Novel Menopause Perspectives & Data

As the name suggests, the Novel Menopause Perspectives & Data session provided some truly thought-provoking insights from three global experts.

Changes in intervertebral discs with menopause and HRT  - Mark Brincat

Mark Brincat opened with data relating to HRT and its effects on the intervertebral discs in post-menopausal women.

Intervertebral discs, Mark argued, are components of the spine that have been largely overlooked, despite fractures being very common. Acting as shock absorbers in the spine, the loss of the discs increases fracture risk and occurs rapidly following the menopause.  

The loss of intervertebral discs during and after menopause is due to the changes in the composition of the complex connective tissue consisting of glycosaminoglycans. Previous studies had demonstrated that disc height can be increased with HRT - with data showing a dose-dependent relationship.  

In this cross-sectional study, patients were recruited from a large bone densitometer directory. They were divided into categories according to whether they were pre-menopausal women, untreated post-menopausal women or women on calcium supplements, HRT or strontium ranelate.

Results showed a statistically significant difference in intervertebral disc height compared with patients not receiving treatment. Thus, HRT seems to have a protective effect on the intervertebral disc height loss which occurs after menopause.

However, additional studies are needed to determine whether intervertebral disc height can be used as an additional parameter to predict the risk of vertebral fracture in post-menopausal women.

Prevention, gynaecologists at the front-line - Lydia Marie-Scemama

Cardiovascular disease has become the first cause of mortality among women, and the non-medical population is in general unaware of this. This aspect of women’s health has been neglected up to now, because it was strongly believed that women were protected by female hormones. We also know that clinical signs in women are different from those of men.

In order to raise awareness and proceed, Lydia suggested:

  • Scientific societies involved in cardiology and gynaecology/obstetrics work together to inform women of the dangers of CVD.
  • Inform colleagues through the medical media and meetings.
  • Target GPs especially, creating a multidisciplinary net around each patient.

Lydia and her colleagues created an action plan in the form a flyer - this was designed to increase the impact on doctors and patients. Elected representatives from across disciplines and industries were enlisted to enforce and change attitudes. This, Lydia argued, is a big step in preventing CVD in women.

Alzheimer disease, why should oestrogens work? - Paulin Villaseca

Oestrogens have consistently demonstrated neuroprotective effects in cellular and animal studies. In monkey studies, when estradiol is low in the cycle, dendrite spines are few. When estradiol is increased, the relationship is reversed and dendrite spines grow.

To determine any intervention in dementia in humans, it will require decades of follow-up, plus the complexity of confounding factors must also be considered. Paulin argued that the study of estradiol could assess the efficacy of preventative strategies.

The initiating pathological factor of Alzheimer's disease (AD) is the amyloid-beta peptide (AB), formed from the precursor protein (APP). APP is proteolysed by enzymes known as secretases: alpha-secretase cuts the AB peptide in the middle of its sequence, destroying its capacity to aggregate and trigger AD. Conversely, beta-secretase releases the peptide, facilitating aggregation.

Estradiol simulates alpha-secretase and inhibits beta-secretase - reducing the capacity for APP to aggregate into amyloid plaques.

Additionally, estradiol inhibits a second pathway, involving Tau proteins. Microtubules require Tau proteins to stabilise their structure and function. In AD, kinases phosphorylate the Tau, destabilising the microtubules and leading to neuronal death. The phosphorylation step is inhibited by estradiol.

Estradiol is a key player in each of these mechanisms and Paulin expressed a keen interest for this to be explored therapeutically. 

Menopause, beyond obesity and metabolic disorders

Obesity is a health problem of a truly global proportion. In this session, a number of speakers offered oral presentations linking menopause to not only obesity, but also metabolic disorders and wider physiological diseases.

Here are two of the highlighted talks:

Epigenetics of Oestrogen Metabolism and Breast Cancer Risk - Jennifer Pearlman

Although tools for screening breast cancer have improved, there has been little advance in further understanding and developing preventative strategies.

The transformative process that occurs in each and every patient from normal cell to invasive ductal carcinoma is very unique. It is driven by a number of factors: genetic, metabolic, epigenetic and environmental forces all play a key role.

One of these factors that has long been a focus of attention is oestrogen. Oestrogen metabolism is a complicated and poorly understood process subject to genetic and epigenetic effects that can have vast implications on health, risk of disease and cancer. 

The metabolism of oestrogen involves a complex biphasic detoxification process that mainly occurs in the liver. The first phase involves hydroxylation; this is followed by a number of conjugation reactions. Such reactions have the potential to generate toxic intermediates including oestrogen-quinones that bind and depurinate DNA increasing mutagenicity and inducing breast cancer.

Epigenetic factors, a result of the complex relationship between our genome and environment also play a key part. Environmental exposure to certain endocrine disrupting chemicals (e.g. BPA and DES) influences the detoxifying pathways and subsequent intermediates.

Jennifer highlighted that  the ability to clinically measure potentially harmful oestrogen intermediates in women at risk holds powerful predictive value in estimating breast cancer and risk stratifying patients to high-risk, more intensive screening programs.

Effects of six-month oral DHEA supplementation on beta-endorphin response to oral glucose tolerance test in obese and non-obese early and late postmenopausal women - Andrea Giannini

Beta-endorphin is a neuropeptide involved in several brain functions, including decreasing bodily stress and maintaining homeostasis. Previously, it has been demonstrated that while in pre-menopausal women the response of plasma beta-endorphin levels to oral glucose tolerance testing is maintained, in post-menopause there is a lack of response.

Beta-endorphin, Andrea hypothesised is therefore dependent on gonadal steroids, while partly influenced by body weight.

Previous data has demonstrated that DHEA increases beta-endorphin levels in menopausal women and restores the peptide's adrenergic, serotoninergic and opiatergic neuroendocrine stimuli. DHEA is not only related increases in beta-endorphin but also beneficial changes in adrenal products, anabolic pathways and decreases in cortisol.

The aim of Andrea's study was to evaluate plasma beta-endorphin levels in response to oral glucose tolerance testing in early and late menopausal women of normal or overweight BMI, treated with oral DHEA for 6 months.

A key question was: could DHEA supplementation increase beta-endorphin and control endocrine modifications?

Results demonstrated that an increase in plasma beta-endorphin levels with DHEA supplementation was observed in both obese and non-obese women. Perhaps, Andrea suggested, DHEA should be considered more than a simple 'diet integrator' but rather an effective hormone replacement treatment.

European Progesteron Club - Update on Menopause

Thursday morning of IMS 2018 started with The European Progestogen Club's Update on Menopause. The organisation was established in 1996; to date it has a published 144 publications and held 25 symposia. Following a brief introduction, Alfred Mueck, Sven Skouby and Lydia Marie-Scemama gave individual presentations.

Choice of progestogen in HRT - Alfred Mueck

Alfred Mueck, President of the German Menopause Society explored the four main risk factors associated with progestogen use in patients:

  • Venous thromboembolism (VTE)
  • Myocardial infarction (MI)
  • Stroke
  • Breast cancer

Mueck explained that the most important effects which may be dependent on the choice of the progestogen in HRT are an increase in MI and stroke.

Additionally, some minor negative progestogen effects also should be considered regarding the risk of VTE whereby the more important impact is derived from the oestrogen component. However, the most important detrimental effect may be the possible increase of breast cancer risk - with doctors and patients alike both sharing this fear.

Progestogen's increased risk of breast cancer has been attributed to its ability to bind to certain membrane-bound proteins and increase cell proliferation. Interestingly, if baseline proliferation is low, the protective effects of progestogen outweigh excessive division. However, this balance is altered when baseline proliferation is high.

