Abstract
Many young women are at increased risk for premature menopause following adjuvant treatment for breast cancer. These women must deal with consequences of menopause, including loss of fertility and physiologic symptoms such as night sweats, hot flashes, vaginal dryness, and weight gain. These symptoms can be particularly distressing for young women and can adversely affect both health-related and psychosocial quality of life (QOL). While there are a wide range of pharmacologic and non-pharmacologic interventions available to help with these symptoms and in turn, improve QOL, there is little data available about the use and efficacy of these interventions in younger women who become menopausal as a result of their breast cancer treatment. Future studies should focus on this vulnerable population, with the goal of identifying effective strategies to relieve symptoms and improve quality of life in young breast cancer survivors.
KEY WORDS : Premature menopause, young women, breast cancer, quality of life (QOL)
Introduction
It is well established that the diagnosis and treatment of breast cancer can have a profound impact on a patient’s short and long term quality of life (QOL). Young women with breast cancer have unique health and psychosocial concerns and are also more likely to experience poorer QOL outcomes following diagnosis compared to older women (1-3). In particular, fertility concerns and outcomes as well as associated menopausal issues may greatly impact on a young women’s survivorship (4).
Amenorrhea is a common consequence of systemic breast cancer therapy among young women, the vast majority of whom are premenopausal at diagnosis. In many cases, it is temporary, with menses resuming in the months following the end of treatment. For some women, amenorrhea is permanent, and heralds the onset of early menopause. Even if menses do resume, many breast cancer survivors are at an increased risk of premature ovarian failure (POF) (5). Most women who remain amenorrheic for at least a year will not resume menstruation and will be considered to have POF (6).
POF resulting from chemotherapy is largely dependent on both age and treatment type (7-9). For example, in women under 40, a regimen consisting of cyclophosphomide, methotrexate, and 5-fluorouracil (CMF) for 6 months is associated with a risk of premature menopause approximated to be between 30-40%; in women aged 40 and older this risk is greater than 80% and has been reported to be as high as 96% (10). Treatment with doxorubicin and cyclophosphomide (AC) is associated with a lower risk of menopause: 13% for women younger than 40 and 57-63% in women aged 40 and older (10). Adjuvant tamoxifen therapy has also been identified as a risk factor for premature menopause in young breast cancer survivors. Additionally, choices like bilateral prophylactic oophorectomy as a means of ovarian suppression or as a risk reduction strategy in women at high risk for ovarian cancer (i.e., BRCA 1 or 2 mutation carriers) may also cause early menopause among young women with breast cancer. Regardless of the reason, these women face the physiological changes that frequently accompany menopause, as well as the emotional reality of becoming prematurely potentially infertile. While these experiences might be “normal” for women who are in their 50s, for women in their 20s, 30s and early 40s, these changes can be extremely distressing and have the potential to negatively affect QOL.
Poorer QOL outcomes among younger women are strongly related to the physiologic changes experienced during the menopausal transition. Declining estrogen levels due to ovarian failure is associated with symptoms such as hot flashes, night sweats, vaginal dryness, dyspareunia, and weight changes. Ovarian damage from chemotherapy treatment can also negatively affect sex hormone levels, including androgens (11). Menopausal symptoms have been reported to be more severe among women who become menopausal from treatment, as well as among women who undergo a surgical menopause, as compared to the symptom burden in women experiencing a normal menopausal transition (12-16).
While many symptoms of premature menopause are the consequence of changes in the hormonal milieu and manifest themselves in the domain of physical health, the potential for compromised mental health is also of concern. In their Cancer and Menopause Study (CAMS), Ganz et al. (17) reported lower scores the Mental Component Summary Scale (MCS) of the SF-36 among women who entered menopause following treatment compared to those who did not, indicating that young women are more likely to experience compromised psycho-social QOL following the onset of early menopause.
In this review, we summarize the current body of literature regarding QOL, including that related to both physical and psychosocial functioning, in young breast cancer survivors who experience premature menopause. We also review medical and psychosocial interventions that have been tested and that are available to help improve those areas of QOL most often affected in younger women with early menopause.
