A comment on Climacteric Editor’s Choice "Sexual quality of life in men and women after cancer" by L. R. Schover

Summary

There is a global agreement about the fact that cancers and cancer therapies have a negative impact on the sexual health of men and women with prevalence rates on average of 50-60%. There is also global agreement that patients are very often left alone with their sexual problems and that there is not adequate care. In this review [1], the physical and psychosocial consequences of cancers and cancer treatment on the sexual life of male and female patients are summarized. The barriers and gaps are described. Lack of information and counseling during oncological care, reluctance of patients to bring up sexual issues in a medical environment, lack of training of oncological professionals, lack of time, lack of education material, non-familiarity with the variety of sexual orientations and preferences, focusing on heterosexual penetrative intercourse, etc.. The review [1] describes the short history of initiatives in the US to respond to these barriers and gaps. The National Comprehensive Cancer Network (NCCN) issued guidelines (2019 ()), ASCO also issued a guideline in 2017 () with some agreement on the basic requirements. The cancer team should initiate discussion about sexuality and provide follow-up visits with the possibility to refer to multidisciplinary treatment.

Summary

The ESTEEM trial (Effects of Surgical Treatment Enhanced with Exercise for Mixed Urinary Incontinence) was published in JAMA earlier this year [1]. This is a randomized controlled trial of women with moderate to severe mixed urinary incontinence (both stress and urge) who underwent mid-urethral sling surgery. One group was given behavioral and pelvic floor muscle therapy for 1 session pre-operatively and five sessions post-operatively. The second group just underwent surgery with no other specific intervention. The primary outcome measure was a change in Urinary Incontinence (UI) symptoms at 12 months as assessed by the Uro-genital Distress Inventory (UDI) score (maximum 300), which is a validated tool for this type of analysis. Four hundred eighty women were randomized across nine sites in the US. In the combined group, the UDI score fell from 178 to 30.7 (mean change - 128 points), and in the surgery only group, the score dropped from 176.8 to 34.5 (mean change -114.7 points). Both groups significantly reduced the UDI score. The difference between the two groups just reached significance (p = 0.04), but this did not meet the pre-specified threshold for clinical importance (35 points). The difference between the two groups was noted primarily in the irritative component of the UDI score, whereas there was little difference in the stress component. Episodes of urge incontinence were reduced in the combined group, and this group was significantly less likely to need additional treatment for lower urinary tract symptoms (8.5% vs. 15.7% OR 0.47 95% CI 0.26-0.85). Adverse events occurred in 10.2% of participants. The authors concluded that amongst women with moderate to severe mixed urinary incontinence combined behavioral and pelvic floor muscle therapy resulted in a reduction in urinary incontinence symptoms, which may not be of clinical importance.

Summary

A recent study by Chen et al. (1) analyzed a sample of 2,683 postmenopausal women from the Women’s Health Initiative (WHI) cohort, with normal body mass index (BMI; 18.5 to <25 kg/m2), no known cardiovascular disease (CVD), and for whom data was available on body composition, as determined by dual-energy X-ray absorptiometry (DXA). After a median follow-up of 17.9 years, there were 291 cases of CVD (coronary heart disease [CHD], stroke, or the combination of both). After adjusting for confounding factors (i.e., demographics, lifestyle, clinical factors), neither whole-body fat mass nor fat percentage was found to be related to CVD risk. Higher percent trunk fat and leg fat were associated with an increased and decreased risk of CVD, respectively. The association of trunk fat with CVD risk was attenuated but remained significant even after adjusting for waist circumference or waist-to-hip ratio. A combination of higher trunk and lower leg fat was linked to a higher CVD risk. The authors concluded that, in postmenopausal women with normal BMI, both elevated trunk and reduced leg fat increase the risk of CVD.

Summary

The WHI studies (both the clinical and the observational) have provided a wide arrow of information on many aspects of menopause and hormone therapy. A new WHI release, which included a subset of women enrolled in the WHI trials, correlates DNA-derived data with sleep (1). While it is difficult to put into the format of Menopause Live all the details of this study, here are the main features: 1796 European Americans, 1349 Afro Americans, mean age 64. Blood samples from the participants at entry allowed extraction of leucocyte DNA and determining the telomere length (TL). Sleep duration was recorded through a questionnaire, asking women to disclose their normal sleep duration (in round hours) and the degree of sleep disturbance (using the WHI Insomnia Rating Scale). As part of the WHI study protocol, many other demographic, clinical and laboratory variables a ; some were used in the statistical evaluation and adjustments of the current main study data. The bottom-line results can be summarized as follows: mean TL was 214-base-pairs longer in Afro Americans than in European Americans; each 1-year increase in age was associated with 23-base-pair shorter TL, on average; each additional daily hour of sleep beyond 5 hours, approximately, was associated with a 27-base-pair longer TL in the entire sample.

Commentary

A telomere is a nucleoprotein complex found in the extremes of the chromosomes, where its structure is different from the rest of the chromatin since it contains non-coding DNA. The role of the telomeres is to hinder the loss of important DNA from chromosome ends during replication. Short leukocyte TL is associated with increased risks of mortality, cardiovascular disease, diabetes, Alzheimer's disease and probably with cancer as well.

a comment on Climacteric Editor’s Choice 

“Safety of hormone replacement therapy following risk-reducing salpingo-oophorectomy: systematic review of literature and guidelines” by RFM Vermeulen et al.