Progestogens and the haemostatic system. The clinical translation - Sven Skouby

Heightened publicity surrounding hormone contraception and post-menopausal HT in regards to thrombosis risk has led to multidisciplinary discussions on the impacts of progestogens. The risk is affected by oestrogen combination, type of progestogen, mechanism of delivery and length of therapy.

Risk factors include family/personal history, covering pharmacogenomics and environmental modifiable epigenetics factors as well as drug interactions.

The largest existing meta-analysis of 8 observational studies did not identify any association between oral progestin-only contraception and risk of VTE. Neither was any risk associated to the use of the LNS system.

However, subgroup analysis suggests that injectable progestin contraception is associated with an approximate twofold increased risk of VTE relative to women not taking hormonal contraception.

Endometriosis and the menopause - Lydia Marie-Scemama

Vice president of the AFEM, Lydia posed the question: does endometriosis persist after menopause?

Lydia explained there are two common misconceptions in regards to endometriosis:

  1. It only affects pre-menopausal women. Persistence or recurrence of pre-existing disease, de-novo development, environmental factors and stress are some of examples of possible causes in post-menopausal women.
  2. Endometriosis is not related with ovarian cancer. 

Endometriosis is in fact strongly associated with the increased risk of ovarian cancer, although the cancer typically shows favourable characteristics including early-stage disease, low-grade disease and a specific histology.

Medical treatment for post-menopause endometriosis includes second line aromatase inhibitors and levonorgestrel-IUD. It should be noted that HRT increase the risk - it is imperative to weigh up the risk-benefit.

 

Plenary Lecture: Mary Ann Lumsden, President of the IMS

In the much anticipated plenary lecture, Mary Ann Lumsden, President of the IMS gave an inspiring talk on the status and future of women's health.

Mary began by offering a number of analogies describing the role of post-reproductive females in society and even wider biology. In orca society, the post-reproductive matriarchs lead the pod when food is scarce. In hunter-gatherer societies, older women are particularly good at foraging for food. And more recently, grandparents are increasingly taking a greater role in raising their grandchildren.

However, as life expectancy continues to increase, so does the burden of disease. And with this the roles and perception of the elderly are changing.

What are the diseases that affect post-menopausal women as they continue to age? Ischemic heart disease, cerebral vascular pathology, diabetes - all huge global burdens of disease. And all influenced by sociodemographic factors.

Unable to attend the conference, Mary played a short clip of Lesley Regan, President of the Royal College of Obstetricians and Gynaecologists. In a global society influenced by social, economic and lifestyle factors, Lesley highlighted the importance of a life course approach to treating menopausal women.

A life course approach does not just focus on treating menopause, but instead improving women's health generally. Where possible, lifestyle changes should be encouraged to women and embraced by all.

Best abstracts Greenblatt award

In Wednesday's afternoon session we listened to 6 abstract presentations shortlisted for the Greenblatt award. Robert B. Greenblatt, co-founder and first President of the International Menopause Society, originally conceived the idea of awarding prizes to the two junior researchers who present the best abstracts in the field of the menopause.

There are two prizes each of £2500, for the best papers presented, in either basic research or clinical work.

Cerebrovascular resistance is an early marker of slow gait and cognitive deficits in overweight postmenopausal women - Rachel Wong

Rachel's research examined baseline associations between adiposity, cerebrovascular function, cognition and gait in postmenopausal women enrolled in an intervention trial. 

Results found that poor cerebrovascular function led to gait slowing and therefore higher fall rate. As well as this, poor processing speed was associated with gait slowing. Visceral adipose tissue was associated with poor cognitive function. Risk factors included age, hypertension, obesity and diabetes.

Targeting these risk factors from mid-life may be a useful target for dementia prevention and slowing of gait in old age.

Subjective memory complaint is associated with cerebrovascular dysfunction in healthy older women - Jay Jay Thaung Zaw

Due to the success of healthcare in the past century many people are now living with dementia. By 2050 it is predicted there will 132 million people living with the disease.

Jay Jay explored the relationship between subjective memory complaint SMC), cerebrovascular dysfunction and depression with regards to dementia.

SMC was associated with depressive symptoms. Cerebrovascular dysfunction is associated with increasing SMC scores, reflecting early cognitive decline. Therefore, maintaining optimal cerebrovascular function is crucial for delaying the onset of cognitive impairment.

Testosterone restores the bladder and urethra alteration of ovariectomized rats independently of the genomic pathway - Sandra Bonilla

Sandra and her team evaluated the effects of testosterone on the contractile responses of bladder and urethra isolated from 4-month ovariectomized rats to mimic menopause.

They found the protective effect of testosterone in preventing the alterations of bladder and urethra smooth muscle contractions by ovariectomy did not involve the activation classical genomic pathway through androgen receptors.

Evaluation of the body mass index of postmenopausal women and their relation to sexual dysfunction - Gustavo Dutra da Silva

The objective of Gustavo's study was to evaluate the sexual function of post-menopausal women with a BMI >30. 1,100 women were interviewed for sexual function at a number of sites; the results were then analysed against the BMI scores.

Overweight and obese women did not present more sexual dysfunction compared to those with normal BMI. However, overweight and obese women did have significantly lower satisfaction.  

NK3R antagonist reduces flush frequency and alters connectivity in the salience network - Jenifer Sassarini

Hot flushes are very common in menopausal women and persist much longer than initially thought. Despite this, little is known about the exact underlying mechanism.

Using functional Magnetic Resonance Imaging (fMRI), a rise in brainstem activity has been shown to precede a detectable onset of a flush, suggesting pre-flush may have brainstem functional origin, and activity in the insula and prefrontal cortices

Jenifer's demonstrated that an antagonist (MLE4901) of Neurokinin B, a peptide that has been shown to induce hot flushes in pre-menopausal women, reduces self-reported hot flushes. Interestingly, objective hot flushes were not affected. This suggests that the inter-neural network involved is a key player in external and internal perception.

Constipation and diarrhoea during the menopause transition and early post-menopause: observations from the Seattle Midlife Women’s Health Study - Nini Callan

Nini's objective was to assess the relationship of constipation and diarrhoea severity during the menopause transition.

It is becoming increasingly apparent that gut function requires a finely tuned balance between a number of factors - sex hormones, microbiota and the CNS. In women, some of these factors are subject to change during the menopause transition.

Interestingly, Nini's team found that key reproductive hormones do not play a significant role in constipation or diarrhoea severity in the MT. In contrast, stress perception, tension, and cortisol do. These factors may be evaluated in further research involving constipation and diarrhoea.

Cardiovascular window of opportunity

Rogerio Lobo, Rebecca Thurston, Cynthisa Stuenkel and Rachel Wong kicked off the Wednesday morning session of IMS 2018 with a cardiovascular focussed symposium. Underlining themes of the presentations included the cardiovascular window of opportunity, vasomotor symptoms and their association with subclinical risk factors, as well as broader risk factors and prevention of cardiovascular disease (CVD) in women.

Below are the presentations in more detail:

Physiology and clinical data regarding the window of opportunity - Rogerio Lobo

For a long time Framingham data has shown that regardless of age or menopause, endogenous oestrogen is protective against CVD. By the same concept, women who have a late reproductive life also show increased cardio-protection.

These and other data speak to the protective effects of oestrogen, primarily through interactions with arteries. The direct protective effects of oestrogen occur through non-genomic and longer-term genomic pathways.

