weeks

  • “Analysis of light-scattering characteristics of cells from both control (lypholized microcapsules alone) and Lupron (lypholized microcapsules with Leuprolide Acetate) treated animals revealed 3 readily identifiable populations. The precise identity of these cells has not been established.” Why wasn’t the precise identity of these cells established?
  • “The percentage of B cells significantly decreased in the 2nd week in the treated group over controls.” (1)

REFERENCES

  1. Rao LV, Cleveland RP, Ataya KM. GnRH Agonist Induces Suppression of Lymphocyte Subpopulations in Secondary Lymphoid Tissues of Prepubertal Female Mice. American Journal of Reproductive Immunology. 30: 1993; p. 15-25.
  2. Grau E, Torrecila T, Real E, Sempere J. Leukopenia induced by leuprolide acetate depot. Annals of Pharmacotherapy. 28: 1994. p. 283-284.
  3. Miller DS, Brady MF, Barrett RJ. A Phase II Trial of Leuprolide Acetate in Patients with Advanced Epithelial Ovarian Carcinoma. A Gynecologic Oncology Group Study. American Journal of Clinical Oncology. 15: 2: 125-128, 1992.
  4. NDA # 19-943; US Food and Drug Administration.
  5. NDA # 20-011; US Food and Drug Administration.
  6. Rao LV, Cleveland R, McMullen S, Hagen R, Ataya K. Effect of GnRH Agonist on Sequential Changes in Peripheral Blood Leucocyte Subpopulations in Women With Endometriosis and/or Uterine Fibroids. Fertility & Sterility . 1994.Supplement p.S148.
  7. Rao LV, Cleveland RP, Ataya KM. Alterations in thymic and bone marrow lymphocyte subpopulations in GnRh agonist treated prepubertal female mice. American Journal of Reproductive Immunology. 25 : 1993; p. 167-184.
  8. Fritzler, MJ Drugs Recently Associated With Lupus Syndrome. Lupus. 3: 1994; 455-459.

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