Fatigue and sleep problems
Fatigue is frequently reported both during and after breast cancer treatment, and can negatively impact many aspects of QOL (18). The presence of menopausal symptoms has been found to be positively associated with more problems with fatigue following the end of chemotherapy treatment (15,19,20). Furthermore, fatigue is also linked to increased depressive symptoms (18). However the directionality of the relationship between fatigue and menopausal symptoms is unclear. Alternatively, fatigue might be an independent symptom related to the onset of menopause, i.e., a consequence of changing hormonal levels.
Sleep disturbance can be a direct consequence of hot flashes and/or night sweats, in turn leading to increased levels of fatigue. In one study inclusive of both pre- and post- menopausal women, hot flashes and night sweats were not predictive of changes in sleep quality, however women with a history of chemotherapy treatment were more likely to experience altered sleeping patterns in the months and years after treatment (21).
It is unclear if fatigue or compromised sleep quality is worse among women with POF vs. women who are menopausal before diagnosis, as most studies do not distinguish between these types of women. However given the severity of menopausal symptoms is often worse among women with POF, because of the strong relationship between vasomotor symptoms and fatigue, it is conceivable that fatigue and sleep problems can be significant issues for women experiencing an early menopause following breast cancer treatment.
Weight gain
Weight gain is commonly seen in both women of all ages both during and after breast cancer treatment (22). Among women who are pre-menopausal at diagnosis, those who become menopausal as a result of treatment seem to experience more weight gain relative to those who do not (23,24). A recent study exploring weight gain in a small cohort of young women found that those with POF due to chemotherapy gained more truncal fat compared to women who did not experience treatment-associated ovarian failure, though this difference was not statistically significant (25). Additionally, the women who became menopausal also lost truncal lean mass, in contrast to the women who remained premenopausal, who did not experience any significant lean mass loss (25).
Weight gain is a distressing issue for many young women. Nearly two-thirds of women diagnosed with breast cancer at age 40 or younger who responded to a web-based survey said that weight gain was at least moderately bothersome (12) and another study inclusive of women up to 50 years old at diagnosis found that approximately 40% of women reported weight gain to be at least somewhat bothersome (26). Other studies have also identified weight gain as an important determinant of body image concerns, an important psycho-social QOL domain, among young women (27,28).
Bone health
Women with POF are at increased risk for reduced bone mineral density (BMD) following adjuvant chemotherapy compared to women who remain premenopausal (29,30). Bone loss can lead to osteopenia and osteoporosis if not intervened upon, putting women at increased risk for fractures at an earlier age. Of concern, it appears many women are not following recommended bone health guidelines, including BMD screening, physical activity, and taking supplemental calcium and vitamin D when warranted (31,32).
Tamoxifen appears to have a protective effect on BMD specifically among women with POF, similar to what is seen in women who are post-menopausal. In one study, women who remained premenopausal following chemotherapy who were also treated with tamoxifen experienced significant BMD loss relative to their baseline levels; in contrast, women with POF on tamoxifen had reduced bone loss (33).
Cognitive function
Most studies have not detected measurable differences in cognitive function between women who become menopausal from treatment and those who remain premenopausal or who were post-menopausal at diagnosis (34-36). However, inherent in many of the studies that have examined whether POF is a risk factor for adverse cognitive outcomes are methodological limitations that preclude any conclusions about this outcome in younger women (37). Additional studies, including those that evaluate longer-term outcomes are needed to better evaluate the effect of POF on cognition.
Cardiovascular health
In the general population, women with POF are at increased risk for developing cardiovascular disease (CVD) (38). There is little data about CVD risk in young breast cancer survivors with POF. Additional long-term studies are needed of young survivors to determine the burden of excess CVD risk among women with POF as a consequence of breast cancer treatment.