Summary

Risk-reducing bilateral salpingo-oophorectomy (RRBSO), is the gold standard preventive method to avoid ovarian cancer in women at increased risk. However, by choosing this option, a significant number of women end up with premature iatrogenic surgical menopause with several unwanted health effects. Although hormone (HT) is the only effective strategy to compensate significantly for the hormonal deprivation, there are concerns about the safety of HT in these women with regards to breast cancer (BC) and this is an ongoing challenge for clinicians. Hence, it is important to bridge the gap between risk perception and HT prescription with evidence-based clear advice on HT for women considering RRBSO. The recent publication by Vermeulen et al. is a review of seven articles and 11 National guidelines, which recognized that the short-term use of HT following RRBSO is safe in BRCA1 and BRCA2 mutation carriers [1]. The literature is more reassuring regarding the use of estrogen alone than of combined preparations, however, the use of progestogens cannot be avoided in women with uterus preservation in order to achieve endometrial protection. The evidence for HT safety in premenopausal women without a personal history of BC who undergo RRBSO is scarce. The authors advocate that these subsets of women with prematurely induced menopause need to be counseled for shared decision making on the ideal dose and duration of HT, using the best available information on safety and efficacy.

Commentary

Women carrying a BRCA mutation have an increased risk of developing breast and ovarian cancer [2] In the absence of robust screening tools, prophylactic surgical removal of the adnexa is the current key strategy to reduce the burden of ovarian cancer in BRCA1/2 carriers [3]. The bilateral salpingo-oophorectomy, with or without the additional risk-reducing mastectomy, reduces the risk of ovarian cancer by 80- 96% and breast cancer up to 50%. [4,5] Sixty-five percent of women will opt for RRBSO; women carrying a BRCA 1 mutation will undergo the procedure between 35 and 40 years of age, those with a BRCA1 and BRCA2 mutation, between 40 and 45 years and those with a RAD1C/1D mutation, between 40 and 50 years of age.[6] There is growing evidence from observational studies that RRBSO has a detrimental impact on the quality of life, longevity and on all-cause non-survival endpoints in these women, in particular in those carrying a BRCA1 mutation, who are likely to have surgery earlier than those carrying a BRCA2 mutation.[7]

a comment on Climacteric Editor's Choice "Benefit-risk profile of black cohosh (isopropanolic Cimicifuga racemosa extract) with and without St John’s wort in breast cancer"

Summary

Breast cancer patients treated with endocrine therapies can suffer severe climacteric vasomotor and psychological symptoms as a consequence of the anti-estrogenic effects; hence, treatment adherence can be compromised. To determine if these symptoms can be treated with specific herbal medications, the authors of the present paper reviewed the benefit-risk profile of a standardized extract of isopropanol Cimicifuga racemosa (iCR) REMIFEMIN®, and a higher dose iCR preparation in a fixed combination with Hypericum perforatum (HP/iCR) REMIFEMIN PLUS®, in women surviving breast cancer, treated or not with tamoxifen (TMX) or aromatase inhibitors. The review is based on a systematic literature search (1997 - April 2018) analyzing clinical studies in breast cancer patients, as well as experimental data on biological effects in breast cancer cells, in animal models of breast cancer, in human breast cancer tissue, and studies on the metabolism of endocrine therapies. The authors concluded that there is a favorable benefit/risk profile of both herbal medicinal products, that could offer a non-hormonal therapeutic option for these women [1].

Commentary

Knowledge of the efficacy and safety of phytopharmaceutical treatment options for climacteric symptoms is much needed, especially for women undergoing endocrine treatment for breast cancer. Ruan and colleagues analyzed data on Remifemin® (iCR) and Remifemim Plus® (HP/iCR), standardized registered phytopharmaceuticals produced in Germany by Schaper & Brümmer GmbH–Co.KG, with certified quality of manufacturing [1]. These specific extracts were already reviewed in 2013, with results distinguishing them from other CR preparations [2]. In 2012, a Cochrane Systematic Review had concluded that there was insufficient evidence to support the use of black cohosh for menopausal symptoms [3]. However, a later review reported a significant efficacy of black cohosh on vasomotor symptoms and on psychological climacteric symptoms [2]; this review was based on 9 clinical studies, of which two were double-blinded placebo-controlled (Remifemin® (n=304 women 12-week duration), and Remifemin Plus® (n=301 and 16-week duration)), another was blinded versus tibolone, and the others were open versus low-dose transdermal estradiol. Ruan and colleagues state this is Oxford Level 1 evidence of efficacy [1].

Mrs. X is 50 years old and recently postmenopausal, having had her last menstrual period a year ago. She laments climacteric symptoms and asks about the risks and benefits of menopausal hormone therapy (MHT). During the consultation, she refers that she has been affected by Systemic Lupus Erythematosus (SLE) since the age of 38 years. She has no other health problem. Mrs. X experienced a miscarriage at the age of 24 years and then had a live birth at the age of 25. The pregnancy was uneventful. In her family, there is no history of breast or ovarian cancer; her father has had type 2 diabetes since the age of 6O, with some vascular complications, and her mother suffers from hypertension and hypercholesterolemia. Her first SLE flare occurred at the age of 37 years and presented with fatigue, joint pains, hair loss and skin lesions especially on the face and the upper thorax. She first consulted her general practitioner who prescribed some tests and suspected SLE. She was sent to a specialist who confirmed the diagnosis based on clinical and biological criteria; arthritis, skin lesions, alopecia, fatigue and an increase in c-reactive protein, discrete leukopenia, a decrease in total complement levels and positive anti-DNA and anti-smooth muscle antibodies. She underwent a series of tests that excluded kidney, brain, heart or lung involvement and antiphospholipid antibodies. It was concluded therefore that Mrs. X had cutaneous articular SLE. She took hydroxychloroquine for 10 years but had to stop it. She has had several flares over the years with increasing involvement of joints but of no other sites. She has taken corticosteroids 3 times for short periods. She is currently without treatment and her last flare occurred more than 5 years ago.

