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Originally published as JCO Early Release 10.1200/JCO.2005.03.3969 on February 13 2006 © 2006 American Society of Clinical Oncology. Incidence, Time Course, and Determinants of Menstrual Bleeding After Breast Cancer Treatment: A Prospective Study
From the Memorial Sloan-Kettering Cancer Center, New York, NY; Wake Forest University School of Medicine, Winston-Salem, NC; Ohio State University, Columbus, OH; University of Texas-Southwestern, Dallas; The University of Texas M.D. Anderson Cancer Center, Houston, TX; University of Pittsburgh, Pittsburgh, PA Address reprint requests to Michelle J. Naughton, PhD, Department of Public Health Sciences, Wake Forest University School of Medicine, 2000 W First St, Rm 224, Winston-Salem, NC 27104; e-mail: naughton{at}wfubmc.edu
PURPOSE: To assess ovarian function using the surrogate of monthly bleeding after breast cancer treatment in premenopausal women. PATIENTS AND METHODS: Five hundred ninety-five US women age 20 to 45 years were accrued from January 1998 to July 2002 within 8 months of diagnosis with stages I to III breast cancer (median follow-up 45 months). Daily bleeding records were obtained prospectively, as well as extensive clinical, demographic, quality of life, and treatment data. Repeated measures logistic regression was used to assess which variables were predictive of monthly bleeding. RESULTS: Significantly different proportions of women had monthly bleeding depending on their age (P < .001), chemotherapy program (P < .001), and time since treatment regimen. In the month after the standard course of doxorubicin and cyclophosphamide (AC), whether or not followed by paclitaxel or docetaxel, approximately 16% had monthly bleeding compared with the cyclophosphamide, methotrexate, fluorouracil (CMF) group, in which 48% bled (P < .001). Following any AC regimen, there was a slow recovery phase of about 9 months followed by a plateau, during which almost half continued monthly bleeding for the remainder of the follow-up period compared with after CMF in which there was no recovery phase and a continual decline in monthly bleeding to approximately 18% of women at study end (P < .001). Tamoxifen use decreased bleeding between months 12 and 24 after chemotherapy with 15% fewer women having bleeding. CONCLUSION: Using daily menstrual bleeding records, it is demonstrated that age, the specific chemotherapy regimen received, and tamoxifen use impact ovarian function.
With advances in treatment, most breast cancer patients will be long-term survivors.1 For premenopausal patients, their quality of life can be disrupted by premature, chemotherapy-induced ovarian dysfunction, resulting in vasomotor symptoms, disrupted sleep, dyspareunia, dysuria, and vaginitis. Younger breast cancer survivors are known to experience more psychosocial distress than older women,2-4 and the menopausal transition and infertility may be important components of this distress.5-6 The incidence, time course, and determinants of ovarian dysfunction are not as well studied as the life-threatening complications of systemic therapy, such as cardiotoxicity or leukemogenesis. Even when it is reported, amenorrhea is noted as one of many secondary end points gathered in trials designed to assess other outcomes.7 Weaknesses of past research include small numbers of young women in chemotherapy trials, varying definitions of end points (eg, oligomenorrhea, amenorrhea), varying intervals of data collection, and limited lengths of follow-up. Recent reviews on chemotherapy-related amenorrhea found rates from 21% to 100%,7-8 suggesting little precision in these estimates. The possible quality-of-life advantage with maintenance of ovarian function must be considered along with conflicting research that shows a survival benefit of chemotherapy-related amenorrhea in some studies,9-10 and not in others,11-13 as well as the benefit of ovarian suppression as an alternative to chemotherapy in premenopausal women with hormone-receptor positive early-stage breast cancer.14,15 We report results from one of the first prospective studies using daily records of menstrual bleeding in premenopausal women to assess which therapies and clinical and demographic factors affected the maintenance of menstrual bleeding up to 5 years post-treatment.
