This document summarizes management strategies for menopausal symptoms in breast cancer survivors. It discusses pharmacological options like clonidine, oxybutynin, antidepressants, black cohosh, and phytoestrogens. It also covers mind-body practices like cognitive behavioral therapy and hypnosis. Non-hormonal treatments for vulvo-vaginal symptoms are discussed, as well as short-term low dose local estrogen therapy. Management of menopausal symptoms requires a personalized approach balancing symptom relief and safety.

1. Management of Menopausal Symptoms for
Breast Cancer Survivors
Tevfik Yoldemir Prof MD. BSc. MA. PhD.
tevfik.yoldemir
profdr.tevfikyoldemir

2. Expert Review of Anticancer Therapy,
DOI: 10.1080/14737140.2018.1520096

3. ecancer 2019, 13:909; www.ecancer.org; DOI: 10.3332/ecancer.2019.909
Vasomotor Symptoms

4. ecancer 2019, 13:909; www.ecancer.org; DOI: 10.3332/ecancer.2019.909

5. ecancer 2019, 13:909; www.ecancer.org; DOI: 10.3332/ecancer.2019.909

6. Clonidine
For breast cancer patients, two placebo-controlled RCTs included in a Cochrane
systematic review showed a moderate reduction in the frequency and severity of HFs.
Furthermore, in the double-blind, placebo-controlled RCT by Boeckhout et al ,
clonidine 0.1 mg/day for 12 weeks significantly decreased by 26% HFs score in 28
breast cancer survivors (p < 0.045) compared to 17 patients who received placebo.
In the same study, another group of 38 breast cancer patients employed venlafaxine
and the decline in HFs score was faster with venlafaxine than with clonidine.
ecancer 2019, 13:909; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2019.909

7. Oxybutynin
For breast cancer patients, oral oxybutynin (2.5 mg twice a day or 5 mg twice a day) or
placebo for 6 weeks.
reductions in the weekly HF score, HF frequency .
Side effects : dry mouth, difficulty urinating, and abdominal pain
JNCI Cancer Spectrum (2020) 4(1): pkz088 doi: 10.1093/jncics/pkz088

8. Oxybutynin oxybutynin chloride ER 15mg
Menopause 2016 Vol. 23, No. 11, pp. 1214-1221
DOI: 10.1097/GME.0000000000000773

9. Breast Cancer Res Treat. 2016 April ; 156(3): 415–426.
doi:10.1007/s10549-016-3765-4.

10. Breast Cancer Res Treat. 2016 April ; 156(3): 415–426.
doi:10.1007/s10549-016-3765-4.

11. Breast Cancer Res Treat. 2016 April ; 156(3): 415–426.
doi:10.1007/s10549-016-3765-4.

12. SpringerPlus (2015) 4:65 DOI 10.1186/s40064-015-0808-y
In a study of 3,077 breast cancer patients, 441 used antidepressants;
controls included 2,994 patients without breast cancer diagnosis, including 372
with antidepressant treatment. (Steingart et al. 2003)
The analysis showed a significantly increased unadjusted risk for breast cancer for
patient with ‘ever’ use of antidepressants (OR1.17, 95% CI 1.01 – 1.36), especially
for SSRI use (OR1.33 (95% CI 1.07-1.66).
Among the SSRIs, sertraline showed a significantly increased risk (OR 1.58 (95% CI
1.03-2.41) and paroxetine a borderline increased risk(OR 1.55, 95% CI 1.00-2.40).
However, when risk was adjusted for other confounding factors associated with
breast cancer risk, significance was lost, although the point estimates remained
more or less the same.