How will we answer her question on the benefits and risks of MHT? [for details see reference 1]

SLE is an autoimmune disease that can be worsened by estrogens. Before puberty and after menopause, the female: male ratio is about 2-3:1, whereas, during childbearing age, this ratio reaches 10-13:1. Genetic factors linked to chromosome X are also associated with the prevalence in women. In 30% of the cases, SLE antiphospholipid antibodies or lupus anticoagulant (APL) may be present. SLE is associated with an increase in cardiovascular disease and osteoporosis at a young age. The frequency of cardiovascular events is proportional to the duration of SLE and associated with renal involvement.

I’ve been reading...

The Broken Eye, by Brent Weeks, described as ' epic fantasy'; I have been reading the series. I usually start during my summer holidays, which unfortunately end too soon, and then I tend to finish the books when I am in the midst of plane travel!

I’ve been researching...

Entertainment options for our international visitors who are coming to the IMS Congress in Melbourne in late April 2020. I am hoping that a large fluffy koala or kangaroo may be involved somehow.....

My team...

I am a member of a few teams! These are The ˛ÝÝ®ĘÓƵ, The Women's Health Research Program at Monash University, and Jean Hailes for Women's Health. I am incredibly lucky to work with people who are passionate about women's health and education and work hard to get evidence-based health information out to both the community and health practitioners.

An anecdote...

If you come to Melbourne to the IMS Congress  next year by plane you may see kangaroos greeting you from within the paddocks (fields) not far from the airport. There are quite a number of them and, apart from being there to welcome you, they are sometimes found hopping around the airport car-park. This is not supposed to happen but never fails to make it onto the nightly TV news bulletin. If you don't see one when you travel from Melbourne airport next year I am still working on the large variety discussed in question 2, as part of the entertainment program!

An interesting case...

One of my patients today described being exceptionally tired some months ago in the setting of having a several months old infant, who was fully breastfed. She thought the lethargy was out of context as she was otherwise managing everything quite well. She then presented to her doctor recently as she felt something moving in her abdomen. Yes, she is having another baby and didn't quite notice until she had reached the second trimester.

I’m worried about...

Being in a world in which it seems that people no longer try to look out for each other.

I’ve been thinking...

About the IMS Congress in Melbourne  next year, of course! I can't wait. It's going to be amazing. (Don't forget!)

Summary

Recent publications have shown that estrogens and vitamin D have a synergistic effect, not only on bone health but also on insulin resistance and metabolic syndrome [1,2,3]. Underlying mechanisms for these associations are not clear and several possible explanations have been suggested. Vitamin D may have an insulinotropic effect by increasing intracellular calcium concentration in pancreatic beta-cells. Vitamin D may also act as an inhibitor of sterol regulatory element-binding proteins activation, thus controlling lipid homeostasis. Finally, vitamin D levels affect the nitric oxide signaling pathway in the arterial muscle, leading to an abnormal vasodilator activity [2,4,5]. Clinical trials have also reported that vitamin D supplementation may reduce visceral adipose tissue in overweight or obese adults [6].

Hui Huang and his group carried out an observational and cross-sectional study [7], evaluating 616 postmenopausal women (aged 49-86 y) from southern China, who were not taking estrogen and vitamin D or calcium supplements, to assess the role of vitamin D levels in relation to metabolic syndrome and estradiol (E2) levels. The participants were classified into two groups based on vitamin D levels (25(OH)D < or ≥ 50 nmol/L). In participants with optimal serum levels of vitamin D (≥ 50 nmol/L), there was no significant correlation between estradiol and metabolic syndrome, after adjusting for confounding factors. In the other group of women,  the adjusted odds ratio (OR) for metabolic syndrome significantly increased with decreasing serum 25(OH)D (OR 2.19, 95% CI, 1.19-4.01 for comparisons of vitamin D deficient versus sufficient; P for trend 0.009). This association remained unchanged after further adjusting for estrogen levels. Postmenopausal women who were vitamin D deficient presented a negative correlation between estradiol levels and metabolic syndrome risk (OR 3.49, 95% CI, 1.45-8.05 for the lowest versus the highest tertile; P for trend 0.006). The present study observed that vitamin D deficiency is an independent risk factor for metabolic syndrome in postmenopausal women. Moreover, the authors observed an inverse association between estradiol levels and metabolic syndrome, which tends to be stronger in participants with vitamin D deficiency than in those with adequate circulating levels of the vitamin.