Participants were recruited to a multicenter, longitudinal observational study assessing menstrual cycle maintenance and quality of life after breast cancer treatment. Inclusion criteria were female patients, age 18 to 45 years, who were diagnosed with stages I to III invasive breast cancer within the previous 8 months. Exclusions were any prior or concurrent history of any cancer, excluding basal or squamous cell skin carcinoma and stage 0 cervical cancer. Participants were required to have regular menstrual cycles at the time of diagnosis. Thus, women who had a previous hysterectomy, even with intact ovaries, were ineligible for this protocol. Recruitment to this study began in January 1998 and for the purposes of this article, ended in July 2002 (median follow-up 45 months). Recruitment and follow-up still continue. Participants were recruited through four sites: Memorial Sloan-Kettering Cancer Center in New York City, NY (426 women); M.D. Anderson Cancer Center in Houston, TX (86); Presbyterian Hospital in Dallas, TX (36); and the Wake Forest University Baptist Medical Center in Winston-Salem, NC (47). Patients from these centers were identified using tumor or surgical registries and patient or physician referrals. This study was approved by the institutional review board of each hospital as well as the US Department of Defense Human Subjects Committee.
Data Collection and Instruments Medical and reproductive history. This included contraceptive use, births and incomplete pregnancies, pelvic surgery, and plans for future childbearing. Personal habits questionnaire. Questionnaire included smoking and alcohol use, current height and weight, weight change, and exercise habits. Medical chart review. Extensive chart reviews were performed at the recruiting institution and included the date and technique of breast cancer diagnosis, tumor size, location, grade, hormone receptor status, number of nodes examined, number of positive lymph nodes, type of definitive cancer surgery, reconstructive surgery, and other surgeries (eg, oophorectomy). Chemotherapy information (ie, dates, drugs, and dosages in milligrams) was gathered from medical oncology office records. For those receiving radiation, dose per treatment, treatment area, total dosage, and duration of treatment were recorded. Hormonal therapies, such as tamoxifen, were recorded with dates, routes of administration, and dosages. Monthly bleeding calendars. Bleeding calendars were completed each month beginning on the date of recruitment. Participants marked on each day whether they experienced any menstrual bleeding and, if yes, if it was mild, moderate, or heavy. No hormone levels, such as follicle-stimulating hormone or estradiol levels, were collected. Follow-up questionnaires. At baseline and every 6 months, patients completed quality-of-life questionnaires and health status updates, including cancer recurrences, reproductive events, surgical procedures or conditions that could change monthly bleeding status (eg, hysterectomy), and current or newly initiated drugs, including tamoxifen or other hormonal treatments, with dose, route, and dates of administration recorded. All follow-up data collection was conducted by mail through the study coordinating center at the Wake Forest University School of Medicine (Winston-Salem, NC).
Statistical Methods The mean percentage of women who experienced bleeding was calculated across time within selected subsets of interest (eg, age groups and chemotherapy regimens). Splines were used to generate smoothed curves through these mean percentages. Logistic regression models were used to assess the effect of selected demographic, pathologic, and clinical characteristics on monthly bleeding. The generalized estimating equations method was used to account for the repeated (ie, monthly) records for each participant. The correlation within participants was modeled using an autoregressive covariance structure, assuming that responses closer in time are more highly correlated than those far apart in time. All covariates were fixed except for hormonal treatment, which was included as a lag1 time-varying covariate. Time was included in the model as a quadratic factor. Interactions between time and treatment were assessed.
Demographic and Clinical Characteristics Six hundred twenty-seven women were accrued between January 1998 and July 2002. Of those, 595 returned one or more monthly bleeding calendars and are included in these analyses. Median age was 39.5 years (range, 20 to 45 years; Table 1). The majority of women were white (88%), married (75%), had children (63%), and were college graduates (66%).
