Black Cohosh and Breast Cancer a Systematic Review

Abstruse

Managing the symptoms of menopause after a diagnosis of chest cancer offers some unique clinical challenges. For some women, vasomotor symptoms can be severe and debilitating, and hormone therapy is at to the lowest degree relatively contraindicated. Non-oestrogen therapies for hot flushes include SSRIs, clonidine, gabapentin and possibly black cohosh extracts. Vulvovaginal cloudburst tin usually be alleviated by simple moisturizers, although some may need specialized physiotherapy such as vaginal dilators. In a small number, topical oestrogens may be the only treatment that works. The CO_two laser may exist a novel, not-oestrogen therapy to alleviate this unpleasant symptom. Bone loss can be accelerated in some patients on AIs or those who had early menopause induced by chemotherapy.

Invited Author'southward contour

Dr J Eden (MB BS, Doc, FRANZCOG, FRCOG, CREI) is a certificated reproductive endocrinologist and gynaecologist. He is a Conjoint Associate Professor at The University of New Due south Wales in Sydney. He is a visiting medical officer at the Regal Hospital for Women, Sydney, Australia where he is Director of the Sydney Menopause Centre and the Barbara Gross Inquiry Unit. He also works at the Moree Aboriginal Health Service. John is a Director of the Women'southward Health and Research Found of Australia (WHRIA). His research interests include managing menopause after breast cancer, early menopause, polycystic ovary syndrome (PCOS), osteoporosis, biofilms, hormone replacement therapy too as herbal medicine.

Introduction

For many menopausal women, symptoms such as hot flushes, insomnia, mood swings and vaginal dryness are problematic. Hormone replacement therapy (HRT) and topical oestrogens are highly constructive and safe when used for the brusk-term. Even so, for those with a personal history of chest cancer HRT, even topical oestrogens are considered at least relatively contra-indicated. Non only that, chemotherapy tin induce premature menopause, provoking severe hot flushes. Many of the endocrine therapies used to treat ER+ breast cancer (tamoxifen and aromatase inhibitors (AIs)) can aggravate or induce hot flushes. Thus many breast cancer survivors volition have poor quality of life and painful, unpleasant intercourse, if non treated.

Likewise, menopause per se, has long been associated with osteoporosis. Early menopause, induced by chemotherapy, and the AIs can advance this potentially devastating bone trouble. Fortunately, there are many not-controversial options, such as the bisphosphonates, bachelor to help these women (Table 1). The direction of menopausal symptoms after a diagnosis of breast cancer is much more than controversial and difficult.

Table 1

Handling options for menopausal women with a personal history of breast cancer.

Symptom	Treatment option
Hot flushes	Remifemin
	SSRIs
	Clonidine
	Gabapentin (Moderate-dose progestin) (HRT)
Vulvo-vaginal dryness	Soap-complimentary washes
	Moisturizers
	Lubricants (CO_two laser)
Osteoporosis	Bisphosphonates
	Denosumab
	Tamoxifen/Raloxifene

Health professionals working with breast cancer survivors are very aware of the quality of life issues after chest cancer. Over the terminal two decades, there has been much research and many clinical trials aimed at finding effective non-oestrogen therapies to aid such menopausal women.

For this review, a literature search was performed using the search engine Primoa at UNSW, using the following keywords: non-hormonal, meta-analysis, antidepressant, gabapentin, hot flush, hot wink, vaginal dryness, SSRI, SNRI, clonidine, progestin, medroxyprogesterone acetate and osteoporosis. Preference was given to more recent papers and reviews.

Managing hot flushes

For many breast cancer survivors, hot flushes are a major trouble. Sweats and flushes are often worse at dark and so disrupt sleep, often resulting in tiredness and mood swings. Simple measures such as staying cool, avoiding stress, hot drinks, and spicy nutrient can help a little. Many women seek condom options from their medical practitioners to reduce these unpleasant hot sensations. Fortunately, several evidence-based, non-oestrogen options are available and recently, at that place have been several first-class reviews and meta-analyses published on this discipline (1, 2, iii).