Depression and anxiety
There is significant psychological morbidity related to symptoms of depression among younger women with breast cancer (1). Few studies, however, have described specifically how POF is related to depression in younger women. While Gorman et al. did not find an association between treatment-associated amenorrhea and depressive symptoms among women who were diagnosed at age 40 or younger, they did find that women with more reproductive concerns, less social support, and worse physical functioning had more symptoms of depression (39). Bloom et al. reported a relationship between depression and several health related and psycho-social QOL domains, including symptom severity, pain, and body image, suggesting these variables primarily affected depression through illness intrusiveness (40).
Anxiety surrounding a cancer diagnosis—both early in the treatment period and many years after treatment has ended—can have a measurable impact on QOL. One study examining the potential role of oophorectomy and abrupt onset of menopause on QOL in young survivors found anxious symptoms to be prevalent, however no differences were detected between women who were treated with chemotherapy and those who did not, and between women who had an oophorectomy and those who did not (41).
Sexuality
Premature menopause has a major impact on sexuality and intimacy, with sexual problems more prevalent among young women who become amenorrheic from treatment compared to women who continue to menstruate (17,42-44). Vaginal dryness and dyspareunia are the main drivers of sexual dysfunction, and are strongly related to the onset of menopause. In addition to physiologic symptoms, decreased interest in sex is another significant factor. It is important to consider that sexual problems are complex, often interrelated, and if ignored or untreated, can lead to long term sexual health issues. When intercourse is painful, women are less likely to be interested in sex, sex can become less frequent, and vaginal atrophy may result. Adding to the complexity of sexual dysfunction is the potential of other QOL issues to affect intimacy. Anxiety, depression, body image concerns, fatigue, and side effects from medication (i.e., anti-depressants) can influence both sexual interest and functioning.
Interventions for symptom management
Interventions aimed at ameliorating menopausal symptoms in breast cancer survivors, with the goal of improving QOL, are varied and include pharmacologic, psycho-educational, and behavioral interventions (See Table 1). It is important to consider that because many aspects of QOL are inter-related, intervening in one often leads to improvement of others. For example, managing symptoms of fatigue can potentially help improve other related QOL domains, such as sexual dysfunction and depression.
Table 1. Interventions to consider for menopausal symptom management in young breast cancer survivors.
Hormonal medication (often contraindicated in this setting) |
---|
Non-hormonal medication |
• Antidepressants, gabapentin, and clonidine for hot flashes |
• Topical lubricants and moisturizers for vaginal health |
Behavioral strategies and interventions |
• Exercise |
• Yoga |
• Acupuncture |
• Cold packs, dressing in layers, etc. |
Psychoeducation |
• Cognitive behavioral therapy (CBT) |
• Individual or couples counseling |
An important limitation of most trials assessing the efficacy of interventions aimed to improve QOL in cancer survivors is that they have generally been conducted in older women who were post-menopausal at diagnosis, and it is unclear how generalizable findings are to young women with POF.
Pharmacologic
Hormonal
In the general population, hormone replacement therapy (HRT) is very efficacious in managing menopausal symptoms. However, systemic treatment with exogenous hormones is generally contraindicated in women who have a history of breast cancer, particularly when they have had hormone sensitive disease. Several trials have evaluated localized estrogen therapeutic options, such as vaginal rings, tablets and creams, to help ameliorate vaginal dryness in breast cancer survivors. While these improve symptoms and rely on a low, localized dose of estrogen, some estrogen is released systemically into the blood stream, leading to a consensus among experts that is a highly individualized decision, with women advised to speak with their physicians (42,45,46). Testosterone-based therapies have been considered as well but have not been shown to be effective without HRT (45).
Non-hormonal
A wide range of non-hormonal pharmacological agents have been tested in an effort to diminish both the occurrence and intensity of hot flashes. Anti-depressants, including venlafaxine and paroxetine, as well as other pharmacologic, most notably gabapentin and clonidine, have been found to be effective in improving hot flash burden in randomized controlled trials (RCTs) (47-50). In contrast, there has not been strong evidence that natural supplements, including Vitamin E, phyto-estrogens (e.g., soy), and black cohosh are better compared to placebos (51-53).
