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Journal of Clinical Oncology, Vol 25, No 24 (August 20), 2007: pp. 3788-3789 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.5998
In ReplyBreast Cancer Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Adelaide and Meath Hospital incorporating the National Children's Hospital, Tallaght, Dublin, Ireland
Washington Cancer Institute, Washington Hospital Center, Washington, DC We thank Mourits et al for further emphasizing that amenorrhea, which occurs after chemotherapy and/or tamoxifen in premenopausal women, may indeed be reversible. We agree that there is no consensus on the definition of drug-induced amenorrhea. Mouritis et al also reiterate that drug-induced amenorrhea is not always synonymous with lack of ovarian function, and correctly point out that tamoxifen may cause an increase in estrogen concentration and thus contribute to ovarian cysts.1,2 As we stated in our review, it is not clear how tamoxifen induces increases in estradiol or why there may be increased rates of amenorrhea.3 We will provide further clarification herein on the endocrine changes encountered during tamoxifen therapy. Multiple small studies describing the hormone changes associated with tamoxifen therapy note increases in estradiol levels in premenopausal women.4-7 In one study, 2 to 3 months of tamoxifen in healthy volunteers resulted in increased estradiol levels, but did not suppress luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels.5 A second study evaluated the levels of estradiol and gonadotropins in women who received 4 to 72 months of adjuvant tamoxifen and also in control subjects. The women taking tamoxifen continued to menstruate, and had increased estradiol levels and stable LH and FSH levels compared with controls.7 Endocrine changes after the combination of chemotherapy and tamoxifen have also been studied. One particular study evaluated the impact of cyclophosphamide, methotrexate, and fluorouracil (CMF), CMF plus prednisone (CMFP), and CMFP plus tamoxifen (CMFPT) on ovarian and adrenal function in premenopausal breast cancer patients.8 Women that achieved amenorrhea after CMF or CMFP had decreased estradiol levels and elevations of FSH and LH. Women receiving CMFPT who achieved amenorrhea also had decreased estradiol levels, but did not have elevations of LH or FSH. In contrast, women who received CMFPT but did not achieve amenorrhea had elevated estradiol levels. Another study compared hormone levels in premenopausal patients who were treated with CMF, CMF and concurrent tamoxifen, or tamoxifen alone before and after stimulation with gonadotropin releasing hormone (GnRH) and thyrotropin releasing hormone.9,10 Estradiol levels were decreased and FSH and LH were increased in women who achieved amenorrhea with CMF and tamoxifen, while gonadotropin elevation was less pronounced in the group that received tamoxifen alone. Gonadotropin response to GnRH was suppressed in women who achieved amenorrhea after CMF. However, in women who received tamoxifen alone or concurrently with CMF who continued to menstruate, estrogen levels increased and levels of FSH and LH were unchanged. After GnRH and thyrotropin releasing hormone administration, the FSH and LH levels were markedly elevated. This exaggerated response of FSH and LH to GnRH in the presence of tamoxifen suggests that tamoxifen may block the hypothalamic estrogen receptors and interfere with normal feedback regulation of ovarian steroidogenesis. Not all trials show stable FSH levels in premenopausal women receiving tamoxifen, suggesting that other mechanisms may play a role in elevating estradiol levels. Ravdin et al4 evaluated gonadotropin and estradiol levels after 100 days of tamoxifen alone in patients younger than 50 years of age. Patients taking tamoxifen who continued to menstruate were found to have supraphysiologic estradiol levels and increased FSH levels compared with controls. These data suggest that tamoxifen may have a direct stimulatory effect on ovarian estrogen production. In summary, tamoxifen may induce changes in the hypothalamus-pituitary axis as well as lead to increases in estrogen levels by direct ovarian stimulation. Not all patients that take tamoxifen achieve amenorrhea, and the mechanisms of the increased rates of amenorrhea remain unclear. Furthermore, tamoxifen may complicate the assessment of menstrual status in women receiving adjuvant therapy. Yes, amenorrhea after chemotherapy and/or hormone therapy may indeed be a wolf in sheep's clothing. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: Sandra M. Swain, Genentech, Sanofi Aventis ACKNOWLEDGMENTS Supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. REFERENCES 1. Mourits MJ, de Vries EG, Willemse PH, et al: Ovarian cysts in women receiving tamoxifen for breast cancer. Br J Cancer 79:1761-1764, 1999[CrossRef][Medline] 2. Metindir J, Aslan S, Bilir G: Ovarian cyst formation in patients using tamoxifen for breast cancer. J Clin Oncol 35:607-611, 2005 3. Walshe JM, Denduluri N, Swain SM: Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol 24:5769-5779, 2006 4. Ravdin PM, Fritz NF, Tormey DC, et al: Endocrine status of premenopausal node-positive breast cancer patients following adjuvant chemotherapy and long-term tamoxifen. Cancer Res 48:1026-1029, 1988 5. Sherman BM, Chapler FK, Crickard K, et al: Endocrine consequences of continuous antiestrogen therapy with tamoxifen in premenopausal women. J Clin Invest 64:398-404, 1979[Medline] 6. Groom GV, Griffiths K: Effect of the anti-oestrogen tamoxifen on plasma levels of luteinizing hormone, follicle-stimulating hormone, prolactin, oestradiol and progesterone in normal pre-menopausal women. J Endocrinol 70:421-428, 1976[Abstract] 7. Jordan VC, Fritz NF, Langan-Fahey S, et al: Alteration of endocrine parameters in premenopausal women with breast cancer during long-term adjuvant therapy with tamoxifen as the single agent. J Natl Cancer Inst 83:1488-1491, 1991 8. Rose DP, Davis TE: Effects of adjuvant chemohormonal therapy on the ovarian and adrenal function of breast cancer patients. Cancer Res 40:4043-4047, 1980 9. Bianco AR, De Placido S, Pagliarulo C, et al: Effect of adjuvant tamoxifen and CMF on endocrine function of patients with operable breast cancer. Chemioterapia 4:252-255, 1985[Medline] 10. Delrio G, De Placido S, Pagliarulo C, et al: Hypothalamic-pituitary-ovarian axis in women with operable breast cancer treated with adjuvant CMF and tamoxifen. Tumori 72:53-61, 1986[Medline] Related Correspondence
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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