Commentary

The risk of cardiovascular disease increases after menopause and may be related to the substantial metabolic changes that take place as women transition from premenopause to postmenopause. The prevalence of metabolic syndrome increases with age. Many cross-sectional studies have shown an increased risk of metabolic syndrome in postmenopausal women, which varies from 32.6% to 41.5% [8,9]. In medical literature, observational studies suggest that vitamin D plays a role in the pathogenesis of type 2 diabetes [10]. However, the results of intervention studies have been inconsistent [11, 12]. This observational study emphasizes the possible synergistic role of vitamin D and estradiol deficiency in causing metabolic syndrome in postmenopausal women. If these results are confirmed in randomized controlled trials, correction of inappropriate levels of vitamin D may become widespread in clinical practice, not only to preserve bone but reduce the manifestations of the metabolic syndrome and its consequences.

IMS Collaboration with the 11th International Congress on Menopause and Gynecological Endocrinology
Beijing, China, September 6th - 8th 2019

IMS current Board Member Professor Xiangyan Ruan and past Board Member Professor Alfred O.Mueck recently chaired the "11th International Congress on Menopause and Gynecological Endocrinology" in Beijing from September 6th - 8th, 2019. The congress was sponsored by the Beijing Obstetrics and Gynecology Hospital, Capital Medical University in collaboration with the following societies: International Menopause Society (IMS), International Society of Gynecological Endocrinology (ISGE), Chinese Society of Gynecological Endocrinology affiliated to ISGE (CSGE), European Menopause and Andropause Society (EMAS), European Society of Gynecology (ESG), International Academy of Human Reproduction, Chinese-German Society of Obstetrics and Gynecology, German Menopause Society, German Society of Gynecology and Reproductive Medicine, German Society of Endoscopy, German Society of Endometriosis, European Society of Endometriosis, Osteoporosis Society of China Association of Gerontology and Geriatrics (OSCAGG) and Beijing Obstetrics and Gynecology Society of Endocrinology.

Twenty-three speakers from all over the world attended this congress with an audience of 500 participants. Most of the members of the audience were experts in the field of Gynecological Endocrinology in large hospitals coming from the Beijing Region and from all over China. The event was considered the highest-ranking international congress in China to date in this field of medicine. Eight international speakers are presently visiting professors at the Beijing Obstetrics and Gynecology Hospital, Capital Medical University, China. During the Congress, there were outstanding lectures from the Chinese speakers on special diseases like PCOS, POI, endometriosis and hyperprolactinemia, bleeding problems (AUB), endometrial abnormalities, sexual disorders, pregnancy and offspring health, ART, diagnosis, and treatment of fertility problems. There were several lectures from Chinese and international experts on fertility preservation, especially ovarian cryopreservation, a technique that was implemented in China for the first time by the Beijing Obstetrics and Gynecology Hospital. 

The following lectures were presented by current members of the IMS:

• "IMS Guidelines for Menopausal H Professor Ruan’s team for their ongoing effort in translating abstracts into Chinese for CLIMACTERIC. This has encouraged submissions on behalf of Chinese researchers to the journal such that, at present 21% of the papers are published by Chinese scholars.

• ormone Therapy" by current IMS President Professor Susan Davis  

• "Treatment Options for Vaginal Atrophy" by IMS Past President Professor Andrea Riccardo Genazzani

• "POI: Cancer Survivorship - Mitigating (reducing) the Consequences of Iatrogenic POI" by IMS General Secretary and Past Editor-in-Chief of CLIMACTERIC, Professor Nick Panay

• "The different methods of fertility protection in cancer patients" by Professor Sven Skouby  

• "IMS IMPART", a presentation of the IMS internet-based educational program for students and doctors, by Professor Rod Baber, Immediate Past President of IMS and Editor in Chief of the SCI-journal CLIMACTERIC 

• "Prevention and Treatment of Osteoporosis in Peri-and Postmenopausal women" and "Tibolone as Special Option for Treatment of Postmenopausal Patients" by past IMS Board Member and current ISGE Treasurer, Professor Martin Birkhaeuser 

• "Management of PCOS" and "The first Chinese POI database cooperated with the Royal College and prevention and treatment of iatrogenic POI: the first Chinese guideline on ovarian tissue cryopreservation and transplantation"  by Professor Xiangyan Ruan 

• "Breast cancer and MHT", a presentation discussing the carcinogenic mechanism in breast cancer development based on experimental data and clinical data, including that of the very recent publication in The Lancet, by Professor Alfred O. Mueck.

• A number of other excellent lectures were delivered, including that of Professor Thomas Rabe on "Amenorrhoea - etiology, diagnosis, and therapy". Professor Rabe is well known and appreciated in China because his ancestry; his grandfather, John Rabe, saved thousands of Chinese during the Second World War from the Japanese Nanjing Massacre.

All lectures were well received by enthusiastic audiences.

Cardiovascular changes during nocturnal hot flushes

Summary

Baker et al (1) have recently investigated cardiovascular changes that occur with nocturnal hot flushes during sleep. They investigated changes in heart rate, blood pressure, and pre-ejection period in 86 women aged between 43-60 years who had at least one objectively-recorded nocturnal hot flush during an overnight laboratory PSG recording. Fifty-one percent of the nocturnal hot flushes were associated with arousals/awakenings and these were accompanied by an increase in systolic (~6 mmHg) and diastolic (~5mmHg) blood pressure and heart rate (~20% increase), sustained for several minutes. In contrast, nocturnal hot flushes not resulting in arousal/awakening, which occurred in 28.6% cases, were accompanied by a drop in systolic blood pressure and a marginal increase in heart rate, likely components of the heat dissipation response. All nocturnal hot flushes were accompanied by decreased pre-ejection period, suggesting an increased cardiac sympathetic activity, with a prolonged increase for nocturnal hot flushes associated with arousals/awakenings. Older age predicted greater likelihood of nocturnal hot flush arousals/awakening.

