18 March, 2019: 

Publication: Use of postmenopausal hormone therapy and risk of Alzheimer’s disease in Finland: nationwide case-control study by Hanna Savolainen-Peltonen, Paivi Rahkola-Soisalo, Fabian Hoti, Pia Vattulainen, Mika Gissler, Olavi Ylikorkala, Tomi S Mikkola BMJ 2019;364:l665.

Should this warrant a change in prescribing practices for MHT?

The simple answer is no.

This recent publication in the BMJ reports a case-control study from Finland comparing the use of menopausal hormone therapy (MHT) among Finnish women with and without Alzheimer’s disease (AD). The researchers report that systemic MHT ever-use was higher among women with AD (18.6%) compared with those without AD (17.0%). They conclude, “Use of postmenopausal systemic hormone therapy is accompanied with an increase in the risk of Alzheimer’s disease in postmenopausal women” and that, “[this] data should be implemented into information for present and future users of hormone therapy”.

The IMS does not agree with either concluding statements. This is because an association between MHT and AD is not evidence for cause and effect. There are many instances in medicine where research observations have not stood the test of subsequent randomized clinical trials [1,2]. Unfortunately, in this case the chance of an appropriately powered randomised trial ever being done is vanishingly small.

The study was based on the Finnish drug registries, so the sample is large. However, the study has a number of important limitations, acknowledged by the authors, that necessitate caution in interpreting these findings. Like all registry studies there was lack of information about key confounding factors, including other established dementia risk factors, and the timing of initiation of MHT. As an observational study, it is limited by ascertainment bias. Cases of AD were identified via a national reimbursement register. Whereas the Finnish Drug Reimbursement Register has a high positive predictive value for AD (most people identified will actually have AD), the sensitivity is in the order of 65%. This means that up to 35% of people with AD may not be identifiable by this process, and potentially some included as ‘controls’. Such an ascertainment bias may have influenced the study findings either way.

The study collected data on the use of MHT from 1994. Through the nineties, and until the first outcomes of the Women’s Health Initiative Trials, MHT was thought to prevent cardiovascular disease and cognitive decline, such that women at increased risk for both vascular dementia and AD may have been preferentially prescribed MHT. Hence, the finding of a small excess in the present study could simply reflect this bias. As suggested by the authors, women may have been prescribed MHT once they started to develop early signs of cognitive dysfunction, so that at least part of the association could be “reverse causality”. Also, in this study, some women classified as having AD may have had vascular dementia or mixed AD/vascular dementia, both of which may have been worsened by MHT.

12 March 2019

Summary

The Women’s Health Initiative (WHI) was certainly a milestone and a game changer in the history of menopause medicine. Before WHI, menopausal hormone therapy (HT) was considered a panacea, not only as a potent cure for menopause symptoms, but also as an effective strategy to keep women young forever and preventing all major chronic diseases of aging. However, WHI taught us that HT must be regarded as any other drug, to be cautiously prescribed after consideration of individual benefits and risks. Unfortunately, WHI results created a tsunami because of initial mis-interpretation of the data, which were amplified by the media and led to across the board banning of HT. Although more than 16 years elapsed since the first announcement of the preliminary results of the estrogen plus progestin arm of WHI, the study is still in focus, and a new research analyzes some aspects concerning its impact on the use of HT in the US [1]. The investigators followed women recruited for the SWAN study who returned for annual visits during 1996 to 2013. Women were 42-52 years old and were not menopausal at baseline. The study time frame allowed comparison of the pre-WHI period (up to 2002) with the post WHI period (after 2002). The focus was on initiation or continuation of HT among the 3018 participants. The results pointed at a highly significant drop in initiation (from 8.6% pre-WHI to 2.8% post-WHI), and a corresponding decrease in continuation of HT, from 84% to 62%. Menopausal symptom relief and provider advice were common HT initiation reasons both pre- and post-WHI, whereas prevention of heart disease or osteoporosis, which were often cited as reasons for initiation pre-WHI, were infrequently mentioned post-WHI. Interestingly, high in the list of reasons for discontinuation of HT were media reports and advices from healthcare providers. Lower in the list were the expected general reasons relevant to any medication – not needed anymore or suffering from adverse reactions (including undesired vaginal bleedings).