Of class, the endocrine therapies used to treat breast cancer such as the AIs and tamoxifen often induce hot flushes. In some patients, it may exist difficult to know whether their flushes are due to menopause or their drug therapy. Sometimes, the but way to notice out is to temporarily stop the drug therapy for ii–iv weeks. If most of the sweating disappears, and so trying a different amanuensis or reassessing the case may be indicated. Sometimes the patient may choose non to have the drug and accept a small-scale increased risk of recurrence or new breast cancer, rather than putting up with severe flushes.

Black cohosh and other herbals

Many women would like to utilise a natural production to help their menopause symptoms. Among the many herbal preparations offered as therapies for menopausal flushing, the two most common are phytoestrogens (soy or reddish clover based) and black cohosh. Nelson et al. (iii) performed a meta-analysis of non-hormonal therapies for flushes, including cherry clover in their study. They showed that the effect of cherry-red clover extracts on hot flushes was not superior to placebo. As well, since these products are, at least theoretically oestrogenic, they should exist considered relatively contraindicated in the breast cancer setting.

In contrast, black cohosh extracts are not oestrogenic and may in fact accept some anti-oestrogenic properties on breast tissue (4, 5, 6). Einbond (4) exposed a number of human chest cancer cell lines to black cohosh extracts and showed inhibition of growth, especially in those jail cell lines overexpressing HER2. Clinical trials in humans have shown that women taking black cohosh had no change in mammographic density or endometrial thickness over 6 months of usage (6). This would suggest a lack of oestrogenic effect on chest and uterine tissue by the extract. Furthermore, Obi et al. (5) performed a example controlled study of women using herbal extracts to manage menopausal symptoms. They plant that usage of phytoestrogens or black cohosh extracts was associated with a decreased take a chance of breast cancer (OR 0.72, 95% CI 0.threescore–0.87).

Efficacy studies with black cohosh give mixed results (7). Part of the difficulty of performing meta-analyses in this surface area of research is heterogeneity, not just with the studies themselves but besides with the different extracts. They are not all the same. Where and how the herb is grown, the extraction procedure and many other factors tin can influence the final composition of the herbal extract. Specifically, the High german production, Remifemin, has at least iv randomized trials (8, 9, 10, eleven) showing efficacy. One trial (x) even showed equivalence with a low-dose oestradiol patch.

Concerns have been raised about occasional reports of hepatotoxicity associated with black cohosh usage. Teschke (12) has reviewed the cases and cast uncertainty on this clan. Also, to appointment, no instance of liver issues has been described in a patient using black cohosh for less than 6 months. In summary, a high quality black cohosh product like Remifemin would seem a reasonable starting point to help a patient who has been treated for chest cancer to try to reduce her hot flushes.

Antidepressants

The older tricyclic antidepressants commonly crusade sweating and flushes as a side upshot. SSRIs appear to exist unlike in this respect. In the last few years, there take been many trials examining the efficacy of SSRIs on hot flushes and several meta-analyses have been published (2, iii, 13). It seems to be a course issue; they are all helpful in depression-dosage (e.g. citalopram 20 mg). Interestingly, in the high dosage used for severe depression (eastward.chiliad. citalopram lx–80 mg), backlog sweating is a common side consequence. It is usual to commence therapy with a half-dosage for two–4 days to minimize start up side effects such as headache and nausea. After that, the lowest effective dose for low seems to assistance reduce hot flushes (e.m. citalopram twenty mg). They are by and large very well tolerated.

Paroxetine should be avoided in those patients taking tamoxifen. This SSRI has been shown to interfere with the metabolism of tamoxifen (14). Over the long term, SSRIs may inhibit sexual responsiveness and orgasm. Interestingly, a placebo-controlled, randomized trial has shown that loss of orgasm associated with SSRIs tin be restored with sildenafil 50–100 mg (15). Despite these problems, SSRIs are very useful in this setting. Low and mood swings are common after a diagnosis of breast cancer as well as hot flushes. Thus the judicious use of a low-dose SSRI may markedly amend the quality of life after breast cancer.

