IMS Menopause Live

3 June 2019: 

Summary

In 2010 Bolland et al. published a small meta-analysis suggesting increased cardiovascular events among women randomized to calcium.[1] As the initial controversy escalated, driven by fears spread through the popular press, the New Zealand group obtained data from the WHI and published an analysis that they interpreted to show that, in women who were not taking calcium and vitamin D supplements when they were randomized, there were modest increases in cardiovascular events in those assigned to calcium and vitamin D compared to those randomized to placebo.[2] The WHI investigators published a paper attempting to replicate those findings using the same dataset; those analyses demonstrated no such hazards.[3,4] Now this group comes with a strategy similar to their initial run at calcium, combining a large number of mostly small studies into a meta-analysis. [5] They included 81 studies evaluating a range of vitamin D doses that addressed at least one of 3 outcomes: fractures, falls or bone mineral density (n of studies = 41, 37 and 41, respectively). Over two-thirds were of less than one year’s duration. The relative risk for total fracture was 1.0; 95% CI 0.93-1.07, for hip fracture 1.11; 0.97-1.26 and for falls 0.97; 0.93-1.02. Overall, the authors state “In meta-analysis of 81 randomised controlled trials, vitamin D supplementation did not affect incident fractures or falls, and did not have consistent clinically relevant effects on bone mineral density.“ They write that their results show “that there is reliable evidence that vitamin D supplementation does not have meaningful clinical benefits.”

27 May, 2019:

Summary

This publication from the WHI data evaluates the relationship of vasomotor symptoms (VMS) to breast cancer incidence and mortality [1]. It was observed that there was a statistically significant increase of breast cancer incidence in those women with persistent vasomotor symptoms compared to those without vasomotor symptoms HR 1.13 CI (1.02-1.27) yet no statistically significant impact on survival was noted (HR 1.33 CI 0.88-2.02). Vasomotor symptoms were assessed via a self-administered baseline questionnaire in 40 centres across the US to 161,808 women, ages 50-79, between 1993 and 1998. After applying exclusion criteria, such as use of hormone therapy, 25,499 postmenopausal women remained in the analytic sample. Duration of symptoms was determined by VMS history before baseline enrolment. “No vasomotor symptoms” was defined as “never experienced and none experienced over the last 4 weeks. “ Persistent VMS” included moderate or severe symptoms ever or within the 4 weeks before WHI entry. Breast cancers that developed during follow-up for 8.5 years were verified by review of medical records. Cause of death was ascertained via the National Death Index. Breast cancer incidence, mortality and the association with VMS were calculated using time dependent Cox regression analyses adjusted by breast cancer risk factors. 1,399 breast cancers occurred over 17.9 years of follow-up. 9,715 women with persistent VMS for 10+ years had a hazard ratio of 1.13 ( CI 1.02-1.27) for developing breast cancer compared to 15,784 women without VMS. ER - cancers, both regional and metastatic, occurred more frequently in patients with persistent symptoms. Although deaths from breast cancer were higher in the women with persistent VMS, this result was not statistically significant (HR 1.33 (CI 0.88-2.02)) [1].

22 May 2019: 

I’ve been reading…

“21 lectures for the XXI Century”, by Yuval Noah Harari. This is an interesting book which comments about the facts and challenges that new generations have to face. This book presents different points of view regarding the loss of jobs due to new artificial intelligence and other topics, such as immigration and the impact of global warming.

I’ve been researching…

into the development of new drugs for Osteoporosis and for type 2 Diabetes in phase III trials.

My team...

is working on continuing medical education in Endocrinology, Menopause and Osteoporosis. We have optimized National Guidelines on Menopause and Osteoporosis Management. We are now working on the National Recommendations for Calcium and Vitamin D therapy and on the validation of the FRAX score In coordination with the Minister of Health of Costa Rica.

An anecdote…

as the President of FLASCYM (Latin American Federation of Menopause Societies), I organized the IX FLASCYM Congress in Costa Rica, which took place from March 26th to 29th, 2019. After many months of effort we hosted 390 participants and got the collaboration of 47 speakers. We had a Precongress Practitioner Refresher Training course in Menopausal Medecine (IMPART), with 180 attendees, thanks to the great contribution of Professor Susan Davis, IMS President, and Dr. Nick Panay, Dr Camilo Rueda and myself as members of the IMS Board. We received excellent comments about the IMPART Program to the extent that various organizations in Latin America have expressed their interested in including a Precongress IMPART course as part of their local academic events.