Several non-hormonal options also exist to reduce vaginal dryness and help with dyspareunia. Vaginal lubricants can help improve symptoms of vaginal dryness and make sexual intercourse more comfortable. Vaginal moisturizers are designed to hydrate the vaginal mucosa and are effectual for approximately 2-3 days (54). Most importantly, it is crucial to advise women to maintain sexual activity. The potential for long-term detrimental impact—e.g., vaginal atrophy-argues for early intervention to recognize and treat symptoms implicated in poor sexual functioning.
There are several pharmacologic options that have been tested in an effort to prevent or treat bone loss among young women with treatment induced POF, thereby decreasing the risk of osteoporosis. Results from one trial (55) indicate that administering zoledronic acid concomitantly with chemotherapy treatment can effectively reduce BMD loss among young women who develop POF. Findings from other studies of another bisphosphonate, clodronate, in women with POF have been mixed, with one study finding oral clodronate effective at lessening BMD loss (56) while another study (57) found no significant difference in BMD loss between the group randomized to intravenous clodronate and the control group, although the authors acknowledge that this might be due to power limitations due to the small study size, or alternatively, the relatively limited duration women received the drug during this trial. The optimal timing of and indications for treatment with bisphosphonates in this setting are unclear at this time.
Psycho-educational
A wide range of interventions grounded in psycho-social theory have been developed and tested to help achieve better menopausal symptom management, ultimately improving QOL in the both the short and long term. A recent trial demonstrated that cognitive behavioral therapy (CBT), physical activity, and a combination of the two can helping improve menopausal symptoms as well as select QOL outcomes, including sexuality, urinary problems, and physical functioning in women with premature menopause (58). In addition to decreasing the severity of vasomotor symptoms, other trials, inclusive of both pre- and post menopausal breast cancer survivors, have also found CBT to be helpful with sleep, emotional, and cognitive issues (59,60). Interventions teaching relaxation strategies have also demonstrated some effectiveness in improving vasomotor symptoms in breast cancer survivors (61).
Several psycho-educational interventions have been shown to help breast cancer survivors with problems related to sexuality and intimacy. Effective strategies have included both individual and couple–based therapies which focus on improving communication, facilitating coping, and helping couples deal with potential intimacy issues (62).
Exercise
Greater levels of physical activity after breast cancer have been associated with improved survival outcomes (63-65). Exercise has also been associated with better QOL outcomes in breast cancer survivors of all ages, largely the result of improving symptoms of anxiety, depression, and fatigue (66), as well as having a beneficial effect on bone health. There have been promising results from yoga interventions, with reported improvements in fatigue, depressive symptoms, and vasomotor symptoms following the intervention period (67-69), however many of these studies are small, and follow-up data is needed as to whether the initial benefit can be sustained over the longer term. Specifically among prematurely menopausal survivors, a recent RCT demonstrated that a regimen incorporating both a strength and resistance component was effective in both reducing bone loss and maintaining body fat (70).
Additional strategies
There are some additional behavioral modifications that should be considered in an effort to reduce distressing side effects and improve overall QOL in breast cancer survivors. Simple changes, such as dressing in layers, using cold packs, or temperature adjustments, can often help women suffering from hot flashes and night sweats. Acupuncture is another alternative medical approach that has been investigated in breast cancer patients, with mixed findings as to the effectiveness in relieving menopausal symptoms. While one randomized found acupuncture was just as effective as venlafaxine in reducing hot flashes and depressive symptoms, as well as improving other QOL domains in women with hormone positive breast cancer (71), other studies have not confirmed that acupuncture is any better sham interventions (72).
Concerning sexual dysfunction, strategies to address vaginal atrophy and stenosis include pelvic floor strengthening and vaginal dilation. It is vital to maintain blood flow to the vagina to prevent atrophy, and as noted above, it is therefore important to maintain regular sexual activity.