Commentary

The findings of this study suggest that nocturnal hot flushes associated with arousals/awakenings, which are in the majority and more likely in older women, lead to increases in heart rate and blood pressure, which could have a long-term impact on nocturnal cardiovascular restoration in women with multiple nocturnal hot flushes. Sleep is not a passive event, but rather an active process involving characteristic physiological changes that occur throughout the body(2). There are a variety of physiological and behavioral changes during normal wakefulness, NREM and REM sleep which are most commonly noted in the somatic and autonomic nervous system and affect the respiratory, cardiovascular, gastrointestinal, endocrine, renal, sexual and thermoregulatory systems. Heart rate, blood pressure, cardiac output, and peripheral vascular resistance decrease during NREM sleep and decrease further in REM sleep.

Summary

The REPLENISH trial was a phase 3, randomized, double-blind, placebo-controlled, multicenter study, in postmenopausal women with a uterus, evaluating a new form of menopausal hormone therapy (MHT). Capsules containing estradiol plus progesterone (E2/P4) with four different dosages (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, and 0.25 mg/50 mg) were tested. The primary endpoints were the efficacy to treat vasomotor symptoms within a three months substudy and the proof of endometrial safety after 12 months treatment. The positive results of these two primary trial endpoints have already been reported [1]. The REPLENISH trial also tested the changes in cardiometabolic parameters during treatment with these oral E2/P4 formulations in comparison to placebo, as recently published in "Climacteric", the official journal of the International Menopause Society [2]. One thousand six hundred eighty-four postmenopausal women received one of the four E2/P4 doses (1 mg/100mg [n=415], 0.5 mg/100mg [n=424], 0.5 mg/50mg [n=421], 0.25 mg/ 50mg [n=424]), and 151 women received placebo. Participants’ mean age was 54.6 years (range: 40–66 years) and mean body mass index was 26.7 kg/m2 (range:14.0–34.5 kg/m2); most were white (65.4%) or African American (32.1%). Changes in lipid and coagulation parameters and blood glucose from baseline at 6, 9, and 12 months were assessed. Minimal increases of potential clinical importance were observed in total cholesterol, triglycerides, and glucose at month 12 with E2/P4 (1–4%, 6–11%, and 1%, respectively) and placebo (3%, 7%, and 2%, respectively). Overall no clinically significant changes in lipid parameters, coagulation factors or glucose were seen between the treatment groups.

Commentary

From the evaluation of the cardiometabolic parameters in the REPLENISH study, it can be concluded that oral E2/P4 combinations are neutral on lipid and glucose metabolism and on the coagulation system. This is the result of a study using the prospective, placebo-controlled "golden standard design". Total cholesterol, HDL, LDL, triglycerides were assessed, as well as glucose; these parameters are  widely used in clinical practice to screen for cardiovascular risks. Measured coagulation factors included prothrombin time, activated partial thromboplastin time (aPTT), fibrinogen, protein C (factor XIV), protein S, antithrombin III, and factor V Leiden. These parameters are also widely assessed in other studies investigating changes in hemostatis under MHT. Changes in fasting lipids and glucose levels were not significant and these parameters remained within normal ranges. In contrast, negative changes in lipid and glucose metabolism have been seen in a variety of studies using oral estrogens combined with synthetic progestogens; oral formulations have often induced hypercoagulability and other negative vascular (e.g. vasoconstrictory) effects [3-6]. Only five women discontinued the study because of changes in lipids or coagulation factors, reported as adverse events [2].

Systematic reviews and meta-analyses are increasingly popular since they provide the best and most reliable unbiased analysis of the existing evidence, which is essential for evidence-based clinical practice. Different approaches and techniques are commonly used to generate this evidence. Understanding the benefits and limitations of these techniques is essential when interpreting the results of a meta-analysis. Riley et al. published an important methodological article in the British Medical Journal [1] that precisely explained two important approaches used in meta-analyses: the fixed effects and random effects models, and when each should be used. They also introduced the concept of the prediction interval (PI) which will be increasingly used in meta-analyses studies. They explained the difference between the confidence interval (CI) and the PI and their applications and interpretations in evidence-based clinical practice. They explained why a PI could provide a more complete summary of the clinical implications of the findings of a meta-analysis that is generally provided by a CI. In meta-analyses, fixed effects models assume that the true effect of treatment for each study included in the meta-analysis is the same or fixed. In other words, there is no between-study difference or heterogeneity in the true treatment effect (assessed by a statistical analysis called the I²) [2]. The differences seen between studies in a fixed effect model are due to random or chance variations in sampling, such that if all studies had a large (infinite) sample size, the differences in study estimates would vanish. On the other hand, the random effects models allow for real differences (heterogeneity) in the treatment effect from study to study. So, the observed estimates of treatment effect can vary between studies because of real differences due to both random and non-random variation. Sources of heterogeneity could include differences in study populations (e.g. age of patients), interventions received (e.g. dose of drug), follow-up length etc. as well as sample size [1, 3]. In meta-analyses, when data are pooled and analysed using random effects models, it is standard to report a CI around the effect estimate. However, when heterogeneity is large, some authors have proposed reporting a PI along with a CI to have a better appreciation of the uncertainty around the effect estimate [1, 4]. The PI, used in this way, is a relatively new concept. The CI and PI are not the same thing. A CI is a range of values, which indicates the degree of uncertainty about a population parameter, for example, the mean blood pressure of a population. A PI, on the other hand, is the interval within which you would expect a future mean value of blood pressure to fall in a new research study.