An interesting case...

is that last week I received a 73-year old lady at my office, which had been taking oral MHT since her 50s. She had many questions about a mild plasma glucose increase, spongiform thyroid nodule with a biopsy indication, and oral/ transdemal MHT. She referred that each time that she had tried to stop MHT, sleep became disturbed and multiple daily episodes of intense vasomotor symptoms recurred. She had an excellent densitometry report, with normal t-score at her spine and mild low hip bone density. I just proposed some lifestyle modifications, such as more excercise and a reduction in carbohydrate and fat intake. Moreover I switched her MHT from oral to transdermal, recommended against the thyroid biopsy as it was not indicated and suggested a check-up after four months. This case makes me think about the need we have to support clinical care of older MHT users, based on scientific evidence.

I’m worried about...

the overpopulation of doctors in my country who have no work, after long years of study. This means that in order to survive economically, they leave aside their continuous medical update that is so important in our profession. I’ve been thinking... what the best way is to transfer knowledge in continuous medical education programs. We should probably prefer active clinical case discussion sessions to theoretical lectures.

In my spare time…

I love to cook and experiment with new recipes on Sundays during family lunch. I also like to organize family field trips to places far away from San José, capital of Costa Rica, to admire nature; we like to get up early in the morning to go bird-watching.

13 May 2019

Commentary on “Is there a role for mindfulness-based interventions (here defined as MBCT and MBSR) in facilitating optimal psychological adjustment in the menopause?” by Wendy Molefi-Youri.

Summary

As life expectancy increases worldwide, a growing number of menopausal women are facing psychological and physical symptoms. This calls for individualized patient care in view of unique bio-psycho-sociocultural and environmental factors and variation in ethnicity and access to care. Furthermore, the efficacy of various therapeutic interventions needs to be considered in view of the long-term adverse effects. Recently published, the overview by Wendy Molefi-Youri summarizes the literature of efficacy for mindfulness-based interventions (MBI). [1] The author explored the potential aetiology of distress during menopausal transition and paid attention to the mechanism by which mindfulness training facilitates optimal psychological adjustment during menopause and beyond. Although current available evidence is promising, considering these interventions in our clinical practice, the author raised reasonable practical questions: Would menopausal women be interested in engaging with these interventions? Are there any potential barriers? Would it be necessary to adapt the existing MBIs in order to meet the needs of this population?

Commentary

Women suffer from a cluster of symptoms during menopausal transition which adversely affect their overall quality of life. They often seek attention for non-hormonal treatment due to medications risks or personal preference or contraindications to menopausal hormone therapy (MHT). There is a need for psychological and behavioural interventions which can potentially mediate the reaction to menopause-related symptoms and increase resilience and coping skills. Many organizations have emphasized the need for a comprehensive multi-faceted approach to women’s needs which includes holistic interventions. [2,3,4,5]. Studies have suggested that reducing negative emotion such as anxiety, stress and depression, may help women make a smooth menopausal transition. Non-hormonal strategies for vasomotor symptoms include Mindfulness-based Stress Reduction (MBSR) [6,7]. Mindfulness-based training, i.e. a psychological intervention that targets perception and acceptance, may be a non-pharmaceutical alternative. Mindfulness-based cognitive therapy can also complement existing treatments for menopausal symptoms by teaching women self-compassion and thereby reducing distress. MBSR therapies consist of sitting and walking meditation, gentle yoga poses, and body awareness exercises such as body scan. The technique helps women pay attention to the present moment in a non-judgmental and accepting way. The resulting calming effect helps to relieve stress. Studies have indicated that MBIs are effective in mitigating menopausal symptoms. Although better understanding of the mechanism is needed, these interventions primarily affect the psychological aspects of the symptoms, by reducing the reactivity to stimuli and dampening the perceived severity of symptoms. Preliminary research has suggested a significant reduction in cortisol levels, which corelate with the stress response.[8]

22 April 2019: 

I’ve been reading…

The Gathering Storm by Winston Churchill; Churchill’s perspective on the events leading up to and into the second world war.

I’ve been researching…

pharmacologic approaches to relieving menopausal symptoms.

An anecdote…

you may wonder what governments and camels have in common. According to an old Saudi Arabian proverb, "if the camel once gets his nose in a tent, his body will soon follow”.

I’m worried about…

the illusion that government funded studies are not associated with conflicts of interest.

I’ve been thinking…

about approaches to treating conflicts of interest associated with journal publications equally regardless of the funding source of the research.

In my spare time…

I enjoy traveling to get together with friends around the world.

15 April 2019: 

Summary

Ablation of estrogen receptor alpha (ERα) in the medial basal hypothalamus results in a robust bone phenotype only in female mice that ends in exceptionally strong trabecular and cortical bones, the density of which surpasses that reported in other mouse models.