13. In a large retrospective cohort study of 109,004 female health plan members who used
various antidepressants between 1995 and 2000, paroxetine use was evaluated
against breast cancer risk (Haque et al. 2005)
It was shown that the age-adjusted relative risk (RR) comparing “ever” users of
paroxetine with other antidepressants was 1.12 (95% CI 0.96–1.31). (Haque et al. 2005)
Women who used paroxetine for 2 or more years did not show an increased risk of
breast cancer compared to women who used it for a shorter period.
Furthermore, use of SSRIs in general did not result in a statistically increased risk (RR 1.14
(95% CI 0.87-1.49)).
SpringerPlus (2015) 4:65 DOI 10.1186/s40064-015-0808-y

14. Results from another hospital-based case–control study (Kelly et al. 1999) in 5,814
women with breast cancer, 5,095 patients with other malignancies and 5,814
women without malignancies, researchers investigated the relative risk for
developing breast cancer with regular use of antidepressants and structurally
similar drugs.
Though no significant increases in risk for any category of regular use were noted,
the relative risk estimate for regular SSRI use in the previous year, was 1.8 (95%
confidence interval: 1.0 - 3.3)
SpringerPlus (2015) 4:65 DOI 10.1186/s40064-015-0808-y

15. In a large, retrospective cohort study based on prescription fillings by breast-
cancer free women, (Wang et al. 2001), 38,273 females taking any antidepressant
drug were compared to 32,949 women who took any other medication between
1989–1991.
Use of antidepressant drugs was unrelated to the development of breast cancer
(HR 1.04, 95% CI 0.87-1.25)
SpringerPlus (2015) 4:65 DOI 10.1186/s40064-015-0808-y

16. BMJ 2017;359:j5101 doi: 10.1136/bmj.j5101

17. Menopause 2015 Vol. 22, No. 11, pp. 1155-1174
DOI: 10.1097/GME.0000000000000546

18. Supportive Care in Cancer (2021) 29:1183–1193
https://doi.org/10.1007/s00520-020-05754-w
Mind-Body Practices

19. Supportive Care in Cancer (2021) 29:1183–1193
https://doi.org/10.1007/s00520-020-05754-w

20. Cognitive reactions can exacerbate distress and VMS.
Negative thoughts and beliefs about menopause and about VMS (relating to social
embarrassment, disgust, feeling out of control and worry about sleep) and certain
behavioral reactions, such as avoiding social situations, are associated with more
problematic VMS.
In contrast, calm thoughts and behaviors, such as using calm breathing, shifting
attentional focus to breathing, accepting the symptoms and not reacting with
frustration or anxiety, are associated with less problematic VMS.
Two mind-body therapies have level-1 evidence showing efficacy in alleviating VMS:
clinical hypnosis according to the Elkins’ protocol and
cognitive behavior therapy (CBT) according to the MENOS 1 and MENOS 2 protocols.
Climacteric, 24:1, 51-56, DOI: 10.1080/13697137.2020.1777965

21. Cognitive Behavior Therapy
The treatment includes several components which are worked on over four or six
weekly sessions comprising 8 h in total. These include:
1. Information about menopause and VMS with physiological explanation and
introduction to the cognitive behavioral model,
2. Monitoring and modifying hot flush triggers or precipitants,
3. Relaxation and breathing exercise and CBT to reduce stress,
4. Exploring and challenging unhelpful thoughts and beliefs about menopause and
VMS,
5. Encouraging helpful behavioral strategies, e.g. reducing avoidance, pacing
activities,
6. Information and strategies for managing night sweats and sleep.
Climacteric, 24:1, 51-56, DOI: 10.1080/13697137.2020.1777965

22. Supportive Care in Cancer (2021) 29:1183–1193
https://doi.org/10.1007/s00520-020-05754-w

23. Supportive Care in Cancer (2021) 29:1183–1193
https://doi.org/10.1007/s00520-020-05754-w

24. Supportive Care in Cancer (2021) 29:1183–1193
https://doi.org/10.1007/s00520-020-05754-w

25. Supportive Care in Cancer (2021) 29:1183–1193
https://doi.org/10.1007/s00520-020-05754-w

26. Supportive Care in Cancer (2021) 29:1183–1193
https://doi.org/10.1007/s00520-020-05754-w

27. Supportive Care in Cancer (2021) 29:1183–1193
https://doi.org/10.1007/s00520-020-05754-w

28. Black Cohosh
The use of black cohosh in breast cancer patients is still controversial due to its
SERM–like mechanism of action.
ecancer 2019, 13:909; www.ecancer.org; DOI: 10.3332/ecancer.2019.909
Plant-derived Products - Herbs