Commentary

Although the results of WHI should have been considered as reflecting the outcomes of HT initiated in women who, on average, were 65 years old or more than 10 years in menopause, they were extrapolated to all menopausal women. As well known, the consequences were much less initiation and much more discontinuation of HT all over the world. Exposure to the WHI data introduced real fear, both for women to use and physicians to recommend or prescribe HT. Higher risks for breast cancer in HT users probably became the main cause of worry among women. A telephone survey in the US, which investigated women’s perceptions about their greatest health concerns, showed that while more than a third pointed at breast cancer, only 8% regarded cardiovascular diseases as a problem [2]. It seems that the first announcements of WHI data, combined with wrong real-world insights about the commonest causes of morbidity and mortality in women, created this dramatic change in the use of postmenopausal hormones. Despite later analyses, which provided more accurate data on the impact of age or type of hormone use, mainly demonstrating favorable outcomes in younger women who use estrogen-alone therapy, the psychological impact of the initial results still prevails. I believe the quote from Manson and Kaunitz says it all [3]: “Women’s decisions regarding such therapy are now surrounded by anxiety and confusion. The new generation of medical graduates and primary care providers often lacks training and core competencies in management of menopausal symptoms and prescribing of hormonal treatments. Reluctance to treat menopausal symptoms has derailed and fragmented the clinical care of midlife women, creating a large and unnecessary burden of suffering”. Many reports compared the pre- versus post-WHI era regarding the use of HT, all showing a significant decline in prescriptions [4,5]. Some studies even demonstrated the downside of a lesser use of HT, primarily highlighting an increase in fracture rate [5]. The key for change lies in awareness and knowledge. Fortunately, many healthcare organizations and medical societies are putting efforts to promote unbiased information to both women and physicians. Updated guidelines and recommendations, as well as web-based education are now available for all. It is mandatory to put forward reassuring messages, such as that from NAMS that says, “For women aged younger than 60 years or who are within 10 years of menopause onset and have no contraindications, the benefit-risk ratio is most favorable for treatment of bothersome VMS and for those at elevated risk for bone loss or fracture” [6]. The big question is of course whether these educational measures will be effective. Marko & Simon phrased it nicely as follows: “If this is enough to change clinical practice, however, remains to be seen, given the general fear of HT by many with prescriptive authority, and also the women in our care” [7]. As leaders in the field of menopause and midlife women’s health it is our duty to disseminate the relevant knowledge to the public and the health providers.

26 February 2019: 

At the 16th World Congress on Menopause, held in Vancouver in 2018, a lecture on the ethical reporting of data addressed concerns related to the Conflicts Of Interest (COI) form provided by the International Committee of Medical Journal Editors (ICMJE). This form is used by many medical journals when manuscripts are submitted for publication. Currently, there exists a public funding exemption on the form. Under Instructions, (section 3), “Relevant financial activities outside the submitted work” the current document states “Public funding sources, such as government agencies, charitable foundations or academic institutions, need not be disclosed. For example, if a government agency sponsored a study in which you have been involved and drugs were provided by a pharmaceutical company, you need only list the pharmaceutical company.” Although it may have at one time been appropriate, it is now time for this exemption to be removed from the Instructions and from the ICMJE COI form. Indeed many present felt this exemption should be removed from all COI forms used in medical publishing. Accordingly, the editor, associate editors, and the editorial board of Climacteric supported an effort to seek to work with the ICMJE to remove the exemption. The executive director of NAMS, the NAMS executive board and the editor of Menopause also agreed to support this effort. A joint letter requesting this change to the ICMJE’s COI form was emailed to the ICMJE last summer and on February 16th we were notified by the ICMJE that they had agreed to the changes. They did note, however, that due to technical issues involved in changing the form and the associated investment, that there would be a delay in implementing the change. We will continue to follow the progress in ultimately having the changes to the ICMJE’s form implemented. We thank NAMS and ICMJE for their support of this proposal.

