Correspondence

More on Ovarian Insufficiency with Imatinib

N Engl J Med 2008; 358:2648-2649June 12, 2008

Article

To the Editor:

Christopoulos et al. (March 6 issue)1 report a case of primary ovarian insufficiency associated with imatinib. Although the data provided are suggestive of primary ovarian insufficiency, the cause-and-effect relationship is speculative, not reaching the “probable” level on an objective causality-assessment scale.2 It is noteworthy that fertility in female rats is not adversely affected by imatinib, and pregnancy in women taking imatinib has occurred.3,4 Also, despite the expanding use of imatinib, no other cases of primary ovarian insufficiency have been reported. All these facts, along with the presence of follicles in the patient's ovaries on ultrasonography and the delay in the development of her amenorrhea, are inconsistent with the proposed mechanism and with the understanding of toxicant-induced apoptosis of female germ cells.5 Moreover, alternative etiologic factors, including other exposures, were not addressed, and the possibility of spontaneous, karyotypically normal primary ovarian insufficiency — a largely idiopathic condition in which ovarian function is generally intermittent and unpredictable — was not systematically ruled out. This finding may well be a chance association, and only careful, long-term evaluation of patients receiving imatinib can determine its validity.

Saul Malozowski, M.D., Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892-5460
sm87j@nih.gov

Lawrence Nelson, M.D.
National Institute of Child Health and Human Development, Bethesda, MD 20892-1103

Karim Anton Calis, Pharm.D., M.P.H.
Mark O. Hatfield Clinical Research Center, Bethesda, MD 20892

The views expressed in this letter are those of the authors and do not constitute an official position of the Department of Health and Human Services.

5 References

1. 1

   Christopoulos C, Dimakopoulou V, Rotas E. Primary ovarian insufficiency associated with imatinib therapy. N Engl J Med 2008;358:1079-1080
   Full Text | Web of Science | Medline

2. 2

   Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-245
   CrossRef | Web of Science | Medline

3. 3

   Novartis. Gleevec prescribing information. (Accessed May 23, 2008, at http://www.pharma.us.novartis.com/product/pi/pdf/gleevec_tabs.pdf.)
   

4. 4

   Hensley ML, Ford JM. Imatinib treatment: specific issues related to safety, fertility, and pregnancy. Semin Hematol 2003;40:Suppl 2:21-25
   CrossRef | Web of Science | Medline

5. 5

   Tilly JL. Molecular and genetic basis of normal and toxicant-induced apoptosis in female germ cells. Toxicol Lett 1998;102:497-501
   CrossRef | Medline

Author/Editor Response

The Naranjo probability scale referred to by Malozowski et al. was recently reported to lack reproducibility and have a poor negative predictive value.1 It should be noted that plasma levels of imatinib in patients given high doses of the drug exceed those of the no-effect level in the study of rat fertility. We also disagree with the specific reservations expressed by the correspondents. The time relationship was reasonable, with oligomenorrhea occurring a few months after the increase in the dose of imatinib. There were no other exposures, and no alternative causes were found on routine investigation of amenorrhea. Finally, the hypothesis of an etiologic link between imatinib and ovarian insufficiency is biologically plausible, since pathways involving kinases targeted by imatinib appear to play critical roles in the survival and maturation of follicles and oocytes.2-4

Constantinos Christopoulos, M.D., Ph.D.
Vasiliki Dimakopoulou, M.D.
Evangelos Rotas, M.D.
Amalia Fleming General Hospital, 15127 Athens, Greece
cgchristopoulos@yahoo.gr

4 References

1. 1

   Garcia-Cortes M, Lucena MI, Pachkoria K, Borraz Y, Hidalgo R, Andrade RJ. Evaluation of Naranjo Adverse Drug Reactions Probability Scale in causality assessment of drug-induced liver injury. Aliment Pharmacol Ther 2008;27:780-789
   CrossRef | Web of Science | Medline

2. 2

   Hutt KJ, McLaughlin EA, Holland MK. Kit ligand and c-Kit have diverse roles during mammalian oogenesis and folliculogenesis. Mol Hum Reprod 2006;12:61-69
   CrossRef | Web of Science | Medline

3. 3

   Nilsson EE, Detzel C, Skinner MK. Platelet-derived growth factor modulates the primordial to primary follicle transition. Reproduction 2006;131:1007-1015
   CrossRef | Web of Science | Medline

4. 4

   Carlsson IB, Laitinen MP, Scott JE, et al. Kit ligand and c-Kit are expressed during early human ovarian follicular development and their interaction is required for the survival of follicles in long-term culture. Reproduction 2006;131:641-649
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   (2008) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 17:11, i-xvi
   CrossRef