Conclusions
Life following a cancer diagnosis will invariably be different for every breast cancer survivor, however many young women will be faced with the additional physical and emotional challenges of menopause years earlier than would otherwise be expected. There is a clear need for additional studies of interventions among women in younger age groups in order to identify useful and effective therapies for these young survivors, with the goal of improving the QOL in young women through treatment and into long-term survivorship.
Acknowledgements
Dr. Rosenberg is funded by NIH 5 R25 CA057711.
Disclosure: The authors declare no conflict of interest.
References
- 1.Howard-Anderson J, Ganz PA, Bower JE, et al. Quality of life, fertility concerns, and behavioral health outcomes in younger breast cancer survivors: a systematic review. J Natl Cancer Inst 2012;104:386-405 [DOI] [PubMed] [Google Scholar]
- 2.Wenzel LB, Fairclough DL, Brady MJ, et al. Age-related differences in the quality of life of breast carcinoma patients after treatment. Cancer 1999;86:1768-74 [PubMed] [Google Scholar]
- 3.Kroenke CH, Rosner B, Chen WY, et al. Functional impact of breast cancer by age at diagnosis. J Clin Oncol 2004;22:1849-56 [DOI] [PubMed] [Google Scholar]
- 4.Ruddy KJ, Partridge AH. Fertility (male and female) and menopause. J Clin Oncol 2012;30:3705-11 [DOI] [PubMed] [Google Scholar]
- 5.Partridge A, Gelber S, Gelber RD, et al. Age of menopause among women who remain premenopausal following treatment for early breast cancer: long-term results from International Breast Cancer Study Group Trials V and VI. Eur J Cancer 2007;43:1646-53 [DOI] [PubMed] [Google Scholar]
- 6.Partridge AH, Ruddy KJ. Fertility and adjuvant treatment in young women with breast cancer. Breast 2007;16Suppl 2:S175-81 [DOI] [PubMed] [Google Scholar]
- 7.Goodwin PJ, Ennis M, Pritchard KI, et al. Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 1999;17:2365-70 [DOI] [PubMed] [Google Scholar]
- 8.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 2006;24:1045-51 [DOI] [PubMed] [Google Scholar]
- 9.Abusief ME, Missmer SA, Ginsburg ES, et al. The effects of paclitaxel, dose density, and trastuzumab on treatment-related amenorrhea in premenopausal women with breast cancer. Cancer 2010;116:791-8 [DOI] [PubMed] [Google Scholar]
- 10.Partridge AH, Burstein HJ, Winer EP. Side effects of chemotherapy and combined chemohormonal therapy in women with early-stage breast cancer. J Natl Cancer Inst Monogr 2001;(30):135-42 [DOI] [PubMed] [Google Scholar]
- 11.Alder J, Zanetti R, Wight E, et al. Sexual dysfunction after premenopausal stage I and II breast cancer: do androgens play a role? J Sex Med 2008;5:1898-906 [DOI] [PubMed] [Google Scholar]
- 12.Leining MG, Gelber S, Rosenberg R, et al. Menopausal-type symptoms in young breast cancer survivors. Ann Oncol 2006;17:1777-82 [DOI] [PubMed] [Google Scholar]
- 13.Burstein HJ, Winer EP. Primary care for survivors of breast cancer. N Engl J Med 2000;343:1086-94 [DOI] [PubMed] [Google Scholar]
- 14.Crandall C, Petersen L, Ganz PA, et al. Association of breast cancer and its therapy with menopause-related symptoms. Menopause 2004;11:519-30 [DOI] [PubMed] [Google Scholar]
- 15.Mar Fan HG, Houédé-Tchen N, Chemerynsky I, et al. Menopausal symptoms in women undergoing chemotherapy-induced and natural menopause: a prospective controlled study. Ann Oncol 2010;21:983-7 [DOI] [PubMed] [Google Scholar]
- 16.Benshushan A, Rojansky N, Chaviv M, et al. Climacteric symptoms in women undergoing risk-reducing bilateral salpingo-oophorectomy. Climacteric 2009;12:404-9 [DOI] [PubMed] [Google Scholar]