Treatment and pathologic variables are summarized in Table 2. All women had breast surgery: 306 women (51%) had breast conservative surgery (all but nine with postoperative breast radiotherapy); 289 women had total mastectomy, of which 153 women had a lumpectomy first as an attempt at breast conservation. Of the 289 women with mastectomy, 171 women also underwent immediate reconstructive surgery and 122 of the 289 women received postmastectomy radiation therapy. Five hundred fifty-six women (94%) had a full axillary node dissection, and 26 women had a sentinel node biopsy only. On average, women had 14 nodes examined (range, 0 to 51) and 44% of the women had at least one positive node. The majority of tumors (65%) were  2 cm in diameter; 44% had cancer in their axillary lymph nodes; and 56% had both estrogen and progesterone positive receptors.
Daily Bleeding Records On average, participants returned 92% of the bleeding records due while on study. Of the 595 women, the number of monthly calendars returned per participant was: > 60 months, 111 women; 49 to 60 months, 120 women; 37 to 48 months, 98 women; 25 to 36 months, 101 women; 13 to 24 months, 96 women; 1 to 12 months, 69 women. During the course of follow-up, 118 women stopped returning bleeding calendars but otherwise remained in the study for quality-of-life and medical history follow-ups. The majority of these women had an oophorectomy and/or hysterectomy (66 women), and 40 women reported amenorrhea of greater than 24 consecutive months and were allowed to discontinue their calendars unless bleeding resumed, which did not occur in any of these participants. One hundred sixty-six women stopped the study completely during follow-up because of death (40), lost to follow-up (53), and other reasons (83), including recurrences and lack of time or interest.
Adjuvant Therapy The median, 10th, and 90th percentiles for number of doses, total dose, and mg per m2 are presented in Table 3. Most of the regimens were internally consistent, meaning that women on the same regimen received similar doses and cycles. No patients were treated with dose-dense regimens. Women who were treated with AC, either alone or in combination with T or D, received approximately 4,000 mg of C in four cycles and 400 mg of A in four cycles. In the ACD regimen, the amount and frequency of D administration was quite variable and the dose and frequency for A and C had greater range than in the AC and ACT programs. Only 19 women were treated with ACD, but the data are included as it represents some of the first available information on ovarian toxicity with D in the adjuvant setting. In the FAC regimen, the median number of doses was six, and these women received larger total doses of A and C than those who received the standard regimen of four doses of AC alone. In the FACT regimen, the total median doses of A, C, and F were reduced compared with FAC. The typical schedule of CMF was approximately 600 mg/m2 of C, 600 mg/m2 of F, and 40 mg/m2 of M, each given for eight cycles. Oral C constituted all or part of the C for 11 women. These doses are included in the intravenous C total. Hormonal therapy was given to 340 of the 595 women (57%); 329 of these women received tamoxifen. Of the 72 women who did not receive adjuvant chemotherapy, 31 women (43%) received tamoxifen and one woman received anastrozole.
Menstrual Cycle Maintenance The proportion of women with monthly bleeding dropped dramatically as the study population started the first doses of adjuvant therapy (Fig 1). As chemotherapy ended, the percentage of the women with monthly bleeding began to increase over the following months. A high of almost 55% of women with monthly bleeding by 15 months after diagnosis was reached, after which the proportion gradually declined to 35% experiencing monthly bleeding 5 years after diagnosis.
Figure 2 shows the proportion of women with monthly bleeding after the completion of chemotherapy, according to age at diagnosis. The date therapy was completed is used as the beginning time point in this and subsequent figures. Women of all ages experienced disruptions in their menstrual function. However, a greater proportion of women age 40 or older had no menstrual bleeding at the end of chemotherapy and no recovery of bleeding in the follow-up years compared with younger women. Menstrual cycling recovered rapidly for those younger than 35 years, with the proportion with bleeding rising to approximately 85% at 6 months following the end of chemotherapy and remaining relatively constant. The recovery was less pronounced for women between the ages of 35 and 40, with a peak of 61% experiencing monthly bleeding 6 months following the end of chemotherapy to a low of 45% with bleeding at 5 years.