It was hypothesised that oestrogen could be used therapeutically for cardio-protective purposes. The first trials, Rogerio explained, were secondary; it was thought that if oestrogen is administered in established disease then surely this would lead to improvements. Alas, this was not the case.

Thomas Clarkson was the first to show in a monkey model that the protective effects of oestrogen is age-related: early initiation of oestrogen is protective, while late intervention is not.

What is the underlying mechanism behind this?

An atherosclerotic plaque has a lot of activity in mural wall. One of the effects of oral oestrogen is the induction of matrix metalloproteinases - these act by breaking down the plaque. The breakdown of the plaque can release an atheroma - with the potential to cause a myocardial infarction or stroke. Patients with disease are more likely to have an existing atherosclerotic plaque and therefore are at higher risk of CVD as a result of oestrogen action.

This is considered to be the 'window of opportunity approach' . In the Women's Health Initiative (WHI), those who initiated therapy closer to menopause did not have early harm and tended to have benefit; in these women there were statistically significant benefits in coronary heart disease and mortality.

Similarly, in the ELITE trial (using oral oestradiol 1 mg), women who were within 6 years of menopause had a significant attenuation of the increase in carotid intima-media thickness compared to placebo and women who initiated therapy 6 or more years after menopause, which is in line with the 'window' hypothesis. 

To conclude Rogerio's presentation, data demonstrate that the window hypothesis is operative, and women who initiate certain forms of HRT close to the onset of menopause benefit in terms of a protective effect on CVD.

Menopause and its Symptoms in the Development of Cardiovascular Disease in Women - Rebecca Thurston

Rebecca opened with a broad introduction regarding CVD and women's cardiovascular health. Rebecca explained that although CVD is the leading cause of death in both men and women globally, women do not tend to develop the disease until later in life - post-menopause

The menopause transition is accompanied by symptoms for most midlife women. Vasomotor symptoms (VMS; hot flushes, night sweats) are the hallmark symptoms of menopause, reported by over 70% of midlife women, with 30% experiencing severe VMS. Sleep problems are also prevalent.

Rebecca highlighted that while VMS has long been understood to be important for women's quality of life, there is increasing evidence that is also has an impact on physical health. Menopausal symptoms, particularly VMS and sleep problems have been linked to indicators of CVD.

The SWAN study is a multi-site longitudinal, epidemiologic study designed to examine the health of women during their middle years. The study annually assessed a whole range different effects, physical markers and symptoms. Critically, it showed that women with VMS had an increase adverse cardiovascular risk profile.

What is the mechanism behind this?

Sex hormones, inflammation, CVD risk factors and the autonomic nervous system were all analysed but currently, no mechanism has been identified. More research is required to fully understand the relationship between VMS and CVD.

Do we have new preventive strategies for optimising CV health in women? - Cynthia Stuenkel

Paralleling Rogerio's earlier presentation, Cynthia discussed the importance of the 'window of opportunity' when considering hormone therapy. Cynthia suggested, however, that the window for preventing CVD in women could be opened much wider to encompass the decades prior to menopause. 

Regarding this, Cynthia poised the question: how is risk evaluated? And more importantly, how is it perceived? According to the National Study of Physician Awareness to CVD Prevention Guidelines, perception of risk was the primary factor associated with compliance with CVD preventative recommendations.

Current experts recommend screening for CVD risks as early as age 20 to 25 years. Recognising adverse pregnancy outcomes as red flags portending future development of CVD is essential. Furthermore, autoimmune disorders and breast cancer therapies contribute to CVD and heart failure and as such should be considered risk factors.

How can risk assessment and reduction be improved?

Cynthia argued that it would be far more effective to move forward proactively with CVD preventive strategies immediately following these clinical occurrences.

When we talk about the window of opportunity, open it.

Interrelationships between blood vessel function, cognition and fracture risk - Rachel Wong

Rachel closed the session with her abstract that was especially selected for presentation. In her introduction she highlighted that oestrogen decline and ageing are known to contribute to arterial stiffness, resulting in poor blood perfusion in bones and in the brain, thereby increasing the risk of bone loss and cognitive impairment.

Results from her lab group showed that in the cohort, cerebrovascular stiffness is associated with poor cognition and increased osteoporotic and hip fracture risks. The latter might reflect the effect of systemic arterial stiffness on the diminished blood supply to bones. The association between poor cognition and future fracture risk warrants further investigation.

The truth about MHT use after 65

On the final day of ISGE, Martin Birkhaeuser began by introducing one of his own patient cases - a 78 year old lady that first came to see him in April 2002, still working as an architect, active and independent, still suffering from severe vasomotor symptoms (VMS) but controlled by 2 x 12.5 estradiol patches/week. Then in October 2003 her GP stopped her MHT/HRT, telling her it was “criminal at this age” and it would kill her. In January 2004 she returned to Dr Birkhaeuser because she was suffering from depressive symptoms, loss of concentration, hot flushes - such severe vasomotor symptoms that she had to quit the job she loved, her quality of life suffered greatly. They made the decision to begin the transdermal estradiol again, within 4 months all her symptoms had disappeared, she once again had a good quality of life and at aged 80 she was able to return to her beloved profession, she was happy.

The study that provoked her misery? The Women’s Health Initiative (WHI) trial.                                                                               

Prior to 2002 there was no discussion about whether to continue to prescribe HRT past 65, but after researchers halted the WHI study three years early due to an increased risk of breast cancer, heart disease and stroke, the press reports caused such mass fear that many doctors and their patients immediately stopped their prescription.

In recent years, reanalysis of the study results and further research mean there is a better understanding of risk. Dr Birkhaeuser is of the opinion that the only significant results from the WHI study were an increased risk of venous thromboembolism (VTE) and a reduction in fractures, and everything else was misinformation.

Let’s discuss the research…

Menopause Hormone Therapy (MHT) after 65: Potential benefits

Treatment of persisting VMS and low QOL

Around 25% of women still suffer hot flushes at the age of 65, in some women VMS may last even up to 80-90 years old (Huang et al, 2008) (Vikstrӧm et al, 2013).

A Swedish patient study found that whilst quality of life in post-menopausal women not taking MHT was scored at 87, following a patient questionnaire, those women taking HRT scored 105 - the same as pre-menopausal controls (Wiklund et al, 1993).

Fracture prevention

The WHI study had a mean age of 56, it showed reductions in both the combined arm and the single – proving that if patients begin HT at that age they then have a significantly reduced risk of fractures. Another study, carried out in Denmark, showed reduced fractures in patients taking MHT over the course of 6 years from when they began treatment (Mosekilde et al, 2000).

It’s estimated that 43,000 fractures a year are accounted for by patients stopping MHT following the WHI study (Karim et al, 2011).

Potential CVD risk

Following the WHI study women were told they were at a high risk of a heart attack if they took MHT beyond 65. However, the 27,000+ women included in the WHI study were more than 10 years post menopause when they began taking MHT. Age means they are were likely to already have or have increased risk of cardiovascular disease. Various studies since have shown that MHT use by healthy women soon after the onset of menopause is associated with a reduced risk of CHD (Grodstein et al, 2000) (Grodstein et al, 2001). Though the dose and type of hormone appears to be crucial to this reduced risk. The Framingham study and the Olmsted County study, by Rivera et al, 2009, show us that menopause alone increases the risk of cardiovascular disease.

The low risk patients showed no change in their stroke risk, only patients with high risk factors showed an increased risk of stroke upon taking MHT. Dr Birkhaeuser suggests that age is more likely responsible for the stroke numbers as well as for the DVT numbers, but to be cautious he recommends transdermal HRT.