Putting theory into practice

Our recent systematic review with meta-analyses of 46 reports from 36 randomized controlled trials (RCTs) showed that the effect of testosterone therapy improved a range of sexual function parameters in postmenopausal women [5]. For the sexual desire outcome, in 15 studies that included 3,762 postmenopausal women, we used a random effects meta-analysis as discussed above. This approach assumed that there may be both random and non-random variations (heterogeneity) across the studies that may influence the outcome of interest (sexual desire). In addition, we computed the 95% CI and the 95% PI for the effect estimate of testosterone therapy on sexual desire. The random effects meta-analysis showed that testosterone therapy was effective for improving sexual desire in postmenopausal women when using 95% CI (SMD 0·36, 95% CI 0·22 to 0·50). However, the I2 value for the pooled estimate of sexual desire was 69%, which indicated moderately high heterogeneity between the included studies. So, in order to estimate the potential effects of testosterone on sexual desire in future individual studies, the 95% PI was also estimated. We observed that the PI was much wider than the CI and included zero (SMD 0·36, 95% PI -0.12 to 0.84). This means that although on average the effect of testosterone for the completed studies is positive for sexual desire, a future study may not have a treatment effect, which is different from zero (no difference between treatment and placebo). It is critical to realize that CI and PI convey different but complementary information.

Rakib Islam

Research Fellow, Women’s Health Research Program, Monash University, Australia

The first Global Position Statement on the use of testosterone in the treatment of women, led by the International Menopause Society (IMS), was published on September 2nd in four leading international medical journals:

• Climacteric
• Maturitas
• The Journal of Sexual Medicine
• The Journal of Clinical Endocrinology and Metabolism.

The statement was authored by a diverse team of leading experts belonging to nine leading medical internationally-esteemed organisations:

• The International Menopause Society
• The International Society for Sexual Medicine
• The Federacion Latinoamericana de Sociedades de Climaterio y Menopausia
• The American College of Obstetricians and Gynecologists
• The North American Menopause Society
• The European Menopause and Andropause Society
• The International Society for the Study of Women’s Sexual Health
• The Royal College of Obstetricians and Gynaecologists
• The Endocrine Society

and endorsed by several additional Societies.

Key messages to Health Care Professionals are:

• The consensus follows years of debate regarding testosterone therapy for women and, for the first time, provides agreement from experts about the known benefits and potential risks of testosterone therapy for premenopausal and postmenopausal women.
• Testosterone can be effective at improving sexual wellbeing for postmenopausal women with hypoactive sexual desire dysfunction (HSDD). Benefits include improved sexual desire, function and pleasure, together with reduced concerns and distress about sex.
• There is insufficient data to support the use of testosterone for the treatment of any other symptom or clinical condition, or for disease prevention.
• As female formulations are not available, male formulations can be judiciously used in doses that achieve blood concentrations of testosterone that approximate premenopausal physiological concentrations.
• The panel recommends against the use of compounded testosterone.
• The international panel calls on industry, researchers and funding organisations to recognise the need for further research into testosterone therapy for menopausal women and the development and licensing of products indicated specifically for women.

Summary

A new study from the UK addressed whether a person’s genetic risk of dementia modifies the extent to which healthy lifestyle factors are associated with a reduced risk of dementia. The study included a very large, population-based sample of more than 500,000 White adults age 60 and over from the UK. Participants were categorized into low, intermediate, or high genetic risk of dementia based on a polygenic risk score (i.e., a weighted estimate of genetic risk for dementia from a number of single nucleotide repeats or SNPS). They were also categorized into favorable (3-4 healthy lifestyle factors), intermediate (2 healthy lifestyle factors), and unfavorable (0-1 healthy lifestyle factors) lifestyle categories based on four factors - healthy diet, physical activity, alcohol consumption and smoking. Lifestyle factors were assessed at baseline and incident all-cause dementia was assessed from hospital records and death records an average of 8 years later. Results showed that for those with an intermediate genetic risk of dementia, an intermediate or favorable lifestyle was associated with a decreased risk of dementia compared to an unfavorable lifestyle. Among those at the highest genetic risk of dementia, a favorable lifestyle was associated with a lower risk of dementia compared with an intermediate or unfavorable lifestyle. In other words, findings suggested it may be possible to lower the risk of dementia through lifestyle modification but that the greater the genetic risk of dementia, the healthier the lifestyle must be.

Commentary

The Commentary refers to the paper 'Association of Lifestyle and Genetic Risk With Incidence of Dementia' by Lourida I, et al., published in JAMA 2019 July 19,

Menopause practitioners have an important role to play in counseling patients on how lifestyle factors at midlife can affect their later health, including their risk for dementia. Women are right to fear dementia, as two-thirds of patients with Alzheimer’s disease are female [1] and every clinical trial of a pharmacological agent to prevent or treat Alzheimer’s disease has failed. The benefits of multicomponent lifestyle interventions on cognition and perhaps dementia risk are supported by numerous observational studies as well as a growing number of randomized clinical trials [2]. These lifestyle interventions are multi-faceted and focus on increasing adherence to the Mediterranean Diet, physical activity, cognitive engagement, and social engagement, as well as smoking cessation and moderate use of alcohol. Some but not all of those interventions were evaluated in the JAMA study. The number of healthy behaviors is key, as prior studies [2] and the current JAMA article show an additive role of lifestyle factors. How much physical activity is necessary to minimize cognitive difficulties? Favorable physical activity was defined on either the basis of duration (i.e., > 150 minutes of moderate activity or 75 minutes of vigorous activity per week) or frequency (i.e., moderate physical activity at least 5 days a week or vigorous activity once a week). Moderate consumption of alcohol was defined as 0 to 14 g/d for women, or about one glass of wine per day. Although this study included a white-only population of European ancestry, prior work demonstrates that lifestyle modification works also for diverse populations [2] though the moderating effect of genetic risk of dementia in that population is yet to be determined.