11 February 2019: 

Summary

The paper by Davis SR, et al. entitled “The benefits of adding metformin to tamoxifen to protect the endometrium—A randomized placebo-controlled trial” [1] looked at the effect of an insulin sensitizer, metformin, on the endometrium in post-menopausal women receiving tamoxifen treatment as adjuvant treatment of breast cancer. It is a single-center, randomized, double-blind, placebo-controlled, parallel group trial. A hundred and two women were randomized between metformin 850mg x 2/day, or placebo for 52 weeks. Before the inclusion, ultrasonography was performed to measure endometrial thickness (ET) and hysteroscopy and sampling were carried out if the thickness was >4mm or in case of any other abnormality. Fasting insulin and glucose were measured as well as HOMA-IR calculated. Endometrial histopathology at baseline was available for 28 women and did not show any case of hyperplasia; 15 women had an endometrial polyp, 1 woman had a proliferative endometrium and 1 woman, microglandular hyperplasia. Median age was 60 (42-75) years in the metformin group and 56 (43-72) years in the placebo group. Thirty-six of the 50 women randomized to metformin and 45 of the 51 women randomized to placebo had an ultrasound examination at 52 weeks. Endometrial thickness was significantly smaller in the metformin group: 2.3 mm (range 1.4-7.8) vs 3.0 mm (1.2-11.3) (P = 0.05); women on metformin lost more weight than those on placebo (P < 0.001) and had better HOMA-IR values (P<0.001). At the end of the study, 10 women had endometrial sampling, 3 in the metformin group and 7 in the placebo group. Apart from one woman under placebo who had an ET of 3.5 mm at baseline and an ET of 11.3 mm at 52 weeks, with disordered endometrial proliferation, no other woman showed signs of proliferation. In terms of tolerance, 9 women withdrew from the metformin group because of gastrointestinal intolerance.

Commentary

Tamoxifen use in post-menopausal women is associated with a 2-3-fold increase in the risk of endometrial cancer. It is also associated with an increased risk of development of polyps and myomas [2,3]. Prevention of benign uterine diseases is a matter of discussion. Levonorgestrel IUD has been evaluated with a proven benefit on polyp occurrence [4]. However, there are risks in using this IUD in women with breast cancer. Other therapies which can prevent the increased risk of benign uterine diseases and endometrial cancer due to tamoxifen are desirable. A thickening of the endometrium during tamoxifen is usually due to hypertrophy of the endometrium with cystic glandular dilatation but the glands remain atrophic. Hyperplasia remains a rare event during tamoxifen, the predominant benign disease being the polyp [2,3]. Insulin resistance can be associated with tamoxifen treatment and is a strong risk factor for endometrial cancer. The hypothesis raised in this paper is that decreasing insulin resistance can possibly prevent the increased risk of endometrial cancer. This study confirms that metformin treatment improves insulin resistance. There is no clear benefit however on the endometrial protection against cancer. The endometrial thickness was significantly lower with metformin and no proliferation was seen in any group. Increased thickness is either the hallmark of cystic glandular hypertrophy (without hyperplasia) or a polyp. This study of excellent design, including an initial accurate appraisal of the endometrium, does not demonstrate any clear benefit in prevention of benign or malignant endometrial disease. However, the decrease in insulin resistance is definitely auspicious in the course of breast cancer. A long-term study could demonstrate the benefit of metformin in prevention of endometrial cancer in women using tamoxifen. There are other ongoing trials on metformin benefits in breast cancer patients. Let us await the results.

Anne Gompel

Outstanding Professor of Gynecology-Endocrinology, Head of the Gynecology Endocrinology at Port Royal Cochin Hospital in Paris and Professor at University Paris Descartes

28 January, 2019: 

The International Menopause Society members extend their sincerest sympathy to the family of Dr Fernand Labrie who passed away this month.