29. Genistein, soy isoflavones, S-equol, could significantly improve VMS.
Evidence has shown that genistein, soy isoflavones, and other phytoestrogens with
structural resemblance to oestradiol relieve VMS by exerting oestrogen-like effects, but
they have 100 to 1000 times less activity than oestrogen and are preferentially expressed
in the central nervous system, vascular system, skin and bone without causing unwanted
oestrogenic effects on the breasts or uterus.
In addition, short term (within 2 years) use of phytoestrogens was considered safe and
was not associated with an increased the risk of breast or endometrial cancers.
Complementary Therapies in Clinical Practice 36 (2019) 181–194 doi 10.1016/j.ctcp.2019.07.007
Plant-derived Products - Phytoestrogens

30. However, because of the antagonistic effects of phytoestrogens on tamoxifen and
anastrozole in women with breast cancer, some have recommended that isoflavones be
avoided in patients taking these drugs.
After reviewing food questionnaires from 3088 breast cancer survivors in the Women’s
Healthy Eating and Living (WHEL) study, Caan et al. (2011) reported no adverse effects of
soy food intake, either alone or in combination with tamoxifen, on the incidence of breast
cancer recurrence or total mortality.
Rather, they found a trend toward lower mortality with increasing soy intake that did not
differ by the breast tumor hormone receptor status
Journal of Steroid Biochemistry & Molecular Biology 139 (2014) 225–236
doi:10.1016/j.jsbmb.2012.12.004

31. The Shanghai Breast Cancer Study demonstrated a lack of tumor promoting effect
in breast cancer patients (X.O. Shu, 2009).
In this study dietary soy consumption by breast cancer survivors was associated
with significantly lower risk of recurrence and death (P < 0.01) .
Similar findings were encountered in western US women and women receiving
anastrozole therapy in the Life After Cancer Epidemiology trial; in these trials the
consumption of isoflavones before diagnosis was not associated with adverse
effect on survival (N. Guha, 2009; X. Kang, 2010).
Journal of Steroid Biochemistry & Molecular Biology 139 (2014) 225–236
doi:10.1016/j.jsbmb.2012.12.004

32. Similar to the effects of isoflavones, a prospective study in 2007 found a decrease
in breast cancer risk with dietary lignan intake (M.S. Touillaud, , 2007).
They followed 58,049 postmenopausal French women (who were not taking
isoflavone supplements) for a median of 7.7 years and found that subjects in the
highest quartile of lignan intake (>1395 mg/day) had a reduced risk of ER- and PR
positive breast cancer (P = 0.02)
Journal of Steroid Biochemistry & Molecular Biology 139 (2014) 225–236
doi:10.1016/j.jsbmb.2012.12.004

33. One prospective population-based cohort study of 45,448 pre- and
postmenopausal women found that intermediate levels of coumestrol
intake were associated with a decreased risk for receptor-negative breast
tumors (M. Hedelin, ,2008).
Journal of Steroid Biochemistry & Molecular Biology 139 (2014) 225–236
doi:10.1016/j.jsbmb.2012.12.004

34. CLIMACTERIC
2020, VOL. 23, NO. 6, 532–
538
https://doi.org/10.1080/1369
7137.2020.1789093

35. Non-hormonal strategies (moisturizers or lubricants) are considered the first line.
The main limitation of non-hormonal therapies is the short-term efficacy.
Among the trials included in this systematic review, 85% described efficacy with a 30-day
follow-up or less.
The limited absorption of low and ultra-low doses of estrogens for short period of
treatment may be also considered.
Higher absorption was reported with higher vaginal estradiol doses (25 micrograms, 10
micrograms) than with the lowest available dose (4 micrograms)
Maturitas 148 (2021) 55–61 doi:10.1016/j.maturitas.2021.04.005
Maturitas 143 (2021) 47–58 doi:10.1016/j.maturitas.2020.08.010
Vulvo-vaginal Symptoms

