The aim of this 2024 White Paper is to provide an International Menopause Society (IMS) position statement about menopause and menopause hormone therapy (MHT), and in particular to address some of the key controversies. The paper’s purpose is to act as a blueprint upon which to base the future ethical management of menopause from both practical and aspirational perspectives. The mission of the IMS is to work globally to promote and support access to best-practice health care for women through their menopause transition and post-reproductive years, enabling them to achieve this with optimal health and well-being. Through effective communication and evidencebased education about menopause, women can be empowered to make informed personalized choices aligned with their individual goals.
After many years of neglect, we have finally seen long overdue unprecedented attention given to menopause in the popular media, empowering women to seek care for menopause symptoms. Yet the media and even academic literature present polarized views on its management. These contrasting views often leave women feeling confused and disempowered rather than supported through their menopause transition and susceptible to unproven marketed products. Very few therapeutic medical interventions have generated as much controversy, and very few have waxed and waned in popularity as much as MHT. Opinions about MHT appear to be driven as much by the sociocultural climate as they are by the emerging evidence from clinical trials.
These sociocultural factors include demographics, education, religion, beliefs, values, social classes, sexuality and attitudes. The search for a well-balanced narrative of the menopause momentum continues [1]. This paper serves to lay the groundwork for this well-balanced narrative by defining the history and current context of menopause and MHT. This aim of this White Paper is not to provide a comprehensive toolkit of therapeutic options and evidence for efficacy and safety; this is well covered by recommendations guidelines and consensus statements. The paper is primarily intended to explore the following:
Menopause and MHT continue to be topics of considerable controversy and debate to the detriment of many women and society as a whole. The perspectives and attitudes toward menopause driving this controversy can be understood from anthropological, evolutionary, historical and modern medicine perspectives.
The stages of the menopause have been well defined by the Stages of Reproductive Aging Workshop (STRAW)+10 group [2], primarily being classified according to menstrual regularity, with hormonal markers of secondary importance. Although the mean age of natural menopause is often quoted in some regions such as Europe at 51years, meta-analyses of global data indicate that the mean age at natural menopause is actually 48.8years [3]. Studies such as the US Study of Women’s Health Across the Nation (SWAN) [4] and from other regions, for example sub-Saharan Africa [5], show that this age varies according to many socioeconomic and other factors such as HIV and can also occur early and prematurely in a significant proportion of the population [3–5].
Distressing symptoms typically start in the perimenopause, and often even before women enter the perimenopause as defined by the STRAW +10 criteria. Yet government-regulated therapies are approved for postmenopausal women, with no specific approved therapies for perimenopausal women. Menopause healthcare systems and treatments that are more ‘symptom-focused’ rather than ‘stage-focused’ can better meet women’s needs [6].
Better still, a ‘life course approach’ can identify individuals at risk of early menopause and premature ovarian insufficiency, which are associated with osteoporosis, cardiovascular disease and cognitive problems. For instance, smoking in childhood and early adulthood is correlated with early menopause, while regular exercise and minimal alcohol consumption correlate with reduced risk of early menopause [7].
In many women 50% of life is now spent in a postmenopausal state, and given that we generally have an aging population globally it is expected that by 2025 more than one billion women globally will be in a perimenopausal or postmenopausal age group.
It is therefore imperative that health strategies are put into place to optimize the health and quality of life of women at this stage of life. Menopause is a key factor contributing to non-communicable diseases in women, including cardiovascular, bone and cognitive health. It is therefore necessary that the menopause is taken into account in this United Nations Decade of Healthy Aging [8, 9].
Three characteristics make ‘natural’ menopause unique to the human female. Menopause occurs universally among individuals living into later years, occurs halfway through the maximum lifespan of our species and is quite age specific, albeit that there is some variation across populations and geographical regions, with the mean age of natural menopause ranging from 46 to 52years [3].
Reproductive senescence (biological aging) is not unique to humans in the animal kingdom. Some rhesus and macaque monkeys stop menstruating 1–2years before their maximum lifespan, and there are sporadic cases of menopause described in some apes late in their lifespan such as the pygmy chimpanzee (Pan Troglodytes), the bonobo (Pan Paniscus) and also in some whale species [10, 11].