Dr Labrie was a man with a great passion for science, who was prepared to challenge dogma. This resulted in his having a distinguished career, acknowledged by his many national and international awards including the Prince of Wales Award, the Medal of the Governor General of Canada, Officer of the Order of Canada and the Queen's Diamond Jubilee Medal. He has mentored many of our Society members through their careers, including present Board Members. I first met Fernand in 1995 at a DHEA meeting in Washington DC after which he invited me to a subsequent meeting in Quebec City. His belief in the importance of DHEA for postmenopausal women resulted in his founding Endoceutics in 2006 to progress DHEA as a treatment option. His determination resulted in a very successful program of clinical research that led to the approval of Prasterone for women in many countries. I recently spoke with Fernand at a Congress as he stood proudly by the Endoceutic’s stand. We chatted for a while about various things. I asked Fernand when he was planning to retire. He simply smiled and said “Never.”

21 January, 2019: 

Professor Tevfik Yoldemir is the Director of the Assisted Conception Unit and the Menopause Clinic at Marmara University, Istanbul. He is currently one of the Associate Editors of Climacteric.

I’ve been reading…

“21 Lessons for the 21st Century” by Yuval Noah Harari. The main theme is “Change is the only constant”. The book is like the SWOT analysis of existence of mankind on the market, in this scenario, the Earth. How biotech and infotech will shape the future jobs and communities, as well as the changes in policies of nations that enable them to stand up on the world stage are some of the points of view which are brought to the reader’s attention.

I’ve been researching...

three topics currently; each one is a survey I am conducting on infertile couples. The first one is on the impact of the service brand expansion on the corporate image and the consumer's attitude towards expansion- a hospital services model. The second study is aimed to investigate the expected and perceived service quality in patients receiving IVF treatment. The third project in progress is looking at the customer satisfaction and loyalty among patients in a university IVF program.

14 January 2019: 

Perimenopause marks the initiation of the transition into female reproductive senescence. It is well known that in general, the age at onset and duration of the menopause transition are associated with heritage on the one hand, but with many environmental, socioeconomic, lifestyle and other extrinsic factors on the other hand (1). Entering natural menopause at an early age carries potential long-term higher risks for chronic diseases, such as coronary heart disease and osteoporosis. Thus, prediction of the age at menopause might be important, allowing those with a forecast for premature or early menopause to be well prepared for such a scenario (2). What seems to be more challenging is whether we can manipulate the time sequence and delay menopause transition in women prone to early ovarian failure and the resultant rapid decline in estrogen production. The human genome, our basic genetic code, is largely static within an individual, yet chemical changes to the DNA and histone proteins may occur frequently as a result of what is defined as epigenetic alterations. This means that epigenomic deviations can result in changes to the structure of chromatin and to the function of the genome. To note, the epigenome can be dynamically altered by environmental conditions. A new study in rats claimed that understanding the hypothalamic neuroendocrine derangements which occur prior to the appearance of early signs of oocyte exhaustion could lead to the development of active interventions that will impact these complex mechanisms and delay the menopause by maintaining the normal hormonal milieu (3).

WHI observational study: Fracture risk in younger women using the Garvan and FRAX Risk Calculators without DXA-derived BMD

Fracture risk assessment after menopause is generally advised. The study [1] applied risk assessment by FRAX and Garvan to 63723 women, aged 50-64 years, in the WHI observational study to predict hip fractures and major osteoporotic fractures (MOF) during a 10-year follow-up and to compare it to actual incidental fractures. The specificity of both tools for detecting incident hip fracture was low: Garvan 30.6% (95% confidence interval [CI] 30.3–31.0%) and FRAX 43.1% (95% CI 42.7–43.5%). Both models discriminated poorly between postmenopausal women aged 50–64 years who do and do not experience hip fracture, MOF or clinical fractures during a 10-year follow-up. Specificity was even worse in women of African American and Hispanic ethnicity.