Potential breast cancer risk

In the WHI study, the risks for breast cancer seemed to depend on the regimen - a estrogen-progestin combination therapy increased risk, whilst a estrogen-only MHT decreased risk. However, Dr Birkhaeuser evaluates that perhaps the data was over-optimistic for estrogen-only and if you look at other studies you can summarise that there’s no increased risk.

Risk of Alzheimer’s disease

There is no data on Alzheimers from WHI as they mixed up all the dementia data instead of separating it into different groups, this means no reliable conclusions can be found.

Dr Birkheiser explained that a study by Zandi et al, in JAMA showed that the risk of Alzheimers decreased with HRT, there are also hints that other forms of dementia decrease too but we need more studies on this to properly evaluate.

Mortality

The total mortality data in the WHI study did not show an increase in mortality as was intimated in 2002. This was finally put to rest recently when the principal investigators followed up with the women all these years on and didn’t find they died any faster, sooner or worse deaths than those that took placebo.

Oestrogens after menopause – continuation for >10 years – So what’s the conclusion?

There are no reasons to place arbitrary limitations on the duration of MHT. The decision on whether to continue has to be based on a woman’s individual risk profile.

The lowest effective dose should be administered (Additionally, the patches can be cut in half to build up tolerance, if side-effects).

A non-oral route of administration should be preferred, oral and transdermal have the same level of efficacy (Nelson, 2004).

If needed, micronized progesterone or dydrogesterone should be preferred.

Depression and cognition in the menopausal transition

Pauline Maki (US) presented the results from a systematic review of scientific literature on depressive disorders in peri- and postmenopausal women. The review was carried out by an 11 member expert panel and convened by the North American Menopause Society (NAMS) and the National Network of Depression Centres (NNDC), American centres of excellence in depression research.

The following are their conclusions:

Epidemiology

  1. There is a window of vulnerability in the menopausal transition extending until early post-menopause for the development of depressive symptoms (elevated mood symptoms that do not meet the diagnostic criteria for clinical depression) and clinical depression
  2. The risk of depressive symptoms is elevated during the menopause transition and post menopause, even in women with no history of clinical depression.
  3. Most women who experience a major depressive episode during the menopause transition have a prior episode of depression; therefore, the episode represents recurrence of the illness.

Clinical presentation and diagnosis

  1. Depression during midlife presents with classic depressive symptoms, commonly in combination with menopause-specific syndrome (i.e., vasomotor symptoms, VMS), sleep disturbance) and psychosocial challenges.
  2. Several common symptoms of the menopause transition and postmenopause (hot flashes, night sweats, sleep and sexual disturbance, weight/energy changes, cognitive shifts) complicate, co-occur, and overlap with the presentation of depression during this stage.

Therapeutic effects of antidepressants

  1. Proven therapeutic options for depression (i.e., antidepressants, evidence-based psychotherapies such as cognitive behaviour therapy) should remain as front-line antidepressant treatments for major depressive disorder at any given time in life, including during the menopause transition.

Hormone therapy

  1. There is some evidence that oestrogen therapy has antidepressant effects in perimenopausal women with clinical depression, with or without vasomotor symptoms.
  2. There is also evidence that oestrogen therapy enhances mood and improves well-being in nondepressed perimenopausal and early postmenopausal women.
  3. Hormonal contraceptives, particularly when used continuously, have shown some benefits for mood regulation and could be helpful for women experiencing depressive symptoms while approaching menopause.
  4. Oestrogen therapy is ineffective as a treatment for depressive disorders in postmenopausal women
  5. Most studies on hormone therapy (HT) for the treatment of depression examined the effects of unopposed oestrogen
  6. Oestrogen-based therapies should not be considered as a strategy for prevention in nondepressed, asymptomatic peri- or postmenopausal women.
  7. Oestrogen-based therapies might augment clinical response to antidepressants, including SSRIs and SNRIs, in periomenopausal women with VMS
  8. Oestrogen is not FDA approved to treat depression

Other therapies

The available evidence is insufficient for recommending any of the following or treating depression related to the menopause transition.

  1. Botanical extracts (e.g. St John’s wort, black cohosh, Gingko biloba, ginseng)
  2. Vitamins/Nutritional supplements (folate, omega-3 fatty acids)
  3.  Isoflavones/Phytoestrogens
  4. Neuromodulatory interventions (e.g. transcranial magnetic stimulation)
  5. Other complementary/alternative approaches (e.g. acupuncture, light therapy)

Gaps in knowledge (insufficient data)

  1. Does HT affect cognition in women for whom HT is indicated – i.e. women with moderate to severe VMS?
  2. Does use of HT or oral contraceptives in the perimenopause – as distinct from the early postmenopause – enhance cognition?
  3. Does early use of HT have effects on Alzheimer’s disease risk and the neuropathology underlying risk?
  4. Is HT effective in preventing cognitive decline in women who undergo early surgical menopause?

Although this review found many interesting conclusions, it also identified areas of missing or insufficient data that are in need of research. An area not covered in the research review was that of the gut microbiome and its influence. The gut microbiome is a primary source of neurotransmitters, the stress hormone cortisol seems to impede the development of these neurotransmitters, which could explain why stress can modify the effects of menopausal transition on depression. Infact, one of Pauline's team's current areas of research is measuring the gut microbiome in women that develop perinatal depression compared to women that don’t, so perhaps there will be more on this very soon!

Developments in vaginal rings & MPT

Day 4's early morning session was on the interesting developments in vaginal rings, delivered by Regine Sitruk Ware.

Vaginal rings in development

Regine shared favourable patient satisfaction study data from the new ST-1435/EE 1 year vaginal ring. It's used on the same basis as many existing rings - 21 days on, 7 off, but it can be re-used for 13 consecutive cycles. A particularly important characteristic for use in developing countries is that it requires no refrigeration. It's currently awaiting approval by the FDA so watch this space.

A fairly recent study (Beksinska et al, 2006) found that 68% of women surveyed would be interested in a contraceptive MPT if it was available.

MPT vaginal rings in development

Multipurpose prevention technology (MPT) is in early development but at the trial stages is a 60 day combination vaginal ring (DPV+LNG) that could prevent pregnancy and HIV. Still in development are a 30 day MPT ring (MIV-150 + Zinc Acetate + LNG) and a 90 day MPT ring (TFV+LNG) that could both prevent pregnancy, HIV and HSV-2.

The pod vaginal ring design

A newly developed pod vaginal ring technology could hold great potential for MPT medicine. The polymer-coated drug cores known as ‘pods’ can contain different active pharmaceutical ingredients and are embedded in an unmedicated silicone elastomer ring, with the incorporation of 10 pods being possible. So far, the rings have shown sustained release in macaques over 30 days.

It's great to hear so much research is going into this area, providing more choice for women and their physicians, and addressing the unmet contraceptive needs of so many women worldwide.

The importance of understanding paracrine pathways for endometrial diseases

Fernando Reis kicked off day 3 with his presentation, Progesterone-induced paracrine factors in human endometrium: the key for decidualization and receptivity.

The cyclical phenomenon that is decidualization

Decidualization occurs in the mid-luteal phase of the menstrual cycle, with paracrine and autocrine factors causing changes in the endometrium to enable receptivity and therefore implantation of the embryo. These changes, include enlargement of endometrial stromal cells (ESCs), the presence of decidual white blood cells (leukocytes), and vascular changes to maternal arteries. In pregnancy, this decidualized endometrial lining (desidua) remains in order to prolong receptivity and therefore pregnancy, the decidua of course forms the maternal part of the placenta.

How does it occur?