- 17.Ganz PA, Greendale GA, Petersen L, et al. Breast cancer in younger women: reproductive and late health effects of treatment. J Clin Oncol 2003;21:4184-93 [DOI] [PubMed] [Google Scholar]
- 18.Ganz PA, Bower JE. Cancer related fatigue: a focus on breast cancer and Hodgkin's disease survivors. Acta Oncol 2007;46:474-9 [DOI] [PubMed] [Google Scholar]
- 19.Broeckel JA, Jacobsen PB, Horton J, et al. Characteristics and correlates of fatigue after adjuvant chemotherapy for breast cancer. J Clin Oncol 1998;16:1689-96 [DOI] [PubMed] [Google Scholar]
- 20.Glaus A, Boehme Ch, Thürlimann B, et al. Fatigue and menopausal symptoms in women with breast cancer undergoing hormonal cancer treatment. Ann Oncol 2006;17:801-6 [DOI] [PubMed] [Google Scholar]
- 21.Alfano CM, Lichstein KL, Vander Wal GS, et al. Sleep duration change across breast cancer survivorship: associations with symptoms and health-related quality of life. Breast Cancer Res Treat 2011;130:243-54 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Helms RL, O’Hea EL, Corso M. Body image issues in women with breast cancer. Psychol Health Med 2008;13:313-25 [DOI] [PubMed] [Google Scholar]
- 23.Goodwin PJ, Ennis M, Pritchard KI, et al. Adjuvant treatment and onset of menopause predict weight gain after breast cancer diagnosis. J Clin Oncol 1999;17:120-9 [DOI] [PubMed] [Google Scholar]
- 24.McInnes JA, Knobf MT. Weight gain and quality of life in women treated with adjuvant chemotherapy for early-stage breast cancer. Oncol Nurs Forum 2001;28:675-84 [PubMed] [Google Scholar]
- 25.Gordon AM, Hurwitz S, Shapiro CL, et al. Premature ovarian failure and body composition changes with adjuvant chemotherapy for breast cancer. Menopause 2011;18:1244-8 [DOI] [PubMed] [Google Scholar]
- 26.Avis NE, Crawford S, Manuel J. Psychosocial problems among younger women with breast cancer. Psychooncology 2004;13:295-308 [DOI] [PubMed] [Google Scholar]
- 27.Rosenberg SM, Tamimi RM, Gelber S, et al. Body image in recently diagnosed young women with early breast cancer. Psychooncology. 2012 doi: 10.1002/pon.3221. [Epub ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Fobair P, Stewart SL, Chang S, et al. Body image and sexual problems in young women with breast cancer. Psychooncology 2006;15:579-94 [DOI] [PubMed] [Google Scholar]
- 29.Shapiro CL, Manola J, Leboff M. Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 2001;19:3306-11 [DOI] [PubMed] [Google Scholar]
- 30.Bruning PF, Pit MJ, de Jong-Bakker M, et al. Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer. Br J Cancer 1990;61:308-10 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Tham YL, Sexton K, Weiss HL, et al. The adherence to practice guidelines in the assessment of bone health in women with chemotherapy-induced menopause. J Support Oncol 2006;4:295-8, 304 [PubMed] [Google Scholar]
- 32.McCune JS, Games DM, Espirito JL. Assessment of ovarian failure and osteoporosis in premenopausal breast cancer survivors. J Oncol Pharm Pract 2005;11:37-43 [DOI] [PubMed] [Google Scholar]
- 33.Vehmanen L, Elomaa I, Blomqvist C, et al. Tamoxifen treatment after adjuvant chemotherapy has opposite effects on bone mineral density in premenopausal patients depending on menstrual status. J Clin Oncol 2006;24:675-80 [DOI] [PubMed] [Google Scholar]
- 34.Hermelink K, Henschel V, Untch M, et al. Short-term effects of treatment-induced hormonal changes on cognitive function in breast cancer patients: results of a multicenter, prospective, longitudinal study. Cancer 2008;113:2431-9 [DOI] [PubMed] [Google Scholar]
- 35.Vearncombe KJ, Rolfe M, Andrew B, et al. Cognitive effects of chemotherapy-induced menopause in breast cancer. Clin Neuropsychol 2011;25:1295-313 [DOI] [PubMed] [Google Scholar]