UK media recently reported that a Birmingham-based company called ProFaM (Protecting Fertility and Menopause) were offering a “new” procedure for women: cryopreservation of autologous ovarian tissue to delay menopause through later reimplantation. The company, co-founded by Arri Coomarasamy, Christiani Amorim, Yousri Afifi and Simon Fishel, four world-renowned experts in reproductive medicine, are proposing to perform laparoscopy in premenopausal women, within 40 years of age, to collect sections of ovarian tissue. The ovarian tissue is frozen at -150C and preserved in an authorised bank until women reach the menopause, when it is then thawed and transplanted back into the body, where it will replace the function of the original ovaries.

This is not a new procedure. It was developed for cancer patients undergoing potentially gonadotoxic treatments and was first described by Kutluk Oktay and collegues in 2000 in a patient who had undergone bilateral salpingo-oophorectomy by age 29 and for whom wedges of ovarian tissue had been cryopreserved. Ovarian tissue was later reimplanted in an attempt to cure persistent menopausal symptoms [1]. In 2004, another pioneering group lead by Jacques Donnez achieved a livebirth after successful orthotopic transplantation of cryopreserved ovarian tissue in a woman with stage IV Hodgkin's lymphoma [2]. Other groups worldwide, like that lead by Xiangyan Ruan, have gone on to successfully perform the procedure on patients with the specific short-term goal of achieving a pregnancy [3, 4]. The procedure is specifically indicated for fertility preservation in child and adolescent patients and patients who cannot delay cancer treatment to pursue other methods of fertility preservation such as oocyte or embryo cryopreservation[5,6].

ProFaM’s objective, in the case of naturally menopausal women, is hormonal preservation. The idea behind this procedure is to prevent, by reimplanting functioning ovarian tissue, debilitating conditions which occur more frequently in women after the menopause, such as cardiovascular disease and osteoporosis. Moreover, the procedure would potentially delay bothersome symptoms of the menopause to an age when a woman is not struggling with family and career issues. Nine cases of UK women, age range 22-36, were reported to have undergone the protocol thus far.

However, authors note that non-oral formulations are preferred because of the adverse lipoprotein effects of oral testosterone. So far, adverse side effects of non-oral formulations appear to be restricted to small weight gain, mild acne and increased hair growth, but more research on long-term effects is needed.

The most comprehensive systematic review and meta-analysis of testosterone treatment for women undertaken, including 46 reports on 36 trials, involving 8,480 women, published in The Lancet Diabetes & Endocrinology journal, suggests it can significantly improve sexual wellbeing for postmenopausal women. Benefits include improved sexual desire, function and pleasure, together with reduced concerns and distress about sex. Although best known as a male hormone, testosterone is important for female sexual health, contributing to libido and orgasm as well as helping to maintain normal metabolic function, muscle strength, cognitive function and mood. Levels decline naturally over a woman’s lifespan, and can also drop sharply following surgical menopause.

Prior research has suggested that testosterone therapy can improve sexual function in women, but the available formulations have been designed for men and evidence for their safety or for adverse side-effects in women is scant.

“Our results suggest it is time to develop testosterone treatment tailored to postmenopausal women rather than treating them with higher concentrations formulated for men,” says senior author Professor Susan Davis from Monash University, Australia. “Nearly a third of women experience low sexual desire at midlife, with associated distress, but no approved testosterone formulation or product exists for them in any country and there are no internationally-agreed guidelines for testosterone use by women. Considering the benefits we found for women’s sex lives and personal wellbeing, new guidelines and new formulations are urgently needed.” [1]

In this study, scientists reviewed 46 reports about 36 randomised controlled trials, conducted between January 1990 and December 2018 and involving 8,480 participants aged 18 to 75 years, approximately 95% of whom were post-menopausal. The trials compared testosterone treatment to a placebo or to an alternative hormone treatment such as oestrogen, with or without progestogen. The authors reviewed the effects of treatments on sexual function and on measures of heart, cognitive and musculoskeletal health.

Summary

In a randomized cross-over study by Park et al., the expression of structural proteins and protein regulatory markers was measured in muscle samples collected from women who had received transdermal estradiol (E2) or placebo the preceding week and were either in the early postmenopause (EPM, ≤6 years since menopause, n=13) or late postmenopause (LPM, >10 years since menopause, n=14) stages [1]. In response to acute E2 treatment, dephosphorylation (activation) of forkhead box O3 (FOXO3) protein, that triggers apoptosis, and expression of muscle-specific ring finger protein (MuRF1), that triggers muscle protein degradation, were found to decrease in EPM but not in LPM women. This suggests that the beneficial effects of E2 on muscle protein breakdown may be dependent on the time after menopause.