The key difference is in the timing, with reproductive senescence occurring at the end of the maximum lifespan in chimpanzees and whales compared to the middle of the lifespan in humans. One of the key questions is whether menopause has a purpose in humans (Homo sapiens). There are a number of hypotheses to explain human menopause [12, 13], and the following are among the most widely recognized:
The cessation of menstruation and women’s ability to conceive was described as far back as the fifth century BC by Hippocrates, but no particular treatment of menopause was proposed.
The ancient Chinese Medical text Huangdi Neijing (黄帝内经, 475–221 BC), also known as Yellow Emperor’s Inner Canon, describes 7-year life cycles for women. The fifth cycle which is at age 35years is where skin complexion declines and frequent miscarriages are experienced, and the seventh cycle which is at age 49years is where there is cessation of menses leading to inability to bear children and hence the menopausal stage. In the first century AC under the Roman Empire, the narration of Pliny the Elder in his Natural History fostered the idea that menstruation was attached to some specific properties significantly contributing to the menstrual taboo [17].
In the Middle Ages it was thought that the disorderly uterus rose or descended and committed actions difficult to endure, leading to faintness of the heart, tightness of the chest, breathlessness, hiccups and troublesome accidents [18].
Menopause became a medical entity in the early nineteenth century and was increasingly linked to pathology and disease. The boundaries were blurred between menopause and the effects of aging, and physicians identified a series of unpleasant, even fatal complaints, associated with the ‘condition’. Menopause was associated with various diseases that warranted treatment according to the male physicians of the time using various strategies including medicines, bloodletting with leeches and surgery.
After diagnosis of menopause, Dr Edward John Tilt, a Victorian physician, recommended carbonated soda, opium and a large belladonna plaster placed at the pit of the stomach, and vaginal injections with a solution of acetate of lead followed by prescriptions of hydrochlorate of morphine, chloric ether and distilled water [19].
It was not until 1923 that the scientists Edgar Allen and Edward A. Doisy first isolated estrogenic steroids [20], and in 1942 Premarin (pregnant mare’s urine) was first patented. In 1966 in his book Feminine Forever, Robert Wilson recommended estrogen as a ‘cure’ for the ‘tragedy of the menopause’.
In 1968, one of the most eminent obstetricians and gynecologists of her time, Dame Josephine Barnes touched on hormonal changes during the menopause transition in Women’s Hour, a popular radio program in the UK. It was deemed by some as ‘acutely embarrassing’ to hear about hot flushes at 2 o’clock in the afternoon! However, by 1970 feminists began to challenge the orthodox medical model of menopause and viewed it as a positive transformation.
Its medicalization was perceived as a conspiracy by the gerontocracy ‘to produce a submissive female patient who could be treated with drugs’. In her book The Change, Germaine Greer stated that ‘menopause is a time for mourning. The menopausal woman should be allowed her quiet time and her melancholy’ [21].
In her publication Hot Flushes, Cold Science in 2010, Louise Foxcroft stated that current attitudes to menopause have been reached through the filter of thousands of years of rampant chauvinism, collusion, trial, error and secrecy [22]. The controversy and polarization of views about management of the menopause and MHT deepened even further following publication of major MHT trials at the turn of the new millennium.
The initial reports from the Women’s Health Initiative (WHI) study in the USA in 2002 [23] and The Million Women Study(MWS) in the UK in 2003 [24] resulted in a significant decline in the use of MHT (by 80%) due to concerns about the reported risks of cardiovascular events and breast cancer
The reporting of these two studies came as a shock to conventional wisdom. Prior to this, MHT was viewed extremely positively because of the favorable findings of observational studies, which led to women being regularly counseled about use of MHT for preventive reasons, as well as for symptom relief [25].
Although the absolute risks of MHT on health outcomes in the WHI were rare to very rare by common standards, the data were alarmingly presented as percentage changes rather than absolute numbers by the media, and the risks were said to apply across all age groups. The fall in prescribing, especially in primary care, resulted in many women ‘suffering in silence’ and seeking other solutions for their symptoms.