Clonidine

The α-blocker, clonidine, in low-dosage has been shown in meta-analyses to be superior to placebo for hot flushes (3). The usual starting dose is half a tablet twice a day, increasing if needed to 1 twice a day. The half tablet twice a day dosage usually does not affect blood pressure, whereas the 1 twice daily dosage typically lowers blood pressure past around five mmHg. In these low doses, side effects are uncommon but may include dizziness (due to lowering claret pressure), dry out rima oris (anti-cholinergic effects) and in high dosage (non used for hot flushes), it may aggravate depression. Clonidine in these doses has been used equally a migraine preventive agent besides and the combination of hot flushes and migraine is common during the menopause transition. Thus for some patients, this agent may help ii medical conditions.

Comparative trials of venlafaxine vs clonidine

In that location take been iii trials published comparing the antidepressant venlafaxine with clonidine (16, 17, eighteen). Buijs performed a crossover study of venlafaxine 75 mg vs clonidine l μg twice daily (one half of a 100 μg tablet). Both agents had a like flush-reducing activity (around l% improvement) and more patients had side effects (and stopped medication) with venlafaxine than clonidine. Loibl (17) compared venlafaxine 37.5 mg twice daily with clonidine 75 μg twice daily for four weeks. Venlafaxine was superior to clonidine for the relief of hot flushes. Boekhout (18) used a 2:two:i design to compare venlafaxine 75 mg, clonidine 100 μg and placebo for 12 weeks. Both active drugs were superior to placebo for hot flushes. Venlafaxine had a quicker effect than clonidine; clonidine was more effective than venlafaxine at 12 weeks and more subjects had side effects from venlafaxine (specially nausea and constipation).

Gabapentin

Gabapentin was initially adult as an anticonvulsant and was later institute to have nerve-stabilizing effects making it useful for nervus pain (e.g. trigeminal neuralgia, shingles pain). Information technology can be helpful for migraines, bipolar disorder and fibromyalgia (xix, 20). There are numerous trials using gabapentin to salvage hot flushes. Three meta-analyses (2, nineteen, twenty) accept shown superiority over placebo. The usual dosage used was 900 mg daily in divided doses, although in a small number of studies much larger doses have been used.

Typically, treatment is commenced with 300 mg at night and then the dosage is increased every 4–7 days by 300 mg (in divided doses). Gabapentin is usually well tolerated. Notwithstanding, side effects may include dizziness, unsteadiness, fatigue and somnolence. In the setting of breast cancer, some patients develop nerve pain in surgical wounds and and so gabapentin may help salve pain every bit well as hot flushes. Gabapentin may also be an option for the migranous patient suffering concomitant hot flushes.

Moderate–high dose progestins

In the 1980s and 1990s, high dose progestin was one of the standard treatments for advanced chest cancer (21) and moderate to high dose progestins such as medroxyprogesterone acetate (MPA) and Megestrol were besides used to relieve hot flushes (1, 22, 23). In dissimilarity, the Women's Health Initiative study (WHI, (24)) showed that the combination of conjugated equine oestrogen 0.625 mg and MPA 2.5 mg daily was associated with an increased risk of breast cancer (eight actress breast cancers/10 000 women/year after 5 years). This apparent paradox can be explained in several means.

First, avant-garde breast cancer is likely to carry differently than very small chest cancer beingness stimulated by hormone therapy (HT). Second, the dose of progestin was markedly different. Sutherland et al. (25, 26) through a serial of elegant experiments showed in the 1990s that low doses of progestins tended to stimulate the cell wheel of normal and malignant breast cells, in dissimilarity to high-dose progestins which typically hurried the jail cell through one cell cycle and then arrested growth.

In current clinical practice, high-dose progestins are hardly ever used to treat breast cancer. As a handling for hot flushes, loftier-dose progestins can cause fluid retention, glucocorticoid effects, mood swings and weight gain.

Hormone therapy

Today, the apply of HT after breast cancer would seem an anathema. Still, a few years agone, a number of clinical trials were performed to examine the safety of using HT afterward a diagnosis of breast cancer (23, 27, 28, 29).

The first was a retrospective observational study of 1122 women with a personal diagnosis of breast cancer, treated by v Sydney doctors betwixt 1964 and 1999 (23). Two hundred and lxxx six used HT after their diagnosis of breast cancer. Typically the patients were offered MPA 50–100 mg daily to relieve their hot flushes. If that did not relieve their hot flushes and so oestrogen was added to the moderate dose progestin (138 took combined HT). Relative risks (RR) were adamant using Cox regression analyses, adjusting to patient and neoplasm characteristics. Yard one hundred and twenty two patients were followed up for an average of half dozen years. The HT users had a reduced run a risk of recurrence (RR 0.62, 95% CI 0.43–0.87). This was a unique study that took into account the probable beneficial impact of a moderately high dose progestin in this setting.