The decidualization process is induced by progesterone binding to progesterone a and b receptors, following oesterogen priming. The progesterone’s effects are then mediated by multiple downstream mechanisms involving an array of growth factors, cytokines and regulatory peptides in the endometrium.

Progesterone essential but so is oestrogen

We know that progesterone is essential for this process and as such, it increases in the mid-luteal phase in order to inititate the decidualization process. However, increased availability of both progesterone receptors a (PGR-A) and b (PGR-B) also needs to occur, animal studies have shown that without progesterone receptors decidualization is not possible. This increased availability of receptors is caused by oestrogen priming, meaning oestrogen is also essential for decidualization.

Progesterone receptors in gene activation

Despite the fact PGR-A is most abundant in the endometrium, a recent study found that actually PGR-B is the most important for decidua genes like prolactin – a hormone producer and marker of decidualization. In studies where cells expressed exclusively PGR-A or PGR-B, those with B showed the most prolactin release and therefore most intense decidualization. However, both receptors are essential, as some genes are related by PGR-A, some by PGR-B, and some by both. The cAMP (cyclic adenosine monophosphate) signal transduction cascade also appears to be activated in decidualization with an independent initiating pathway. As well as increasing the availability of progesterone receptors, oestrogen also targets different essential genes. Many genes are involved in decidualization, some are critical like Hoxa10, but there are many others.

Which mediators are essential?

Ramathal et al, 2010 documented a long, but not exhaustive, list of genes that studies have found to be critical in decidualization and implantation. The number of essential genes required to be correctly activated makes this an extremely complex and finely balanced process – with just one gene not activated pregnancy cannot occur.

Cytokines attract leukocytes

Cytokines, glycoprotein mediators, are cyclically upregulated in the endometrium, at least in part by oestrogen. Leukocytes are continually attracted to the cytokines in an inflammatory response, this enables the endometrium to remain active and androgenic, but also tolerate the foetus.

Lack of prolactin expression in unexplained infertility

In the last 20 years, since Fernando first presented this topic at ISGE, his team in Brazil have been studying many growth factors. He explained that unfortunately they’ve not managed to decipher the process using one factor at a time and so going forward they will change their thinking for studies. Interestingly though, a 2004 study found that prolactin may not just be a marker of decidualization, but also an active hormone that shapes the endometrium after decreased expression was seen in women with unexplained infertility.

Understanding holds potential for endometrial disease therapy development

Understanding the complex cascading processes initiated by progesterone receptor activation could aid in defining the pathology of endometrial disease, and in the development of medications that target endometrial immune response, cell growth/survival and tissue remodeling.

Hormone therapy in pelvic floor disorders

Sessions were presented by Dr Tomi Mikkola, Helsinki University, and Professor Tommaso Simoncini, University of Pisa.

A woman has an estimated 20% risk of developing SUI (stress urinary incontinence) or POP (Pelvic Organ Prolapse) by the age of 80 (Wu et al, 2014).

The presence of hormone receptors in pelvic floor structures suggest that hormone therapy could regulate its function, infact oestrogen has traditionally been thought to reduce the risk of common pelvic organ prolapse (POP) and/or stress urinary incontinence (SUI). Multiple studies have found improvements in SUI as well as other urinary complaints, such as urgency, frequency etc.

Is it good quality data though?

Cochrane’s 2012 study review, actually found that systemic oestrogen caused worsening of urinary incontinence but local may have beneficial effects. A more recent systemic review of local oestrogens and UI (urinary incontinence) for 4000 women, found that SUI and urgency were improved, however the studies in SUI were low quality and those in urgency only moderate quality. Based on this and the absence of data on oestradiol, a form of HT commonly used in Europe, Dr Mikkola’s team decided to carry out a study to evaluate the effect of hormone therapy (HT) on POP and SUI.

Significant increase in SUI and POP risks

The, as yet unpublished results, suggested that hormone therapy actually increases the risk of both POP and SUI – with oestradiol-only therapy increasing SUI risk by 4 times. This risk of SUI increases with exposure length and if initiated after 55 years of age. POP risk increased by 40% compared to controls, increased with exposure time however starting age is not a factor in this case.

What about local HT?

Dr Mikkola summarised that local vaginal oestradiol use likely has low/no increase in risk for SUI. Another recent study summarised that systemic HT may have minor negative effect on pelvic organ support.

Oestrogen found to have a detrimental effect on collagen in endopelvic fascia, fascia that is so essential in maintaining pelvic support

A six month study was conducted to assess the impact of 2mg oestradiol treatment on pelvic collagen synthesis and degradation. End study vaginal biopsies revealed total collagen content was reduced and the rate of different tyoe of colleagen synthesis was affected, suggesting the decrease in total collagen was replaced by a weaker collagen type. Increase in proteinase may also have an effect on collagen degradation. Study on paraurethral tissue found similar effect.

Patients should be informed

Dr Mikkola suggests his team’s findings should be incorporated into patient information for women considering hormone therapy.

A need for pelvic floor data in menopause

Professor Simacini stated that although we know there is an association between menopause and pelvic floor dysfunction (PFD), we need more data on the potential implications of menopause on PFD and progression of PFD disorders. Structral effects such as menopausal urogenital atrophy should be investigated more, we’re missing data on how oestrogen and androgens particularly influence nerves, muscles and function – this is so important together with fascia structures and collagens to ensure correct pelvic floor function and on organs themselves within the pelvic floor.

Pain and PFD

Myofascial pain, particularly joint pain, is associated with PFD, many patients can benefit from therapies targeting postural and muscular function. Recurrent UTIs seen in older women are associated with urogenital atrophy, the many of these patients develop bladder pain, which is one of the triggers for chronic pelvic pain in the menopause and during ageing, and of course associated with sexual dysfunction. Urinary incontinence can also cause sexual dysfunction; desire and arousal are prevented by pain, fear of leakage and concentration required to keep control. Bladder function changes throughout life, bladder sensitivity and emptying are not just consequences of PFD, in terms of prolapse, they’re also features of ageing of the pelvic nerve system, particularly if women have diabetes or initial CNS impairment.

Holistic treatment

A Urogynaecologist may need to work with a Colorectal Surgeon and Gastroenterologist, as many other non-gynae areas are modified by the menopause. The intestinal microbiome changes, this can impact constipation, frequency and therefore frequency of infections of the vagina and the bladder, this is an area that we have no knowledge on.

How can we improve PFD and, specifically, POP care?

Can we identify women at risk in the delivery room? We need to establish whether risk scoring works.

Pelvic floor training

Pelvic floor muscle training is interesting, certainly will not cause harm, however, specific nurses and physicians will be required for specific pelvic floor exercises - could also encourage general Pilates though. Reduction of straining and aggressively treating obstructive defecation, a very frequent cause of POP, could also be encouraged.

Lifestyle changes and surgery

Body weight increase prevention, smoking cessation, different surgery methods – surgeries are a risk factor for POP. We don’t have big evidence on these points. Hormones and pelvic floor gym activities are good in decreasing symptoms , could reduce women seeking surgery as most women with intermediate prolapse will not seek surgery, depending on symptoms. Possible strategy to make a difference. Weight loss has many positive effects, reduction of SUI, though on POP there is no information. Big studies insufficient in urinary incontinence and POP.

Hysterectomy and constipation

Chronic constipation is an important risk factor, it's not being tested but it is within clinical appreciation that most patients who have very advanced POP have a history of hysterectomy or obstructive defecation, two big risk factors. We need to consider if we can modify hysterectomy surgery (and other gynaecological surgeries) or treat obstruction aggressively as a means of POP prevention.