Figure 3 shows the proportion of women with monthly bleeding after the completion of chemotherapy, according to chemotherapy regimen. For reference, we have also included the group of women (N = 72) who did not receive chemotherapy (median age, 41 years; range, 25 to 45 years of age). The beginning point for these women is offset by 190 days, which is the median time to the completion of chemotherapy. Treatment with AC alone resulted in a dramatic decrease in the proportion with monthly bleeding. This was followed by several months of a gradually increasing rate of menstrual bleeding, and then a rather steady plateau of a similar proportion of women with monthly bleeding for the remainder of the study period. T added to the AC program led to a small further decline in the proportion with bleeding that was maintained over the course of the study, with a curve somewhat parallel to that of AC alone. D added to AC decreased the proportion with monthly bleeding even more than the addition of T, but, by 3 years, the ACT and ACD patients had similar monthly bleeding. A much different effect of CMF on ovarian function was noted. CMF resulted in a greater percentage of women who continued monthly bleeding in the initial months after treatment, but this initial percentage did not increase as there was no recovery phase, and in the follow-up years, there was a steadily diminishing proportion of women with menstrual bleeding.
A multivariable logistic model incorporating the variables presented in Tables 1 and 2 was completed to simultaneously examine the major clinical and demographic determinants of menstrual bleeding. Age (P < .01) and nodes positive (P < .01) were significantly associated with bleeding. The odds of bleeding decreased by 24% for each additional year of age and decreased by 11% for each additional positive node. Multivariable analyses confirmed the descriptive results that women receiving CMF were more likely to bleed during the first month following chemotherapy than women on any AC containing regimens (CMF v AC: odds ratio [OR] = 2.9; 95% CI, 1.7 to 5.0), but, by 1 year and thereafter, these women were less likely to bleed than those who received the AC regimens (except for ACD; CMF v AC at 2 years: OR = 0.27; 95% CI, 0.16 to 0.47). Women receiving tamoxifen were less likely to have monthly bleeding by 1 year following chemotherapy (OR = 0.50; 95% CI, 0.37 to 0.67). This effect became nonsignificant by 3 years.
This study reaffirmed that older age is strongly related to decreased menstrual bleeding. Age has been acknowledged as a factor in chemotherapy-related premature menopause, as in natural menopause. Younger women require more chemotherapy to develop gonadal failure,7 which probably relates to the smaller number of existing oocytes in older women.16,17 Approximately 25% of American women age 44 to 49 years will experience menopause.18 This age-related entrance into menopause probably accounts for why study subjects with no chemotherapy became amenorrheic during the follow-up period. Similar findings were reported in an untreated group of older premenopausal women in a recent randomized trial.19 A major finding of this study is that the proportion of women at any age with menstrual cycling varied depending on which chemotherapy regimen was used and the number of months since treatment completion. Goldhirsch et al10 found that one perioperative dose of CMF was associated with a 10% incidence of menopause; rates increased to 33% and 61% after 6 and 12 months of CMF, respectively. Previous studies have established the efficacy of intravenous CMF as adjuvant therapy for breast cancer,20,21 which was the primary mode of CMF administration in this study. Similar to our findings, a study of CMF, including both intravenous and oral regimens, as compared with goserelin, showed lower rates of amenorrhea in the CMF group at 6 months (59% v 95%), but greater rates of amenorrhea at 3 years (88% v 23%, respectively).22 Amenorrhea seems most related to the cumulative dosage of C, and probably because of a lower total dose of C, almost all programs based on anthracyclines have less premature ovarian failure,7,8 with one recent exception.23 Much less is known about other combinations. The effect of the newest agents, T and D, has been assessed in several studies.24-26 In one recent report, amenorrhea was present in 61.7% of those receiving D, A, and C versus 52.4% with FAC.25
In the present study, tamoxifen accounted for a modest, but significant decrease ( Limitations of the current study include a highly educated study population, only 12% minorities, and women recruited primarily from the eastern and southern United States. The menstrual bleeding status of those who stopped the study is unknown and the reasons for dropping out are assumed to be unrelated to the menstrual bleeding. Other limitations include the lack of classifying ovarian function with blood or urinary hormone assays. There are, however, no clinical parameters for defining chemotherapy-related amenorrhea.29 Hormone assays could have been confusing because estradiol may remain high after chemotherapy-related amenorrhea.30 Even with age-related (natural) perimenopause and menopause, direct assessment of menopausal status is often difficult.31 Early follicular phase assays of follicle-stimulating hormone, estradiol and inhibin B, may predict ovarian reserve, although, these assays have been used, thus far, only in age-related assessments of women seeking assisted reproduction.32,33 These results provide important contributions regarding menstrual cycling following chemotherapy. For women concerned about the effects of premature menopause, including infertility, it is key to consider their age when considering treatment options. These results can facilitate decision making by women and their physicians who are attempting to balance the risk of breast cancer recurrence with the risk of ovarian failure and the desire to maintain menstrual cycling and/or fertility.