Comment

The need for fracture risk assessment at age 50-64 is widely accepted but the method remains controversial. The present study illustrated that FRAX and Garvan without DXA is insufficient. The authors conclude that additional risk factors should be explored. The obvious question is when DXA-derived BMD should be added. All major societies agree that it should be based on risk factors but the threshold for action is ill defined. IMS [2], NAMS [3], NOF (US) [4], and ACOG [5] regard the presence of two risk factors, in addition to being postmenopausal, as an indication for DXA. IOF recommends that risk be calculated by FRAX (without DXA) but provides no cut-off point.

The British Menopause Society (BMS) has recently released an updated consensus statement on Urogenital atrophy [1]. The statement highlights the prevalence of this distressing condition amongst the postmenopausal population and draws attention to the fact that symptoms often present many years after the menopause and consequently are not always recognized as estrogen-deficient in origin, either by women or their practitioners. The statement also reviews the prevalence and patho-etiology of urogenital atrophy, including the impact this has on the bladder, urethra, uterosacral ligaments and other supporting structures. This often results in a variety of urinary symptoms, in particular symptoms of ‘pseudo-cystitis’ and recurrent urinary tract infections. The key to successful management of these conditions is recognizing the role estrogen has in maintaining the integrity of these structures, and a course of vaginal estrogens will often lead to a dramatic improvement in symptoms. The impact that urogenital atrophy or vulvovaginal atrophy (VVA) can have on sexual function and a woman’s sense of sexual well-being is well established [2]. Equally, we also know that, in general, health professionals are very poor at enquiring about symptoms of urogenital atrophy [3], and this statement highlights the importance of specifically enquiring about symptoms of urogenital atrophy and sexual function as part of the routine consultation. The relationship between urogenital atrophy and sexual dysfunction is explored in more detail in the recent IMS White Paper [4]. It is well established that vaginal estrogens are the principal treatment for VVA, but this statement reminds us that being on systemic HRT is not in itself a guarantee that symptoms will improve and sometimes topical estrogens are required as well. It is quite safe to use standard vaginal and systemic estrogens together as the overall systemic absorption of vaginally administered estradiol and estriol is low. As well as a review of the current data on vaginal estrogens, the statement also has helpful sections on vaginal moisturizers and lubricants and reviews recent evidence for ospemifene, vaginal laser therapy and DHEA. The statement concludes with helpful practice points for clinicians and a comprehensive list of 44 references.

19 November 2018 

Summary

In October, a new analysis [1] based on the data of the prospective observational Women’s Health Initiative Study was published. The aim of this study was to evaluate relationships between weight change and subsequent breast cancer incidence, given that obesity is an established risk factor for postmenopausal breast cancer, but that the results of weight loss and breast cancer studies are inconsistent. Over 61,000 women with no prior breast cancer and normal mammogram were included and subjected to measurement of body weight, height and body mass index (BMI) at baseline and after 3 years. At screening, 32.4% of women were in the 50–59-year age group (n = 19,884), 44.9% were in the 60–69-year age group (n = 27,584) and 22.6% were in the 70–79-year age group (n = 13,867). Weight change was considered stable if it was < 5%, lost or gained if it was ≥ 5%. Self-reporting was used to determine whether the weight loss was intentional or unintentional. Incident invasive breast cancer diagnosed after the year 3 visit was the primary outcome. Participants were observed from the year 3 visit until breast cancer diagnosis, date of death, loss to follow-up or end of follow-up. In the women who lost weight, most weight loss was maintained through year 6. Weight loss was associated with a 12% risk reduction to develop breast cancer (HR 0.88; p = 0.02), with respect to stable weight. There were no interactions with BMI and with the intentionality of the weight loss. Weight gain, on the other hand, was not associated with breast cancer risk (HR 1.02; 95% CI 0.93–1.11) but was associated with higher triple-negative breast cancer (TNBC) incidence (HR 1.54; 95% CI 1.16–2.05). These results suggest that postmenopausal women who lose weight may reduce their breast cancer risk.