Commentary

The role of estrogens in regulating reproduction in females is known, but the role it plays in the brain remains uncharacterized. Estrogen works jointly with vitamin D and calcium to preserve the regulation of bone turnover. After menopause, as the levels of estrogen in the body decline, the rate at which bones are rebuilt increases and the skeleton begins to lose more mineral content than it produces. Central estrogen signaling coordinates energy expenditure, reproduction, and, in concert with peripheral estrogen, affects skeletal homeostasis in females. In this study, Herber and collegues ablated estrogen receptor alpha (ERα) in the medial basal hypothalamus and this action caused the mice to gain weight and become less active. To the authors’ surprise, the weight gain was due to an 800 percent increase in bone mass. Aside from an increased density, the bones of the animals also had an increase in strength. This increased strength and density did not falter as the mice aged,  leading to a robust bone phenotype only in female mice that resulted in exceptionally strong trabecular and cortical bones, the density of which surpassed that of other mouse models [1]. Stereotaxic-guided deletion of ERα in the arcuate nucleus increases bone mass in intact and ovariectomized females, underlining the central role of estrogen signaling in this sex-dependent bone phenotype. Loss of ERα in kisspeptin (Kiss1)-expressing cells is sufficient to recapitulate the bone phenotype, identifying Kiss1 neurons as a critical node in this strong neuroskeletal circuit. The precise neuronal or humoral signals that promote the high mass bone phenotype in females remain to be determined. However, this phenotype is independent of changes in leptin or estradiol and is not directly influenced by ERα neurons in the ventro-medial hypothalamus (VMH). These findings differ from prior reports linking leptin deficiency to high trabecular bone mass [2] via a circuit involving suppression of serotonergic signaling in the VMH [3] or direct effects of leptin on bone [4]. In conclusion, this study demonstrated that estrogen plays a different role in the blood than it does in the brain. In the blood, estrogen contributes to bone stability, while in the brain, estrogen seems to limit bone formation. This newly-identified female brain-to-bone pathway exists as a homeostatic regulator diverting calcium and energy stores from bone building when energetic demands are high. This study reveals a new target for treatment of osteoporosis.

8 April 2019: 

Commentary on "Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases" by Vinogradova Y, et al

Summary

It is well known that postmenopausal estrogen or hormone therapy improve vasomotor symptoms, vulvovaginal atrophy/genitourinary syndrome of menopause, prevent osteoporotic bone loss, and even enhance sexual function. However, since the publication of the initial clinical trial results of the Women’s Health Initiative E+P trial in 2002, use of both estrogen and hormone therapy has decreased despite these benefits. This phenomenon occurred largely due to a shift in focus from the benefits of hormone therapy to the risks of these treatments. Paramount among these risks are the potential for estrogen with or without progestogen to increase deep vein thrombosis and thromboembolism (VTE). While randomized clinical trial information comparing oral vs transdermal or non-oral regimens is lacking, observational studies like this one, demonstrate a reduced risk for DVT and PE with transdermal or non-oral treatments [1]. Risks with such non-oral approaches are comparable to non-users of estrogen therapy even in women with prior thrombotic event histories and obesity, independent risks for thrombosis and thromboembolism [2, 3 for review]. This retrospective analysis by Vinogradova and colleagues consisted of approximately 80,000 women with VTEs compared with about 390,000 non-VTE controls from the QResearch and CPRD databases. The authors found no added risk for VTE associated with estradiol patches, gels, or subcutaneous formulations (adjusted odds ratio: 0.93, 95% CI 0.87-1.01). In contrast, oral estrogen therapy was associated with a significantly increased risk for VTE (adjusted OR 1.58, 95% CI 1.52-1.64). This increased risk remained significant for both estrogen oral preparations (aOR 1.40, 95% CI 1.32-1.48), as well as estrogen+progestogen oral combinations (aOR 1.73, 95% CI 1.65-1.81). Other database reviews document similar findings [4] Further, Vinogradova and colleagues found the risks of VTE with oral conjugated equine estrogens(CEE) or combined formulas of CEE and a progestogen were higher than oral estradiol therapies (aOR 0.85, 95% CI 0.76-0.95; aOR 0.83, 95% CI 0.76-0.91, respectively) and nearly double the VTE risk of women non-users (aOR 2.10, 95% CI 1.92-2.31). Taken together these findings support prior studies documenting the higher procoagulant and thrombotic risks of CEE compared with oral estradiol [5]. Estradiol combined with dydrogesterone, a formulation not available in the US, showed a slightly elevated VTE risk compared to non-users, but the lowest of the combined oral formulations (aOR 1.18, 95% CI 0.98-1.42).