Numerous subsequent WHI publications following the initial report demonstrated that the problems were mainly in the older age groups [26], and probably due to the particular types and doses of hormone therapy used in the WHI. Yet many women and their prescribers were still too anxious to return to use of MHT
Further randomized clinical trials such as the Kronos Early Estrogen Prevention Study (KEEPS) [27], the Early versus Late Intervention Trial with Estradiol (ELITE) [28] and the Danish Osteoporosis Prevention Study (DOPS) [29], focusing on the use of MHT in women at the usual age of menopause transition with more modern types of MHT, showed that there were few risks in this age group. Unfortunately, these studies were not of the scale of the WHI, and therefore could not definitively assess the impact on major outcome measures such as cardiovascular events, fractures and dementia.
Other MHT studies showed findings contradicting the WHI but were not included in influential guidelines. For example, major observational studies such as the French E3N Cohort Study [30] demonstrated lower breast cancer risks with conventional body-identical MHT [31], but these data were excluded from the latest analysis by the Collaborative Group on Hormonal Factors in Breast Cancer [32]. Instead, the Collaborative Group emphasized breast cancer risks over the benefits of MHT, and excluded the majority of the data from MHT studies containing micronized progesterone rather than progestins.
Some recent guidelines present perspectives that contrast, particularly on the issue of primary prevention, with findings of the gold-standard Cochrane meta-analyses. For example, a Cochrane review showed that those who started MHT less than 10years after the menopause had lower mortality (relative risk 0.70, 95% confidence interval [CI] 0.52–0.95; moderate quality evidence) and coronary heart disease (composite of death from cardiovascular causes and non-fatal myocardial infarction) (relative risk 0.52, 95% CI 0.29–0.96; moderate quality evidence), although they were still at increased risk of venous thromboembolism (VTE) (relative risk 1.74, 95% CI 1.11–2.73; high quality evidence) compared to placebo or no treatment [33].
Given the ongoing controversy, there is clearly a need for a definitive long-term randomized clinical trial where conventionally regulated bioidentical/biosimilar MHT is started in women at the usual age of menopause and followed for long enough and in sufficient numbers to assess major outcome measures such as cardiovascular and breast cancer events.
Unfortunately, the costs of such a trial would be prohibitive, making unbiased recommendations based on the current literature all the more critical. Continued collection of high-quality, prospective observational registry data may be the best compromise solution
Menopause specialists should now strive to achieve a coordinated approach to the gathering and amalgamation of data. Societies such as the IMS could coordinate this data ‘trawl’. This important venture could be funded by the IMS Endowment for Education and Research (EER) and the IMS could act as a global repository for this information. This would also facilitate the dissemination of information to HCPs and the public that could be used to influence clinical practice in a positive way. In the meantime, comprehensive systematic reviews and meta-analyses will be performed in connection with the update of the 2016 IMS recommendations on MHT [34].
t is well recognized that although part of a natural life-course progression, menopause can be associated with distressing symptoms which impact on personal, social and professional quality of life. Although the classic symptoms of menopause are vasomotor symptoms (VMS) such as hot flushes and night sweats, and genitourinary symptoms (vulval, vaginal and urinary), there are numerous other symptoms which can occur at this time of the life course.
These may be caused or exacerbated by the loss of estrogen but may also depend on other associated factors, for example genetic/epigenetic, just as genetic variation at the TACR3 locus is associated with VMS [35]. For Asian women, physical symptoms such as body aches and joint pains as well as psychological symptoms are recognized to be more prevalent than VMS [36]. A recent systematic review and meta analysis of prevalence data globally found that joint and muscular discomfort were the most prevalent menopause related symptoms at 65.43% (95% CI 62.51–68.29) [37].
There has been considerable controversy regarding what constitutes a genuine menopause symptom, which has resulted in inconsistency as to what outcomes and best measurements should be assessed in clinical trials. This has led to the recent development of a Core Outcome Set for vasomotor and genitourinary symptoms associated with menopause in the COMMA global initiative [38, 39].