In that location were two studies using 'standard HT' regimens of conjugated equine oestrogens and depression-dose MPA, the Stockholm written report (27) and the HABITS study (28). Both were terminated early. The Stockholm written report was a randomized open label report with ii parallel artillery. Subjects had to be disease-free at time of entry and they were stratified according to tamoxifen usage, type of HT, and fourth dimension since primary diagnosis. They were randomized to HT (n=188) or no HT (n=190). They recently reported on 10 year follow-up of this study group. There was no departure in new breast cancer events between the groups.

HABITS (28) was a randomized, not-placebo controlled non-inferiority trial. Cox models were used to estimate RR of a breast cancer outcome. Four hundred and forty seven women were randomized and 442 were followed upwardly for a median of iv years. Thirty nine of the 221 women on HT and 17 of the control arm experienced a new breast cancer result (HR=2.4, 95% CI ane.3–4.2). After extended follow upwards, at that place was still a significantly increased hazard of a new breast cancer event in the group who used standard HT.

Finally, LIBERATE was a randomized placebo controlled trial of tibolone 2.5 mg daily given to chest cancer patients having significant hot flushes (n=3148). After a median follow upwardly of 3.1 years, in that location was a higher risk of recurrence in the treatment grouping compared to placebo (60 minutes=1.twoscore, 95% CI 1.14–one.seventy) and and then the report was terminated early on. The tibolone treated grouping had a significant improvement of their hot flushes and high os density than the control group.

Managing vulvo-vaginal dryness

The vagina is the most sensitive tissue in the torso to oestrogen. Menopause, natural or induced, unremarkably results in vulvo-vaginal atrophy with concomitant loss of rugal folds, thinning and drying of the vagina epithelium. This results in clinical problems such every bit painful intercourse, vulval 'called-for' sensations, and recurrent urinary tract infections. The AIs typically aggravate these problems. Tamoxifen usage is often associated with an unpleasant yellow vaginal discharge. Oncologists are reticent to prescribe topical oestrogens for fear of systemic absorption and thus an increased take a chance of breast cancer recurrence (especially amidst patients on AIs).

Many women are embarrassed to talk well-nigh such intimate bug. Often when the clinician raises the upshot with the patient, they are greatly relieved that something can be done about it. Many answer to elementary measures such as the abstention of soap, the use of lather-free washes and water-based moisturizers (e.g. Replens). Lubricants such equally olive or kokosnoot oil or Sylk are much more effective than water-based lubricants.

Women who accept had the problem for many years may develop pain in their pelvic floor muscles which get myalgic. Physiotherapy aimed at relaxing these sore pelvic floor muscles can exist very helpful. Sometimes vaginal dilator therapy and/or Botox infiltrated into the muscles (nether full general coldhearted) is needed. In such affected women, pelvic floor exercises should be avoided, every bit they aggravate the problem. A bicycle seat will also brand the soreness much worse so bike riding should be avoided.

There has been a cohort study of vaginal oestrogen usage subsequently a diagnosis of chest cancer (31). Ane thou four hundred and 70 two women with a personal diagnosis of breast cancer were recruited. Threescore-nine had used topical oestrogens subsequently their diagnosis of chest cancer. Cox regression analysis was performed. Hormone usage was entered as a time-dependent covariate with disease–free intervals every bit the outcome. Subjects using topical oestrogens had a correct HR of 0.30 (95% CI 0.20–1.58). Although the numbers were small, these data were reassuring.

A novel recent evolution in this surface area is the use of a fractional, microablative CO₂ laser to treat vulvo-vaginal atrophy. In one uncontrolled prospective study (32), 77 postmenopausal women were treated with the CO₂ laser. Using the Female Sexual Role Index, marked and significant improvement in symptoms was seen over 12 weeks. At the moment, it is not known how long the effect lasts. The procedure itself is usually painless to perform.

