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Beware of Amenorrhea During Tamoxifen: It May Be a Wolf in Sheep's Clothing

Department of Gynecological Oncology, Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

To the Editor:

With great interest we read the review of Walshe et al¹ on the beneficial prognostic effects of developing amenorrhea after chemotherapy for breast cancer in premenopausal women. In their summary of the literature about the influence of tamoxifen on chemotherapy-induced amenorrhea, five studies are cited that found higher rates of amenorrhea after the addition of tamoxifen after adjuvant chemotherapy.^2-6

In evaluating the effect of amenorrhea on breast cancer survival in these retrospective studies, menopausal status and amenorrhea are not defined in a consistent manner, which may even be more erratic and deceiving during tamoxifen use. We would like to underscore this with the data from a study on ovarian function during tamoxifen in 114 young breast cancer patients ( 56 years of age) by performing serial transvaginal ultrasonography and serum follicle stimulating hormone and estradiol.⁷ Menopausal status after chemotherapy was defined by serum estradiol levels of more than 0.10 nmol/L and follicle stimulating hormone 30.0 U/L, irrespective of the presence or absence of menses. Patients treated with high-dose chemotherapy (n = 51) all developed amenorrhea and a postmenopausal hormone status. After standard-dose chemotherapy in 63 patients, 21 developed amenorrhea. In 27 patients with premenopausal hormone levels, 19 patients (70%) developed ovarian cysts, despite amenorrhea in 12. Patients with ovarian cysts had much higher serum estradiol levels (2.18 nmol/L; standard deviation, 1.31; P < .0001) than patients without cysts (0.15 nmol/L; standard deviation, 0.20). Women with ovarian cysts and high estradiol levels often reported a disappearance of hot flashes during amenorrhea, indicating an estrogenic effect overriding tamoxifen (unpublished data).

Therefore, we would like to stress the fact that especially during tamoxifen, amenorrhea may falsely suggest ovarian failure, hiding the presence of hyperactive ovaries due to a positive feedback mechanism, which is the opposite from the ovarian failure caused by chemotherapeutic agents. During tamoxifen, amenorrhea may actually be a wolf in sheep's clothing. The disappearance of flushes during amenorrhea may indicate the presence of hyperactive ovaries with too high estrogen levels. Apart from the epidemiologic and prognostic issues mentioned earlier, this may be particularly of concern when patients, apparently suffering from permanent ovarian failure, are subsequently put on aromatase inhibitors, which will be ineffective in this situation and even may lead to unwarranted pregnancies, while in fact we are dealing with overactive ovaries.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Walshe JM, Denduluri N, Swain SM: Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol 24:5769-5779, 2006[Abstract/Free Full Text]

2. Colleoni M, Gelber S, Goldhirsch A, et al: Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group trial13-93. J Clin Oncol 24:1332-1341, 2006[Abstract/Free Full Text]

3. Petrek JA, Naughton MJ, Case LD, et al: Incidence, time course and determinants of menstrual bleeding after breast cancer treatment: A prospective study. J Clin Oncol 24:1045-1051, 2006[Abstract/Free Full Text]

4. Swain SM, Land SR, Sundry R et al: Amenorrhea in premenopausal women on the doxorubicin (A) and cyclophosphamide (C) -> docetaxel (T) arm of NSABP B-30: Preliminary results. J Clin Oncol 23:13s, 2005 (suppl; abstr 537)

5. Goodwin PJ, Ennis M, Pritchard KI, et al: Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 17:2365-2370, 1999[Abstract/Free Full Text]

6. Boccardo F, Rubagotti A, Bruzzi P, et al: Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, estrogen receptor-positive breast cancer patients: Results of a multicentric Italian study- Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group. J Clin Oncol 8:1310-1320, 1990[Abstract]

7. 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]

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  Neelima Denduluri, Janice M. Walshe, and Sandra M. Swain
  JCO 2007 25: 3788-3789 [Full Text]

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