There is also now good evidence that women predisposed to severe VMS also have a higher incidence of cardiovascular disease [40]. Although it is yet unknown whether this association is causal, it is important that VMS and heart health are assessed in a ‘menopause check’, which is an opportunity for screening, and can be routinely conducted using standardized protocols and algorithms in primary care such as those proposed in an IMS toolkit [41]
The variety of menopause-related symptoms can impact significantly on individuals’ physical, mental and cognitive health as well as their personal and professional relationships. More recently, there has been growing recognition that these symptoms can have a profound impact on performance in the workplace, leading to reduced individual and corporate productivity, loss of efficiency and even loss of employment [42]. A proportion of women will go through menopause with few or no symptoms and as such will not require treatment from this perspective. However, the widespread dissemination of misinformation and disinformation may encourage
some of these women to request MHT from their HCPs purely to maintain skin, nail and hair quality and/or for potential primary prevention benefits such as cardiovascular and brain health, for which there is not currently an indication. This has been one of the key issues which has caused recent controversy given that MHT is not currently recommended solely for primary prevention, although in a number of countries there is also a license for prevention of osteoporosis. Use of MHT should not be considered an anti-aging strategy. This highlights the need for women to receive trusted information about why, and for what purpose, MHT can or cannot be provided.
Holistic management adopting a biopsychosocial approach during this key milestone in a women’s life allows optimization of health for a better quality of life. This approach includes primary prevention of chronic disease through healthy eating, active lifestyle and preventive immunization (e.g. pneumococcal, shingles), timely and appropriate screening for chronic disease and cancers, avoiding harmful substances such as cigarette smoking, avoiding excessive alcohol, staying social engaged and focusing on mental wellness.This may be all that is required, or all that is available in some countries and regions, to achieve healthy aging, and women making this choice should not feel under pressure to medicalize their menopause, as described in a recent review of menopause management [43]. However, it is equally important that the distressing symptoms and potential sequalae of menopause are also not trivialized [1].
Menopause can also be effectively managed with evidence-based cognitive behavioral therapies, hypnotherapy and non-hormonal pharmacological medicines, all of which women should be made aware of. These options should be made more readily accessible given the growing evidence for benefit, particularly for those who cannot, or choose not to, use MHT [41, 43–45].
Numerous complementary therapies are currently accessed by women as first-line treatments for managing menopause before professional help is sought, but often with little evidence for effectiveness and safety. Whilst these preparations are unlikely to cause harm, they can occasionally be associated with significant adverse effects and often lack efficacy.
Ongoing research on complementary therapies is warranted given that there are some favorable data from small clinical trials, but proper regulation of the sale of these products is vital to ensure ethical, safe and cost-effective management of menopause [44, 45].
The aim of this section of the White Paper is to interrogate some of the key controversial issues which have arisen over the last few years and have led to much confusion amongst HCPs and women seeking treatment for menopause-related problems. The aim is not to replicate recent practical prescribing guidance of MHT which can already be found in various toolkits and position statements [34, 41, 46], and which will also be available in updated guidelines from the IMS, and in a subsequent planned update of the global consensus of societies [47].
MHT is conventionally indicated for women with natural and surgical menopause who are experiencing distressing vasomotor and/or vulvovaginal symptoms.
There has been considerable controversy as to whether women who are asymptomatic should be prescribed MHT. Although MHT is primarily indicated for the relief of distressing menopause symptoms, it is often incorrectly promoted to women as an ‘elixir of youth’.
There is good evidence that MHT reduces the incidence of osteoporosis and risk of osteoporosis-related fractures, and in some countries – for example, in the USA and Australia – this is also a primary indication for MHT.
There are also good data supporting its use for reducing the risk of cardiovascular disease, thereby having a positive impact on life expectancy, but MHT is not currently licensed anywhere globally for these indications.There are many other women who might benefit from MHT for whom it is not indicated according to the label. For example, women with premature ovarian insufficiency and early menopause who may require MHT for symptomatic relief, but should also receive it for primary prevention purposes.
However, the research findings regarding the impact of MHT on cognition and dementia are considerably less reliable and require further research. These issues have all been comprehensively reviewed in the last four World Menopause Day IMS White Papers on premature ovarian insufficiency [48], bone health [49], cognitive health [50] and cardiovascular health [51].
As always in such situations, the benefits of treating bothersome symptoms on a woman’s quality of life must be weighed against the potential risks associated with MHT. The definition of ‘acceptable risk’ can vary considerably among HCPs and patients
For example, MHT is conventionally contraindicated in women with hormone receptor-positive breast cancer and endometrial cancer. However, depending on the degree of impact on quality of life, and the efficacy and tolerability of non-hormonal alternatives, some women may be willing to accept the risk of using, or going back to using, MHT, particularly in those treated for early-stage cancer [52].
