Correspondence

Primary Ovarian Insufficiency Associated with Imatinib Therapy

N Engl J Med 2008; 358:1079-1080March 6, 2008

Article

To the Editor:

Imatinib acts through selective inhibition of tyrosine kinases, which are constitutively activated in a number of cancers. Some of the drug's adverse reactions are presumably caused by the inhibition of normal kinases in various tissues. Ovarian failure is not a recognized complication of imatinib treatment, and successful conception and pregnancy have occurred in women receiving the drug.1,2 This outcome is at variance with what might theoretically be expected, given that kinases that are inhibited by imatinib (c-kit, c-abl, and platelet-derived growth factor receptor) are expressed in mammalian ovaries and appear to be important in multiple aspects of the growth and development of oocytes and follicles.3,4 We report the development of ovarian insufficiency in a young woman who was treated with imatinib for chronic myeloid leukemia (CML).

A 28-year-old woman with no personal or family history of gynecologic, endocrine, or developmental disorders was found to have Philadelphia chromosome–positive CML in January 2005, when she was in the fourth month of her first pregnancy. The pregnancy was terminated, and treatment with imatinib mesylate, at a dose of 400 mg per day, was started, with a good hematologic response. The dose was increased to 600 mg per day in July 2006, owing to persistent residual disease. Imatinib was well tolerated; the only undesirable effects were skin discoloration and occasional muscle cramps. The patient's menstrual periods were normal, and she was taking no other medication. In December 2006, a complete cytogenetic and molecular remission was confirmed.

In February 2007 (2 years after the start of imatinib therapy and about 6 months after the dose was increased), the patient noticed oligomenorrhea, which subsequently evolved into amenorrhea. In November 2007, a diagnosis of primary ovarian insufficiency was made on the basis of characteristically high serum levels of follicle-stimulating hormone (median, 73 mIU per milliliter) during a 4-week period, combined with a greatly diminished follicle count, as seen on transvaginal ultrasonography of the ovaries.

These findings suggest that prolonged administration of imatinib may have profound effects on female fertility. The significance of the relatively high dose that the patient received is not known, but a young man in whom oligospermia developed during imatinib treatment for the hypereosinophilic syndrome was also receiving a high dose of the drug (800 mg daily).5 The true incidence, possible dose dependence, and reversibility of imatinib-induced ovarian failure should be examined in future studies. Awareness of this potential complication will enable physicians to offer patients appropriate counseling and to consider strategies of preserving fertility and ovarian function before embarking on imatinib therapy.

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

5 References

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2. 2

   Gleevec prescribing information. (Accessed February 14, 2008, at http://www.pharma.us.novartis.com/product/pi/pdf/gleevec_tabs.pdf.)
   

3. 3

   Schmandt RE, Broaddus R, Lu KH, et al. Expression of c-ABL, c-KIT, and platelet-derived growth factor receptor-beta in ovarian serous carcinoma and normal ovarian surface epithelium. Cancer 2003;98:758-764
   CrossRef | Web of Science | Medline

4. 4

   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

5. 5

   Seshadri T, Seymour JF, McArthur GA. Oligospermia in a patient receiving imatinib therapy for the hypereosinophilic syndrome. N Engl J Med 2004;351:2134-2135
   Full Text | Web of Science | Medline

Citing Articles (6)

Citing Articles

1. 1

   Beate Schultheis, Bart A. Nijmeijer, H. Yin, Roger G. Gosden, Junia V. Melo. (2012) Imatinib mesylate at therapeutic doses has no impact on folliculogenesis or spermatogenesis in a leukaemic mouse model. Leukemia Research 36:3, 271-274
   CrossRef

2. 2

   Charles Chuah. (2012) Imatinib does not impair gonadal function. Leukemia Research 36:3, 262-263
   CrossRef

3. 3

   Avi Leader, Michael Lishner, Jennia Michaeli, Ariel Revel. (2011) Fertility considerations and preservation in haemato-oncology patients undergoing treatment. British Journal of Haematology 153:3, 291-308
   CrossRef

4. 4

   Jane Apperley. (2009) CML in pregnancy and childhood. Best Practice & Research Clinical Haematology 22:3, 455-474
   CrossRef

5. 5

   Kazuhiko Kobayashi, Chiaki Takebayashi, Satoko Miyata, Hiroto Narimatsu, Masahiro Kami. (2009) Successful Delivery after Planned Discontinuation of Imatinib in a Patient with Chronic Myeloid Leukemia. Internal Medicine 48:5, 369-371
   CrossRef

6. 6

   (2008) More on Ovarian Insufficiency with Imatinib. New England Journal of Medicine 358:24, 2648-2649
   Full Text

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