Urinary microbiota in recurrent UTI patients

More studies should be carried out on the change in urinary bacterial colonisation after menopause to try and treat patients with recurrent UTIs.

Pain needs to be addressed

There's not enough of an appreciation of the link between chronic pelvic pain, VVA and urinary dysfunction, which should be addressed.

Diagnostic ultrasonography and dynamic MRIs

New ultrasound devices allow complex sonography to stage prolapse. Dynamic MRIs are the future, these will assist with studies as will provide additional consistency in the prolapse staging for reliable evidence.

Learning programmes and computer assisted surgery

Difficult to teach physicians and students about pelvic floor dysfunction, often comes down to experience and personal development. New imaging techniques will make a difference to learning programmes. Surgery will follow this advancement with computer-assisted surgery becoming a reality in the next few years, this robotic platform will help understanding and planning for surgery.

 

Interesting aspects of contraception

This 2nd day seminar looked into interesting aspects of contraception, specifically the myelin-repairing activity of progsterone in contraception, the association between COCs and menstrual migraines; and contraceptive options in women with epilepsy.

Progesterone in contraception found to repair brain tissue

Reproductive endocrinologist Regine Sitruk-Ware, of the population council, explained that her work with Roberta Diaz Brinton had found progesterone and certain progestins, excluding MPA, regulate neurogenic and neuroprotective responses. A number of studies have shown that progesterone acts on progesterone receptors to provide multiple non-reproductive functions in the body including regulating cognition, mood, inflammation, mitochondrial function, neurogenesis and regeneration, myelination and recovery from traumatic brain injury. With both in Vitro and in Vivo studies demonstrating progesterone and nesterone’s positive effects on myelin repair, this surely warrants the need for further studies in this area.

The Menstrual Migraine

Professor Merki-Field explained that women are 3x more likely to suffer migraines than men. Half of female migraines are associated with the menstrual cycle, being most likely to occur in the 2 days prior to menstruation or 3 days, during when the oestrogen levels drop. The Combined Oral Contraceptive Pill (COC) is significantly associated with migraines – either initiating, increasing the frequency and intensity of attacks or initiating aura migraine in prevously non-aura migrainers. Additionally COC increases ischemic stroke risk, as repeated migraines cause brain lesions, the CAMERA II study demonstrated these steadily progress in women specifically over time.

How to treat the menstrual migraine

Menstrual migraines are difficult to treat with pain medication as they frequently do not respond. These migraines are typically longer lasting and can have a severe impact on a woman’s quality of life – patients that take pain medication can overuse (take for 10 or more, or 15 or more days a month, depending on the medication) and are at risk of developing overuse headaches. A preferred option would be oestrogen patches and gel, to replace lost oestrogen in the hormone free interval, together with a progesterone only contraceptive pill. Short-term prevention can be achieved with triptans, 2-3 doses a day from 2 days prior to menstruation until 3-4 days during. A short-term course reduces the risk of developing medication-overuse headaches, defined as a headache occurring on 15 or more days per month. The drawback with this therapy is that natural cycles are not always predictable and therefore patients may begin taking the triptans too early or too late.

Contraception in WWE (Women With Epilepsy)

The interaction between EiAED (Enzyme-Inducing Anti-epileptic drugs) and COCs is well-documented. With a bidirectional action, both are able to reduce the effects of each other, therefore the risk of contraceptive failure is high (50% of WWE pregnancies are unplanned) and an adverse effect is seen on seizure activity. Additionally many EiAEDs are not recommended in pregnancy due to negative effects on the foetus. Considering this - barrier methods, rather than hormonal,  provide a more effective contraception option in WWE.

Let's talk sexual health

This Morning’s sessions can be summarised by a quote from Nick Panay’s presentation “VVA is an unmet need and cause of silent suffering”, infact that seems to be an over-riding theme of ISGE 2018 so far. As raised in yesterday’s intracrinology session, women are not talking about their sexual health, and commonly physicians are not asking them.

Sexual expectations

Rosella Nappi expressed her alarm at how recent data has shown that despite many women suffering from dyspareunia, pain during sex, they continue having sexual activity. The reasons for this are likely multifaceted but a key reason could be sexual expectations by a partner, and as I discussed in my blog post yesterday, unsurprisingly women with a partner have a much higher incidence of distress over sexual dysfunction, and therefore a reduced quality of life.

Let’s talk sexual health

Providing physicians with the right training and tools can enable them to embark on this “proactive approach” of opening sexual health discussions. A tool such as the Decreased Sexual Desire Screener, which has been validated for use by clinicians to assist in HSDD (Hypoactive Sexual Desire Disorder) diagnosis as per the DSM-IV-TR and ISSWSH criteria. The 5 question tool, completed by the patient, suggests primary care doctors should first ask permission to discuss sexual health with the questions – are you sexually active? Are there sexual concerns you wish to discuss?

How to diagnose and classify VVA/GSM

After opening discussions about sexual health, examination appears to be an essential part of diagnosing VVA and a means to exclude other problems, such as lichen sclerosis. To increase understanding of how to classify the condition, the new nomenclature of GSM (Genitourinary Syndrome of Menopause) should be adopted globally, and standardised universally accepted questionnaires developed to correlate severity with quality of life. There are a number of existing tools, some evaluated and others yet to be, but Dr Panay explained that the Day-to-Day Impact of Vaginal Aging (DIVA) questionnaire, relatively new but evaluated, has shown to have good correlations with vaginal and vulvar atrophy and urinary symptoms.

Treating GSM

IMS guidelines on managing VVA symptoms are available to download for free from the IMS website. Hormone therapy is frequently discussed but the adverse effects of systemic administration mean that the IMS recommend local estrogen therapy as preferential. However, the armamentarium can be widened by considering every treatment option, including lubricants, pelvic floor therapy etc., therefore, making individualised treatment for the patient easier.

Every woman is different and what works for one may not work for another. But whilst treatment is open to change, what we know for sure is that by improving the peripheral sexual response, sexual quality of life can also be improved.

Intracrinology: The open door to the future

Fernand Labrie, Celine Bouchard and Rosella E. Nappi kicked off ISGE 2018 with this opening symposium on Intracrinology in menopause.

Intracrinology and DHEA – the exclusive source of sex hormones post-menopause

Introducing the concept of intracrinology, Dr Labrie explained how the study of intracrinology began in the 1980s with the discovery of a novel combination therapy for prostate cancer and the observation of the role of androgens, made locally in the human prostate. The inactive precursor dehydroepiandrosterone (DHEA, also known as prasterone), produced by the adrenal glands, is transformed by enzymes into estrogen and androgens in peripheral tissue, with no biologically significant release of active hormones in to the circulation; only acting on the cells they are formed within before being deactivated. In the absence of ovarian oestrogen and androgen production, and the resulting loss of estradiol in blood and activity in all tissues, DHEA transformation within the cells becomes the only source of sex steroids within the post-menopausal woman.

DHEA reduces with age

The problem is that serum DHEA, the only source of intracellular estrogens and androgens after menopause, continues to reduce from 30 years of age and in addition, is highly variable between women. With increases in life expectancy, the reducing DHEA levels continue to reduce with the impact on quality of life more likely to be felt. Signs and symptoms of sex steroid deficiency are hot flushes, night sweats, insomnia, nervousness, lack of concentration, depression, vulvovaginal atrophy, sexual dysfunction, muscle loss, bone loss - fractures, loss of memory, loss of cognition, and possibly Alzheimer's disease.