In women with a past history of VTE, MHT may be considered if it had been provoked by certain circumstances, for example major surgery or prolonged immobility, and use of a concomitant anticoagulant for VTE prophylaxis could be considered.
There are ongoing projects to develop medical eligibility criteria for MHT, as per the World Health Organization (WHO)
guidance on contraception, to provide specific graded guidance for a variety of different clinical case scenarios. These
medical eligibility criteria guidelines are likely to be helpful in the future but are still in development and require universal
consensus and application [53, 54].
Factors which determine the type and dose of MHT typically prescribed by HCPs include the following:
Prescribing algorithms in recently published toolkits [41] very clearly guide HCP prescribing with regards to these factors.
The aim of this section is to critically examine some of the controversies which have arisen recently with regards to the
recommended type and dose of MHT
There are four types of estrogens which occur naturally in human beings; estrone, estradiol, estriol and estetrol. There are
some claims, particularly among those promoting compounded bioidentical hormone therapy, that replacement of these estrogens in the correct proportions is important to optimize the efficacy and safety of MHT. This claim has not been proven and remains one of many concerns about the safety and efficacy of compounded bioidentical hormone therapy.
Regulated systemic MHT has conventionally contained conjugated equine estrogens (CEE), estradiol and estradiol
valerate. More recently, estetrol has been investigated as a treatment for VMS in clinical trials and is likely to be brought
to market, as it has been for contraception. Vaginal MHT typically contains estradiol, estriol or, more recently, dehydroepiandrosterone (prasterone).
A systemic oral selective estrogen receptor modulator (ospemifene) and a CO2 and erbium laser have also been marketed for symptoms of vulvovaginal atrophy (VVA)/Genitourinary Syndrome of Menopause (GSM) symptoms. Despite encouraging findings from observational and uncontrolled studies, controlled randomized clinical trials of laser therapy for VVA/
GSM have not yet confirmed the benefits compared to sham laser.
There are very few head-to-head studies evaluating whether one type of commonly used systemic or localestrogen in MHT, such as Conjugated Equine Estrogens (CEE) versus estradiol, is superior to another in alleviating menopause symptoms. Estrone and estriol are biologically weaker estrogens than CEE and estradiol, but these are not typically marketed for systemic MHT.
The recent move toward use of transdermal estradiol (patches/gels/sprays) is supported by evidence from observational and case-controlled studies of reduced risk of VTE [55].
However, there are often considerable variations in serum concentrations of estradiol in women treated with the same transdermal preparation (which may vary by a factor of 10), and large inter-individual differences. A woman’s response to the same dose can therefore be difficult to predict.
The efficacy of transdermal MHT is based on sufficient permeability of the steroid through the skin. Diet, alcohol, drug consumption, smoking, physical activity and stress may all cause rapid and transitory changes in peripheral blood flow, absorption and metabolism. There may also be circadian variations in dermal blood flow with higher levels in the evenings enhancing absorption [56].
In view of all these variables, a transdermal preparation may not always be the best option for an individual. If there
are no particular risk factors (e.g. obesity, history of VTE) there is little reason why oral estrogen could not be prescribed. Patient-informed choice should always prevail.
There is now considerable evidence that micronized progesterone and biologically similar progestogens (e.g. dydrogesterone) appear to have metabolic and possibly breast advantages over androgenic progestogens [30, 55, 57, 58]. Although this is not yet reflected in regulatory guidance or in prescription leaflets, it can make a considerable difference in the individualization of therapy.
The choice of progestogen can also be particularly important from a psychological standpoint in women with a past history of premenstrual syndrome (PMS)/premenstrual dysphoric disorder (PMDD) who often have progestogen intolerance [59]. In these patients it may also be necessary to reduce the dose and duration of micronized progesterone, for example, 7–10days per month at 100mg (rather 200mg) in sequential MHT regimens. However, for progestogen-intolerant women on these suboptimal doses and regimens, regular monitoring with ultrasonography and/or endometrial biopsy is critical to exclude endometrial hyperplasia or carcinoma [60].