Although all authors completed the disclosure declaration, the following author or 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
Supported by research funded by the US Army Medical Research and Materiel Command under DAMD17-96-1-6292 and DAMD17-01-1-0447. Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005 and at the Fourth Era of Hope: Department of Defense Breast Cancer Research Program Meeting, Philadelphia, PA, June 8-11, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Polychemotherapy for early breast cancer: An overview of the randomized trials—Early Breast Cancer Trialists' Collaborative Group. Lancet 352:930-942, 1998 2. Kroenke CH, Rosner B, Chen WY, et al: Functional impact of breast cancer by age at diagnosis. J Clin Oncol 22:1849-1856, 2004 3. Ganz PA, Greendale GA, Peterson L, et al: Breast cancer in younger women: Reproductive and late health effects of treatment. J Clin Oncol 21:4184-4193, 2003 4. Wenzel LB, Fairclough DL, Brady MJ, et al: Age-related differences in the quality of life of breast carcinoma patients after treatment. Cancer 86:1768-1774, 1999[CrossRef][Medline] 5. Partridge AH, Gelber S, Peppercorn J, et al: Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol 22:4174-4183, 2004 6. Ganz PA, Desmond KA, Belin TR, et al: Predictors of sexual health in women after a breast cancer diagnosis. J Clin Oncol 17:2371-2380, 1999 7. Bines J, Oleske DM, Cobleigh MA: Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer [Review]. J Clin Oncol 14:1718-1729, 1996 8. Minton SE, Munster PN: Chemotherapy –induced amenorrhea and fertility in women undergoing adjuvant treatment for breast cancer. Cancer Control 9:466-472, 2002[Medline] 9. Pagani O, O'Neill A, Castiglione M, et al: Prognostic impact of amenorrhea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: Results of the International Breast Cancer Study Group (IBCSG) Trial VI. Eur J Cancer 34:632-640, 1998[CrossRef][Medline] 10. Goldhirsch A, Gelber RD, Castiglione M: The magnitude of endocrine effects of adjuvant chemotherapy for premenopausal breast cancer patients: The International Breast Cancer Study Group. Ann Oncol 1:183-188, 1990 11. Fisher B, Sherman B, Rockette H, et al: L-Phenylalanine mustard (L-PAM) in the management of premenopausal patients with primary breast cancer: Lack of association of disease-free survival with depression of ovarian function. National Surgical Adjuvant Project for Breast and Bowel Cancers. Cancer 44:847-857, 1979[CrossRef][Medline] 12. Parulekar W, Trudear ME, Shepheard L, et al: Incidence and prognostic impact of amenorrhea during adjuvant therapy in high risk premenopausal breast cancer patients: Analysis of a National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) phase III study. Proc Am Soc Clin Oncol 20:25A, 2001 (abstr 97) 13. Bonadonna G, Valagussa P, Moliterni A, et al: Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node positive breast cancer: Twenty year results. N Engl J Med 332:901-906, 1995 14. Baum M, O'Shaughnessy JA: Management of premenopausal women with early-stage breast cancer: Is there is role for ovarian suppression? Clin Breast Cancer 3:260-267, 2002[Medline] 15. Davidson NE: Ovarian ablation as adjuvant therapy for breast cancer. J Natl Cancer Inst Monogr (30):67-71, 2001 16. Damewood MD, Grochow LB: Prospects for fertility after chemotherapy or radiation for neoplastic disease. Fertil Steril 45:443-459, 1986[Medline] 17. Block E: Quantitative morphological