DHEA and the vagina

Dr Celine Bouchard discussed the correlation of vulvovaginal atrophy (VVA) with the decrease in DHEA and how the administration of vaginal DHEA pessaries can be used to treat menopausal symptoms of VVA and GSM (genitourinary syndrome of menopause). DHEA exerts both estrogenic and androgenic activity on the vagina.

What is a healthy vagina?

A healthy vagina consists of 3 layers:

  1. The epithelium protects against infection (vaginal microbiome, immune response), provides lubrication and comfort in sexual activity depending on its length, width and strength.
  2. The lamina propria demonstrates elasticity and vaginal engorgement during sexual activity
  3. The muscularis are 2 muscular layers - circular and longitudinal, providing contraction

Importantly, the nerves present in the lamina propria and muscularis are vital in the sexual response.

The role of estrogen in a healthy vagina

  • Increase in vaginal thickness - associated with a decrease of basal cells and increase in superficial cells, lowering of pH and Increase in vaginal secretions

Both animal and human studies have found that when vaginal estrogen is reduced, collagen fibres also reduce, with increased activity of proteinease causing collagen degradation. Stress urinary incontinence has also been reported by the Women’s Health Initiative (WHI). However, no effect of estrogen has been shown on nerve endings.

DHEA has an androgenic action on all 3 layers of the vagina

Studies have shown that androgens produced by DHEA exhibit the following effects:

  1. Increase epithelium thickness
  2. Increase density of collagen fibres and thickness in the lamina propria
  3. Stimulate nerve endings in the muscularis
  4. Increase density of androgen receptors in all layers
  5. Increase in vaginal weight  - an effect 50% due to estrogens, 50% due to androgens

DHEA clinical trials

Serum DHEA reduces by at least 60% post-menopause, causing VVA symptoms in roughly half of post-menopausal women, increasing with age if untreated.

Clinical trials of DHEA suppositories for symptoms of VVA, including Labrie’s 2016 published study, met FDA guidelines and had 4 primary endpoints:

  • Reduction in parabasal cells
  • Increase in superficial cells
  • Reduction in vaginal pH
  • Improvement of dyspareunia (pain in sexual activity and one of the most problematic VVA symptoms)

Sexual dysfunction: An unmet need

Dr Bouchard explained that sexual dysfunction is a second indication of prasterone and an unmet medical need. Labrie’s 2015 study, a sexual function questionnaire, showed an improvement in all domains including arousal, lubrication, pain, orgasm, and satisfaction when 0.5% prasterone was administered intravaginally. Given that DHEA-formed estrogens and androgens are not released in significant levels in the blood, some other mechanism has to explain the beneficial effects. The androgenic action of DHEA on the nerve endings in the vagina could explain Labrie’s findings, a parasympathetic response would result in these positive effects that intravaginal DHEA seems to have on sexual dysfunction.

The impact of VVA and GSM on quality of life

Dr Rosella Nappi began her presentation by explaining how much of a medical challenge VVA is due to it being underreported by women, under-recognised by HCPs and, as a result, under-treated.  Recent surveys suggest that HCPs should be proactive and encourage open and sensible conversation on intimacy to help patients disclose their symptoms, as well as carry out diagnostic examinations. 

Nappi’s 2012 study surveyed 3520 postmenopausal women between 55-65 years of age to assess knowledge of vaginal atrophy. It found that almost half of those surveyed reported vagina symptoms, with only 4% attributing those symptoms to vaginal atrophy and 63% unaware that vaginal atrophy is a chronic condition. Of the half reporting symptoms, the most common symptom was vaginal dryness followed by dyspareunia.

Use it or lose it

Leiblum and Bachmann’s 1983 study found that women who remained sexually active had significantly higher levels of androgens. Leiblum concluded from this, and other studies that had found women who had regular intercourse had little or no discomfort and greater responsiveness, that some support for the adage ‘use it or lose it’ was obtained in the research. However, Dr Nappi, suggested that reduced blood flow and perhaps a lack of elasticity, for instance, from significantly reduced DHEA could account for feelings of discomfort, but of course DHEA levels were not measured at that time. There is a strong association between VVA and Female Sexual Dysfuntion (FSD), with Levine’s 2008 study finding that women with FSD were nearly 4 times more likely to have VVA than women without FSD.

Terminology & Symptoms

In 2012, the Board of Directors of the International Society for the Study of Women's Sexual Health (ISSWSH) and the Board of Trustees of The North American Menopause Society (NAMS) agreed that GMS is a more medically-accurate, all-encompassing and publicly acceptable term than VVA. They also defined that GMS symptoms may include but are not limited to:

  • Genital symptoms of dryness, burning and irritation
  • Sexual symptoms of lack of lubrication, discomfort or pain, and impaired function
  • Urinary symptoms of urgency, dysuria and recurrent urinary tract infections

In addition, other conditions, such as pelvic floor abnormalities or vulvodynia, should not better account for these symptoms.

The distress of sexual problems

Rosen et al, 2009 found that women in a relationship are nearly 5 times more likely to be distressed from sexual dysfunction. Reed et al, 2009, found that depressive symptoms amplified the menopausal experience or alternatively, severe vasomotor symptoms worsened depressive symptoms.  Infact, Reed’s 2017 study showed that vaginal dryness during intercourse was positively and independently associated with having moderate-to-severe depressive symtoms. 

Summary:

  • The action of both androgens and ostrogens on the 3 layers, make for a healthy vagina
  • A locally-administered therapy with both effects is needed
  • Nerve response from androgenic action is needed for sexual response
  • A proactive approach by HCPs, inc examinations, is needed to encourage women to disclose symptoms

Women should not only live longer but also maintain a good quality of life.

A year in review: Latest developments in women’s health

2017 brought some exciting and novel developments in women’s health, including some of the major updates we shared from the ESG congress last October. We shared interesting developments in women’s health key topics, including hormone-replacement therapy, contraception, and we have also provided some history behind steroid hormone receptor evolution. Let’s recap the key trends we have seen last year:

  • Breast cancer

Estrogen safety in relation to breast cancer (BC) risk is a widely discussed topic, data from the WHI RCT estrogen alone arm showed a decreased risk in breast cancer in women on the estrogen only treatment, this was also demonstrated in the study by Anderson et al., Lancet, Oncology, 2012, which showed a significant decrease in breast cancer incidence in women using estrogen and fewer deaths from breast cancers and other causes in the treatment arm compared to the placebo group. However, The NURSE study (Sisti et al., Int J Cancer, 2016) showed MHT use increased risk of luminal A and B breast cancer in women who used estrogen at long term treatment but not at short term treatment. Evidence from epidemiology also confirms the length of estrogen exposure increases the risk of breast cancer, as does age at menarche and age at menopause. Literature shows estrogen can promote or even initiate breast cancer, whereas preclinical studies show that aromatase inhibitors and antiestrogens can help prevent breast cancer. Data from the collaborative group on hormonal factors in breast cancer have shown that pre-menopausal women have a higher risk than postmenopausal women of the same age.

Although the results from studies seem to lead to different conclusions, comparing all the data available suggests that for women with a high BMI and high insulin resistance, estrogen could help to decrease BC risk by decreasing insulin resistance.  

  • Obesity

One of the most prominent changes during menopause is fat gain and change in a women’s body shape. Unlike other menopausal transitions, hormonal interventions currently available are not targeting this issue, which can have a negative impact on the overall health. The Interheart study and some recent data from the WHI, show it’s the site of fat that’s the biggest cause for concern as an increase in abdominal fat is linked to increased CVD risk.