- 36.Jenkins V, Shilling V, Deutsch G, et al. A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer. Br J Cancer 2006;94:828-34 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Vearncombe KJ, Pachana NA. Is cognitive functioning detrimentally affected after early, induced menopause? Menopause 2009;16:188-98 [DOI] [PubMed] [Google Scholar]
- 38.Archer DF. Premature menopause increases cardiovascular risk. Climacteric 2009;12Suppl 1:26-31 [DOI] [PubMed] [Google Scholar]
- 39.Gorman JR, Malcarne VL, Roesch SC, et al. Depressive symptoms among young breast cancer survivors: the importance of reproductive concerns. Breast Cancer Res Treat 2010;123:477-85 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Bloom JR, Stewart SL, Johnston M, et al. Intrusiveness of illness and quality of life in young women with breast cancer. Psychooncology 1998;7:89-100 [DOI] [PubMed] [Google Scholar]
- 41.Sayakhot P, Vincent A, Deeks A, Potential adverse impact of ovariectomy on physical and psychological function of younger women with breast cancer. Menopause 2011;18:786-93 [DOI] [PubMed] [Google Scholar]
- 42.Schover LR. Premature ovarian failure and its consequences: vasomotor symptoms, sexuality, and fertility. J Clin Oncol 2008;26:753-8 [DOI] [PubMed] [Google Scholar]
- 43.Burwell SR, Case LD, Kaelin C, et al. Sexual problems in younger women after breast cancer surgery. J Clin Oncol 2006;24:2815-21 [DOI] [PubMed] [Google Scholar]
- 44.King J, Wynne CH, Assersohn L, et al. Hormone replacement therapy and women with premature menopause--a cancer survivorship issue. Eur J Cancer 2011;47:1623-32 [DOI] [PubMed] [Google Scholar]
- 45.Melisko ME, Goldman M, Rugo HS. Amelioration of sexual adverse effects in the early breast cancer patient. J Cancer Surviv 2010;4:247-55 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Wills S, Ravipati A, Venuturumilli P, et al. Effects of vaginal estrogens on serum estradiol levels in postmenopausal breast cancer survivors and women at risk of breast cancer taking an aromatase inhibitor or a selective estrogen receptor modulator. J Oncol Pract 2012;8:144-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Boekhout AH, Vincent AD, Dalesio OB, et al. Management of hot flashes in patients who have breast cancer with venlafaxine and clonidine: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2011;29:3862-8 [DOI] [PubMed] [Google Scholar]
- 48.Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000;356:2059-63 [DOI] [PubMed] [Google Scholar]
- 49.Bordeleau L, Pritchard K, Goodwin P, et al. Therapeutic options for the management of hot flashes in breast cancer survivors: an evidence-based review. Clin Ther 2007;29:230-41 [DOI] [PubMed] [Google Scholar]
- 50.Nelson HD, Vesco KK, Haney E, et al. Nonhormonal therapies for menopausal hot flashes: systematic review and meta-analysis. JAMA 2006;295:2057-71 [DOI] [PubMed] [Google Scholar]
- 51.Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol 2001;19:2739-45 [DOI] [PubMed] [Google Scholar]
- 52.Pockaj BA, Gallagher JG, Loprinzi CL, et al. Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. J Clin Oncol 2006;24:2836-41 [DOI] [PubMed] [Google Scholar]
- 53.Rada G, Capurro D, Pantoja T, et al. Non-hormonal interventions for hot flushes in women with a history of breast cancer. Cochrane Database Syst Rev 2010;(9):CD004923. [DOI] [PubMed] [Google Scholar]
- 54.Carter J, Goldfrank D, Schover LR. Simple strategies for vaginal health promotion in cancer survivors. J Sex Med 2011;8:549-59 [DOI] [PubMed] [Google Scholar]
- 55.Shapiro CL, Halabi S, Hars V, et al. Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: final results from CALGB trial 79809. Eur J Cancer 2011;47:683-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Saarto T, Blomqvist C, Välimäki M, et al. Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients. J Clin Oncol 1997;15:1341-7 [DOI] [PubMed] [Google Scholar]