Osteoporosis and breast cancer

Some breast cancer patients are at high chance of developing osteoporosis, either considering of early menopause induced by chemotherapy and/or the utilise of AIs. Fortunately, the bisphosphonates and more recently, denosumab, have a stiff rails tape as successful treatments for avant-garde breast cancer, particularly bone metastases (33, 34, 35). Typically the doses used in this situation are much higher than those used for osteoporosis. For case, in one recent randomized trial, denosumab 120 mg was compared with zoledronic acrid 4 mg, given every 4 weeks as treatment for bone metastases. All took calcium and vitamin D. Denosumab was superior in delaying time to offset skeletal-related outcome (SRE; HR 0.82, 95% CI 0.71–0.95). In general, adverse events (AEs) were similar in the two groups. Osteonecrosis of the jaw occurred infrequently (ii% denosumab; 1.4% zoledronic acid).

Cheung et al. recently reviewed the human relationship between breast cancer and osteoporosis (35). Most patients with ER+ breast cancer benefit from an endocrine treatment and for most menopausal patients, they will be offered an AI. These tin can accelerate bone loss and crusade fractures. Interestingly, bisphosphonates used in the standard (low doses) used for osteoporosis treatment, not only prevented bone loss and fracture but seemed to exist associated with improved disease-gratuitous survival and a decreased adventure of death in postmenopausal women (35, 36, 37, 38). Tamoxifen and other SERMs (e.g. raloxifene) appear to decrease menopausal bone loss, in contrast to the AIs (35, 36). Of course, tamoxifen can cause other side furnishings such as endometrial polyps and cancer equally well every bit eye complications such as cataracts.

All women with a diagnosis of breast cancer should exist offered the same prevention and monitoring of os loss equally other menopausal women. Supplements containing calcium and vitamin D are helpful. The combination of vitamin D deficiency and an AI tin induce marked os loss. Those with osteoporosis (low-T scores; fragility fractures; FRAX score consistent with loftier risk of fracture) especially those on AIs, should exist offered standard doses of bisphosphonates or denosumab.

Conclusions

Over the last twoscore years, in that location has been a steady improvement in survival rates after a diagnosis of breast cancer. Before diagnosis and better therapies have meant that many more than women are surviving breast cancer. However, many accept poor quality of life due to persistent severe hot flushes, insomnia and vulvovaginal dryness. Over the terminal fifteen years, or and so there has been much inquiry aimed at decision-making menopausal symptoms (and side furnishings of endocrine therapies).

When planning therapy, consideration should be given to co-morbidies and other medical conditions. For example, the hypertensive patient with hot flushes might be offered clonidine and a first-line therapy. The migranous flushing patient could be offered gabapentin or clonidine. Many would like to endeavour a herbal therapy first and Remifemin should be considered. If mood swings, feet and/or depression are nowadays also as hot flushes, a low-dose SSRI is likely to exist helpful.

It is important to enquire menopausal women who have had breast cancer nearly genito-urinary health. Most women desire to talk to a health profession about these problems. Most women suffering from vulvovaginal atrophy will respond to unproblematic measures. Some will need referral to a pelvic floor physiotherapist or a gynaecologist. In a few cases, the only treatment that seems to work is a topical oestrogen. Obviously, the theoretical risks need to be discussed on an individual basis.

All menopausal chest cancer patients should be offered bone density screening. Information technology seems articulate that Tamoxifen has a positive bone issue, unlike the AIs which can accelerate os loss. Fortunately, standard doses of bisphosphonates or denosumab are effective and safe in this setting.

In full general, HRT and tibolone should be avoided in this setting. Trials using these therapies later a diagnosis of breast cancer propose a higher risk of recurrence of cancer. In a very small-scale number of cases, a patient having severe intractable hot flushes who has failed to respond to all other treatments may choose to use HRT and accept the modest increased risk of recurrence.

Every bit the medical profession is curing more and more patients who have had chest cancer, it is hoped that we tin also offer them rubber and effective therapies to manage unpleasant menopausal symptoms.

Annunciation of interest

The authors declare that there is no disharmonize of involvement that could be perceived as prejudicing the impartiality of the review.

Funding

This inquiry did non receive whatsoever specific grant from any funding agency in the public, commercial or not-for-profit sector.

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Source: https://eje.bioscientifica.com/view/journals/eje/174/3/R71.xml