investigations of the follicular system in women; variations at different ages. Acta Anat 14:108-123, 1952[Medline] 18. McMahon B, Worcester J: Age at menopause: United States 1960-1962, in US Vital and Health Statistics Series I, No. 19. Rockville, MD, The National Center for Health Statistics, 1966 19. International Breast Center Study Group: Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: A randomized trial. J Natl Cancer Inst 95:1833-1846, 2003 20. Carmo-Pereria J, Costa FO, Henriques E, et al: A randomized trial of two regimens of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone in advanced breast cancer. Cancer Chemother Pharmacol 17:87-90, 1986[CrossRef][Medline] 21. Engelmann E, Klijn JC, Rubens RD, et al: "Classical" CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer: An EORTC Breast Cancer Co-operative Group Phase III Trial (10808). Euro J Cancer 27:966-970, 1991 22. Jonas W, Kaufmann M, Sauerkraut W, et al: Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex early breast cancer research association study. J Clin Oncol 20:4628-4635, 2002 23. Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 16:2651-2658, 1998[Abstract] 24. Stone E, Slack R, Novielli A, et al: Rate of chemotherapy-related amenorrhea (CRA) associated with adjuvant Adriamycin and Cytoxan (AC) and Adriamycin and Cytoxan followed by Taxol (AC + T) in early stage breast cancer. Breast Cancer Res and Treatment 64(1):61, 2000 (abstr 224) 25. Martin M, Pienkowski T, Mackey J, et al: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352:2302-2313, 2005 26. Ibrahim NK, Macneil S, Headley JA, et al: Effect of paclitaxel (P)-based chemotherapy on the ovarian failure (OF) of breast cancer patients (pts): A retrospective study. Proc Am Soc Clin Oncol 22:753, 2003 (abstr 3029) 27. 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(20):1488-1491, 1991 28. Goodwin P, Ennis K, Pritchard K, et al: Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 17:2365-2370, 1999 29. Bath L, Hamish W, Wallace B, et al: Late effects of treatment of childhood cancer on the female reproductive system and the potential for fertility preservation. BJOG 109:107-114, 2002[CrossRef][Medline] 30. Braverman AS, Sawhney H, Tendler A, et al: Pre-menopausal serum estradiol (E2) levels may persist after chemotherapy (CT) induced amenorrhea in breast cancer (BC). Proc Am Soc Clin Oncol 21:42A, 2002 (abstr 164) 31. Sherman BM, West JH, Korenman SG: The menopausal transition: Analysis of LH, FSH, estradiol and progesterone concentrations during menstrual cycles of older women. J Clin Endocrinol Metab 42:629-636, 1976[Abstract] 32. Klein NA, Illingworth PJ, Groome NP, et al: Decreased inhibin B secretion is associated with the monotrophic FSH rise in older, ovulatory women: A study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles. J Clin Endocrinol Metab 81:2742-2745, 1996[Abstract] 33. Elder-Geva T, Robertson DM, Cahir N, et al: Relationship between serum inhibin A and B and ovarian follicle development after a daily fixed dose administration and recombinant follicle-stimulating hormone. J Clin Endocrinol Metab 85:607-613, 2000 Submitted July 7, 2005; accepted December 27, 2005. Related Correspondence
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
15%) in menstrual cycling at 1 and 2 years, regardless of the chemotherapy program. Premenopausal women generally continue to menstruate while on tamoxifen although menses can become irregular.