Vaginal administration of micronized progesterone may be even better tolerated by ‘progestogen-sensitive’ patients but is off-label in most countries for MHT. Other options include the uterine delivery of progestogen (levonorgestrel) from an intrauterine device and the oral tissue-selective estrogen complex (TSEC) (CEE/bazedoxifene), although the latter is only licensed in a few countries currently
Estrogen. There have recently been an increasing number of concerning case reports of women being prescribed doses of estrogen well outside the licensed dose range. It has not been unusual to see three to four times the maximum recommended dosage of systemic estradiol patches and gels, sometimes used in combinations of routes of delivery.Whilst there is some evidence that higher doses are required in order to achieve endogenous cycle stabilization and suppression in women with PMS/PMDD and perimenopausal depression [61, 62], or where absorption is poor, it is important to adhere to the principle of prescribing at the minimum fully effective dose where possible. Higher doses of estrogen are also typically required in women with premature ovarian insufficiency (POI) and early menopause in order to achieve full symptom relief and optimal bone mineralization [48].
The doses of estradiol required to achieve adequate conventional vasomotor symptom relief and bone protection are actually quite low (1–2mg of estradiol orally, 25–50μg patches or 1–2 pumps of estrogen gel), and whilst there is a dose–response effect for both VMS and bone density, benefits can even be achieved with ultra-low-dose MHT formulations containing 0.5mg of estradiol orally, or 14μg transdermally [63–65].The rationale supporting the principle of using lower doses of MHT to achieve adequate benefits is the lower likelihood of adverse estrogen effects (e.g. breast tenderness, bloating, bleeding problems), including a lower risk of VTE with oral estrogen, and of stroke, even with transdermal estrogen [66]. Whilst the risk of hormone-dependent breast cancer has not been proven to be dose-dependent, excessive use of MHT could potentially increase risk. The absence of evidence is not necessarily evidence of absence.
Supraphysiological levels of estrogen also confer a risk of a sudden decrease in treatment effectiveness ‘tachyphylaxis’, due to estrogen receptor insensitivity. Whilst not common, this can occur even with high doses of transdermal estrogen [67], as well as with implanted estrogen pellets. This risk can be mitigated by prescribing estrogen at the minimum (fully) effective doses. Estrogen pellets are unlicensed and require better regulation, but with cautious monitoring of estrogen levels can be an option in some countries for the few women whose symptoms do not respond to oral and transdermal preparations.
Progestogen. It is important to reiterate that the dose of progestogen used provides adequate endometrial protection according to standard guidelines [41], unless it is absolutely necessary to reduce the dose in progestogenintolerant women [68]. This is particularly important with sequential combined MHT regimens where the incidence of hyperplasia tends to be higher with long-term usage, even with standard dose regimens [69]. Typical doses used with standard doses of estrogen in MHT include 200mgof micronized progesterone/10mg of dydrogesterone for 12–14days in a sequential regimen, or 100mg of progesterone/5mg dydrogesterone in continuous regimens.
The levonorgestrel intrauterine device is another way of providing effective endometrial protection as well as contraception, although it is not licensed for endometrial protection in all countries. Other possible options for avoiding or minimizing progestogen intolerance include the TSEC containing a combination of CEE/bazedoxifene [70], and the selective tissue estrogenic activity regulator (STEAR) tibolone [71]. Unfortunately, despite the need for more options to personalize MHT, these products are licensed in only a few countries.
Recent findings from the ELITE study indicate that there may be an increased risk of endometrial hyperplasia with sequential vaginal progesterone gel, even with a relatively low dose of estradiol of only 1mg [72]. Although vaginal progesterone gel is no longer licensed for endometrial protection, if progesterone is administered vaginally, whatever the formulation, similar doses to oral progesterone should be used and monitoring of any unscheduled bleeding should be instituted promptly as previously described. If the dose of estrogen is increased it is important that the dose of progestogen is also increased proportionately to provide sufficient endometrial protection, although there is little evidence from women using higher doses outside the product license [73]. More research is needed to guide the correct dosing of progesterone when higher doses of estrogen are used, such as in women with POI.
The prescribing principle here is that we should ‘first treat the patient, not the result’. As such, if a patient with menopause at the usual age is using MHT purely for symptom relief, and they achieve full relief of their symptoms without any adverse effects, then it is unnecessary to routinely check their hormone levels.It is important to note that estradiol levels are best interpreted with transdermal preparations as oral estrogen is metabolized partly to estrone. Mass spectrometry is the best method for measuring estradiol levels but may not always be available.
Is menopause being over-medicalized?
Access to MHT in low and middle-income countries
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