- 57.Vehmanen L, Saarto T, Risteli J, et al. Short-term intermittent intravenous clodronate in the prevention of bone loss related to chemotherapy-induced ovarian failure. Breast Cancer Res Treat 2004;87:181-8 [DOI] [PubMed] [Google Scholar]
- 58.Duijts SF, van Beurden M, Oldenburg HS, et al. Efficacy of cognitive behavioral therapy and physical exercise in alleviating treatment-induced menopausal symptoms in patients with breast cancer: results of a randomized, controlled, multicenter trial. J Clin Oncol 2012;30:4124-33 [DOI] [PubMed] [Google Scholar]
- 59.Mann E, Smith MJ, Hellier J, et al. Cognitive behavioural treatment for women who have menopausal symptoms after breast cancer treatment (MENOS 1): a randomised controlled trial. Lancet Oncol 2012;13:309-18 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Savard J, Simard S, Ivers H, et al. Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer, part I: Sleep and psychological effects. J Clin Oncol 2005;23:6083-96 [DOI] [PubMed] [Google Scholar]
- 61.Tremblay A, Sheeran L, Aranda SK. Psychoeducational interventions to alleviate hot flashes: a systematic review. Menopause 2008;15:193-202 [DOI] [PubMed] [Google Scholar]
- 62.Taylor S, Harley C, Ziegler L, et al. Interventions for sexual problems following treatment for breast cancer: a systematic review. Breast Cancer Res Treat 2011;130:711-24 [DOI] [PubMed] [Google Scholar]
- 63.Holmes MD, Chen WY, Feskanich D, et al. Physical activity and survival after breast cancer diagnosis. JAMA 2005;293:2479-86 [DOI] [PubMed] [Google Scholar]
- 64.Holick CN, Newcomb PA, Trentham-Dietz A, et al. Physical activity and survival after diagnosis of invasive breast cancer. Cancer Epidemiol Biomarkers Prev 2008;17:379-86 [DOI] [PubMed] [Google Scholar]
- 65.Irwin ML, Smith AW, McTiernan A, et al. Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study. J Clin Oncol 2008;26:3958-64 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Alfano CM, Smith AW, Irwin ML, et al. Physical activity, long-term symptoms, and physical health-related quality of life among breast cancer survivors: a prospective analysis. J Cancer Surviv 2007;1:116-28 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Bower JE, Garet D, Sternlieb B, et al. Yoga for persistent fatigue in breast cancer survivors: a randomized controlled trial. Cancer 2012;118:3766-75 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Carson JW, Carson KM, Porter LS, et al. Yoga of Awareness program for menopausal symptoms in breast cancer survivors: results from a randomized trial. Support Care Cancer 2009;17:1301-9 [DOI] [PubMed] [Google Scholar]
- 69.Harder H, Parlour L, Jenkins V.Randomised controlled trials of yoga interventions for women with breast cancer: a systematic literature review. Support Care Cancer 2012;20:3055-64 [DOI] [PubMed] [Google Scholar]
- 70.Winters-Stone KM, Dobek J, Nail LM, et al. Impact + resistance training improves bone health and body composition in prematurely menopausal breast cancer survivors: a randomized controlled trial. Osteoporos Int 2013;24:1637-46 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Walker EM, Rodriguez AI, Kohn B, et al. Acupuncture versus venlafaxine for the management of vasomotor symptoms in patients with hormone receptor-positive breast cancer: a randomized controlled trial. J Clin Oncol 2010;28:634-40 [DOI] [PubMed] [Google Scholar]
- 72.Loibl S, Lintermans A, Dieudonné AS, et al. Management of menopausal symptoms in breast cancer patients. Maturitas 2011;68:148-54 [DOI] [PubMed] [Google Scholar]