Commentary

Sarcopenia is defined as age-related loss in muscle mass and strength [2]. Its prevalence has been reported to increase from 37% in women in their forties to 57% in women in their fifties, suggesting a link between menopause and the pathogenesis of this disease [3]. Although the mechanism underlying the possible negative effect(s) of estrogen deficiency on the loss of muscle mass and strength are yet to be elucidated, both direct (through estrogen receptors [ER] expressed on skeletal muscle cells) and indirect (via increase in pro-inflammatory cytokines induced by a rapid decrease in estrogen) pathways could be involved [2]. In line with this concept, menopausal hormone therapy has been supposed to protect postmenopausal women from muscle loss. For example, the Women’s Health Initiative trial assessed body composition and found that women on estrogen-progestin treatment did not lose lean body mass, compared to those on placebo who did [4].

Summary

Even though vasomotor symptoms (VMS) and migraine are highly prevalent and often coexist during the menopause transition, interactions between the two are understudied, and it is possible there are shared physiologic mechanisms. The authors of this study investigated potential associations between VMS and migraine using the longitudinal Study of Women’s Health Across the Nation (SWAN).[1] They included 467 women with a self-reported history of migraine diagnosis made by a medical provider, and 2,466 women without a migraine diagnosis served as controls. VMS (assessed as number of days hot flashes and night sweats were experienced in the prior two weeks and converted to a mean symptom frequency) were self-reported at baseline and annually during follow up which varied between 2 and 10 years with greater than half of the women completing all 10 assessment. Vaginal dryness symptoms, also related to menopause, but without vasomotor origin, were also assessed using a frequency score. For an additional control comparison, the authors further examined the association of VMS and vaginal dryness with back pain, another pain disorder, to investigate the specificity of the association of VMS and migraine. Study results showed that a prior diagnosis of migraine predicted a higher frequency of hot flashes (p = 0.0036) and night sweats (p = 0.0138) after adjusting for all covariates. Significant interactions between migraine diagnosis and reproductive stage were noted, with higher frequencies of VMS in women with migraine, particularly in perimenopause. There was no association between migraine diagnosis and vaginal dryness. In a small subgroup of women with back pain, no association between back pain and hot flashes or night sweats was identified when compared to women with no back pain. The authors theorize that declining estrogen levels during the menopause transition are associated with hypothalamic changes which may explain the increased frequency of both VMS and migraine during this time frame.

Commentary on "Impact of natural menopause on multiple sclerosis: a multicentre study" by Baroncini D, et al.

Summary

In their recent paper, Baroncini et al [1] evaluated changes in relapse rate and clinical disability, as measured by the Expanded Disability Status Scale (EDSS) score, associated with menopause in women with multiple sclerosis (MS). They asked 148 women from the Lombardia region of Italy about their menopausal history, and then collected their relevant clinical information from medical records. Most of the women were on self-injectable MS treatments and, at the time of menopause, the group overall had mild-moderate disability (mean EDSS was 2.3, and the range was 0-7.5). Only 3% of women used hormone replacement therapies after menopause. The primary finding was that annualized relapse rate (average number of relapses in one year) decreased from 0.21 relapses a year on average before menopause, to 0.13 relapses a year after menopause. This represented a 38% decrease in relapses. However, this finding was no longer considered statistically significant when the investigators controlled for possible confounding factors, like age and MS duration. The second finding was that after menopause, increases in EDSS score were steeper, i.e there was more rapid worsening of disability. This more rapid progression of disability remained statistically significant after adjusting for confounding factors.

Who are the women that live longer?

Summary

A new study from the Netherlands attempted to find markers that may predict higher longevity in women [1]. A subgroup of the Netherlands Cohort Study (NLCS) consisted of those who were born in 1916-1917 and were followed until death or until reaching age 90 (in the years 2006-2007). Out of 2697 eligible women with complete data, 928 lived to be 90 and 1769 died at earlier ages. Lifestyle, dietary habits, reproductive and medical history, and cancer risk factors were collected when women were around age 70, using a self-administered 11-page questionnaire. Mortality was recorded based on a linkage with central national registries. The results were rather disappointing, as very few parameters were found to significantly correlate with longevity: age at first childbirth, and ever-use of HRT in women with an early menopause (< 50 years) were associated with the likelihood of reaching the age of 90 years. Many other variables, generally thought to be relevant to longevity, failed to show a linkage (i.e., age at menarche or at menopause, menstruation lifespan, history of childbirth).

Commentary

Despite the universal wish to better understand the reasons why women live longer than men, and what might in general be the reasons for extreme longevity, this Dutch study did not provide definite answers. Interestingly for menopause specialists, ever-use of HRT in women entering menopause before age 50 did influence longevity.

Personally, I was not surprised to see the above results, since the issue of longevity is certainly very complex, involving genetic and medical, dietary, socio-economical, environmental and other factors. Just one example that might affect the outcomes of this particular cohort: the participating women were born during World War 1 and lived several years within their occupied country during World War 2. I would imagine that this might have had an impact on future health and disease, on physical and emotional parameters and on reproductive factors. Also, and not taking a view as an expert epidemiologist or a statistician, the fact that the cohort was rather small, and the variables tested were so many, makes it a-priori very difficult to reach significance for any potential association.

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 -- using exposure at the time of WHI enrollment -- 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.”

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.”

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].

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.

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]

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.

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.

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.

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.