36. A meta-analysis of 11 studies concluded that vaginal estrogen administration in
postmenopausal women with a history of breast cancer is not associated with systemic
absorption of sex hormones after 8 weeks of treatment vaginal estriol (0.005% estriol, 50
micrograms/application)
Gel was applied once daily for the first 3 weeks and then twice weekly for weeks 4 to 12.
Women receiving 0.005% estriol vaginal gel had slightly increased estriol levels at weeks
1 and 3, with a subsequent reduction until normalizing at week 12; estradiol and estrone
remained below the limit of quantitation in almost all samples.
Maturitas 148 (2021) 55–61 doi:10.1016/j.maturitas.2021.04.005

37. After 3.5 years of follow-up, treatment with a topical estrogen was not associated with
an increase in breast cancer recurrence among women taking aromatase inhibitors or
tamoxifen
When non-hormonal products are ineffective, topical estrogen could be considered, but
safety data are limited in breast cancer survivors.
The less potent estrogen estriol could be preferred to estradiol, and the lowest available
doses should be used.
Maturitas 148 (2021) 55–61 doi:10.1016/j.maturitas.2021.04.005

38. Gynecological Endocrinology, 33:6, 418-420,
DOI: 10.1080/09513590.2017.1290076

39. Vaginal androgens
Vaginal testosterone cream was compared to estradiol vaginal rings for vaginal dryness or
decreased libido in women with early-stage breast cancer treated with aromatase
inhibitor. The testosterone group had better outcomes in terms of sexual function
without increasing serum estradiol.
A RCT studied vaginal prasterone at two different doses (3.25 and 6.5mg/day), in
comparison with a moisturizer to treat dryness and dyspareunia in postmenopausal
women with breast or genital cancer receiving endocrine therapy.
Serum estradiol was increased only in those in the 6.5mg prasterone arm. However, sex
steroid levels remained within the lowest quartile for postmenopausal women.
Long term efficacy and safety data for vaginal androgens are not available.
GYNECOLOGICAL ENDOCRINOLOGY 2021, VOL. 37, NO. 8, 746–752
doi.10.1080/09513590.2021.1943346

40. Laser
Clinical assays evaluating the efficacy and safety of the use of erbium laser are needed,
since all the trials included in this review were observational; some were prospective
while others were retrospective, with a short follow-up and assessed only subjective
variables regarding VVA improvement.
There is a lack of data regarding safety and BC relapse, since no study provided
information about recurrence during follow up, and serum estradiol levels were not
measured.
Maturitas 143 (2021) 47–58
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41. Ospemifene
its use is not currently recommended for BCS receiving ongoing treatment.
However, the use of ospemifene in BCS is accepted by the US FDA and the European
Medicines Agency after having completed the necessary BC treatment and when
remaining disease free.
In a randomized clinical safety study in 426 postmenopausal women with VVA comparing
ospemifene 60mg/day versus placebo, the levels of estradiol remained within normal
post- menopausal range with mean estradiol levels similar to baseline at week 12
Maturitas 143 (2021) 47–58 doi:10.1016/j.maturitas.2020.08.010
Gynecological Endocrinology, 33:6, 418-420,
DOI: 10.1080/09513590.2017.1290076

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49. Treatment Options to Consider for Vaginal
Dryness and Sexual Pain in Cancer Survivors
Mayo Clin Proc. 2016;91(8):1133-1146

51. neurokinin 3 receptor antagonist - fezolinetant (VESTA)
Menopause 2020 Vol. 27, No. 12, pp. 1350-1356
DOI: 10.1097/GME.0000000000001621

52. Thank you for your attention
Tevfik Yoldemir Prof MD. BSc. MA. PhD.
tevfik.yoldemir@marmara.edu.tr