Commentary

In this study, more than half of the women with VTEs were ≥65 years of age, and were more likely to have additional comorbidities (cancer, heart disease) versus controls (56% vs 36%). Women with VTE also were more likely than controls to have recent medical problems (27% vs 12%), such as respiratory or urinary tract infections, hip fractures, or surgery with or without hospital admission, or hospital admission for other reasons. These events may have added immobilization to their inherent risks.

25 March 2019: 

Summary

Ovarian cryopreservation and retransplantation for fertility protection is well established in Europe, but not in China or other Asian countries. Four recent publications [1-4] stress that this technique is no longer experimental and should be regarded as a valid ART treatment option especially for some cancer types. However, this technique is not only performed to restore fertility but also to restore ovarian function after surgery, radiotherapy and chemotherapy. China's first official "International Center of Fertility Protection Specialized in Ovarian Tissue Cryopreservation and Transplantation" was established in 2012 within the Beijing Obstetrics and Gynecology Hospital, Capital Medical University, with the help of European experts. In 2016 the first retransplantation of cryopreserved ovarian tissue was performed, and has recently been published as a "case report" [5]. The cryopreservation and transplantation was performed to preserve ovarian function in a patient with squamous cell cervical carcinoma I b1 after surgery. The 35-year-old nulliparous patient came in June 2015 for consultation. During cervical cancer surgery half of her left ovary was removed and transferred to the cryobank. Ovarian cortical strips were frozen using a standardized slow-freezing process and stored in liquid nitrogen. Following 19 cycles of radiotherapy and 3 cycles of chemotherapy, between August 2015 and October 2015, severe menopausal symptoms appeared (estradiol (E2) about 30 pg/ml, FSH > 100 IU/l); these were treated with E2 patches 50µg/day until August 2016 (E2 about 90 pg/ml, FSH about 50 IU/l). After oncologists confirmed a disease-free condition, the cryopreserved-thawed ovarian tissue retransplantation was performed in September 2016. Thawing of the cortical strips was performed using a standardized protocol and four ovarian tissue fragments were transplantated into a peritoneal pocket in the area of the right peritoneal ovarian fossa. Restoration of ovarian endocrine function was shown in the third month after transplantation, accompanied by a significant reduction in Kupperman score from 37 before transplantation to 5 in the first month after transplantation. The score subsequently remained low and stable.

Commentary

Cryopreserved-thawed ovarian tissue is mainly transplanted orthotopically (i.e. into the peritoneum, into or onto the ovary) [6]. However, in some cases retransplantation is also performed in heterotopic sites, and one pregnancy has been reported worldwide [7]. In our case, the tissue fragments were retransplanted into a peritoneal pocket lateral to the right ovary where the blood supply was proved to be rich. The same approach has been used in most cases of retransplantation in 16 European centres, and has resulted in high success rates and may be an alternative to transplantation into the ovary [8]. The first signs of ovarian activity usually occur after 3 months based on the time of follicular growth, and most patients recuperate ovulatory cycles within 4-9 months after retransplantation [8]. This case may be  very "normal" for other countries, especially in Europe, where ovarian tissue preservation was introduced years ago but, for China, this first report of successful retransplantation represents a milestone in the field of fertility preservation, although until now no live birth has been reported. Worldwide this technique has lead to more than 130 live births were reported until June 2017, and restoration of ovarian activity in over 95% of cases [2]. No frozen-thawed ovarian tissue retransplantation has been previously reported in China, and, to our knowledge, the center in the Beijing OB/GYN Hospital is still the only one to have performed this technique, although other large hospitals in China have been showing a growing interest in establishing a cryobank and performing ovarian preservation and retransplantation. This large interest finds its expression in the "First Chinese Guideline of Ovarian Tissue Cryopreservation and Transplantation" [9]. With regards to the medical content, the consensus is very similar to Western guidelines but with a focus on practical issues joining gynecologists, embryologists, oncologists, pediatricians, breast oncologists, hematologists and experts in Traditional Chinese Medicine (TCM). The guideline includes: selection criteria, evaluation and indications, standard operating procedures of ovarian tissue removal, transportation, preparation, freezing and thawing, approaches to ovarian tissue transplantation and follow-up, practical recommendations for ovarian tissue cryopreservation and transplantation including recommendations of the diseases for which this method could be applied, and treatment of menopausal symptoms during the time between cryopreservation and retransplantation. In our center, currently, the ovarian tissue of more than 200 patients has been cryopreserved and six other patients have undergone successful retransplantation. To understand the importance of China's first center the special situation of fertility protection in China must be considered. Until 2016 China (with some exceptions in the countryside) was officially ruled under the "One-Child-Policy", without much support to the introduction of new techniques in the field of fertility protection.

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.