Data from the WHI observation study showed women can be separated into four sections: metabolically benign normal weight, at risk normal weight, metabolically benign overweight and at risk overweight. These four categories scored very differently showing links between phenotypes, metabolic type and insulin resistance. Looking at women who have features of metabolic syndrome, showed they had higher markers such as IL-6. The very skinny or the very obese are more at risk than those who are or moderately obese.

  • Contraception

Lower levels of estrogen and progesterone can affect a number of different body functions, such as contraception. It’s important to understand that under the age of 50 women must use contraception for 2 years after diagnosis of menopause, over the age of 50, of they must use contraception for 1 year after diagnosis.

As we discussed in a previous post last October, contraception has also an important impact on diagnosis: if a patients is using a contraceptive doctors need to carry out FSH and LH twice, 6 weeks apart. Whilst tests can be done if a patient has an IUD or is on the POP, patients must stop COC for a cycle and stop DMPA for testing. When diagnosing, it’s important to think about the opportunities for screening and education. Discuss cervical screening, breast self-testing, osteoporosis risk, ovarian cancer, diabetes and incontinence, talk about symptoms and risk factors that increase with age.

  • Technology

Interestingly, now scientists are exploring whether transplanting lab-made ovaries might stop the common symptoms of menopause, such as hot flashes, sleep problems, weight gain, and worse, bone deterioration. In one of the first efforts to explore the potential of such a technique, researchers say they used tissue engineering to construct artificial rat ovaries able to supply female hormones like estrogen and progesterone. The results of the study were published in October last year in Nature communications. When tested in rats, the pieces of tissue, known as organoids, were better than traditional hormone replacement drugs at improving bone health and preventing weight gain. The treatment was also as good as hormone drugs at maintaining healthy tissue in the uterus.

Clinical trials of artificial ovaries are not likely to happen soon but it will definitely be interesting to see what will happen in 2018!

Are estrogens alone really safe for breast in menopausal therapy?

To close off the discussion around the safety of estrogen at ESG, Anne Gompel shared her views on estrogen safety in relation to breast cancer (BC) risk. Data from the WHI RCT estrogen alone arm showed a decreased risk in breast cancer in women on the estrogen only treatment. This was also seen in Anderson et al. Lancet, Oncology, 2012 which demonstrated a significant decrease in breast cancer incidence in women using estrogen and lower deaths from breast cancers and other causes in the treatment arm compared to the placebo group. However this data is the exception not the norm, data from case control and cohort studies between 1996-2005 before the WHI data was published showed there was a significant increase in risk of BC in the estrogen only group, although this risk was still lower than risk increased by combined MHT.

The NURSE study (Sisti et al. Int J Cancer, 2016; 138: 2346-56) showed MHT use increased risk of luminal A and B breast cancer in women who used estrogen (mostly CEE) at long term treatment but not at short term treatment highlighting that length of treatment in WHI was potentially too short to demonstrated increased risk and explain the contradiction in data. New data from the E3N cohort study recently published showed no increased risk of BC in the estrogen only arm either but it is thought this may due to low population density.

So why is the data different between studies? Maybe CEE may act differently on the breast than estradiol. Perhaps it’s due to the population included, the WHI population was older and the prevalence of obesity/ISR was different or maybe the type of BC identified was different. Although it is know that women with a high BMI using MHT are not at a higher risk of BC, the NURSE study showed those with a BMI less than 20 who used MHT had higher BC risk. This may be another reason for inconsistencies in data.

Anne also questioned if oophorectomy could be a cofounding factor? In the WHI estrogen only arm and the NURSE study there was no difference in BC risk observed between those who had a hysterectomy and those who hadn’t only long term use of estrogen resulted in increased risk.

Evidence from epidemiology also confirms the length of estrogen exposure increases the risk of breast cancer, as does age at menarche and age at menopause. Literature shows estrogen can promote or even initiate breast cancer. Preclinical studies show that aromatase inhibitors and antiestrogens can help prevent breast cancer. There are also other estrogen-related risk factors including breast density, plasma E2, age at first live birth and BMI. Data from the collaborative group on hormonal factors in breast cancer have shown that pre-menopausal women have a higher risk than postmenopausal women of the same age.   

The proliferative effects of estrogen

Promotion of estradiol can contribute to maintenance of a proliferative state through genomic and non-genomic pathways through the alpha estrogen receptor and can result in the increased proliferation of breast cancers.  Data from Song et al. shows that E2 is active at much lower concentrations than CEE, but CEE can still activate proliferation even at lower concentrations.  Estrogen can also activate metabolites outside of the alpha receptor including 2-OH, 4-OH and 16 alpha OHE.

The benefit of aromatose inhibitors is that they can stop the conversion of androgens into estrogens, whilst antiestrogens can stop cell proliferation induced mutations that lead to breast cancer. Many studies have demonstrated prevention and indeed protection from breast cancer.  The HOT study looked at use of MHT and Tamoxifen. Data showed that women who had used Tamoxifen with E2 had a significant decrease in the risk of luminal A breast cancer.

The conclusion is not firm, but comparing all the data suggests that for women with a high BMI and high insulin resistance, estrogen could help to decrease BC risk by decreasing insulin resistance.  There may also be a difference on breast impact between E2 and CEE. Anne believes transdermal E2 remains the best option from CVD endpoint perspective but that both options are the same for the breast!

Obesity and contraception

Obesity is defined by the WHO as “a body fat of greater than 35 % in women calculated using dual energy X-ray absorptiometry (DEXA). According to WHO, currently 20-30% of adults in Europe are clinically obese and prevalence of obesity had doubled in less than 20 years.

As prevalence increases it’s important to determine if obesity is a risk factor for pregnancy. It is known that extremes in weight can effect fertility. Obesity is associated with ovulatory dysfunction, a decreased rate of spontaneous pregnancy and a decreased response to fertility treatment.  However despite this, more than 20% of pregnancies in the United Kingdom and other developed countries take place in obese women.

As an important part of obesity, the metabolic syndrome involves numerous metabolic abnormalities that increase the risk of cardiovascular disease and diabetes. It is well documented that pregnancy in obese women often leads to several morbidities.

As a result, it’s important to look at the link between oral contraceptive pills and body weight. To date literature does not suggest that contraceptive pills increase body weight. It is known that most adult’s gain weight over time. Pregnancy is also associated with weight gain. For obese women going though pregnancy, the weight is often retained post-partum.

Are contraceptive efficacious in obese women?

The majority of data shows that there is not a decreased efficacy of contraceptives in obese women with the exception of the transdermal combined contraceptive patch that is less effective in a woman with a body weight of more than 90kg. Pharmacokinetics studies with COC and CVR found reduced ethinylestradiol levels, but no decreased progestin levels in obese women. This didn’t result in decreased ovarian suppression as the progestin is the most relevant for contraceptive efficacy, but as achieving steady state of progestin levels is delayed, it may be beneficial to provide obese women additional protection for the first 14 days.

Are COC pills safe in obese women?

As we’ve heard throughout the conference the biggest concern for use of an estrogen containing treatment is the increased risk of VTE. Obesity doubles the risk of VTE so when combined with COC has a large impact on potential risk. However the combined risk of obesity and pregnancy far exceeds the risk of obesity and COC use. As COC does further increase the risk of VTE and ATE in obese women it should only be used if no other acceptable contraceptive methods are available to the patient.

Obese women are also more likely to have comorbidities such as HTA, hyperlipidaemia, diabetes or high risk of CCV diseases that also increase risk of MI and stroke.

Are there benefits of using COC in obese women?

Obese women have a higher risk of endometrial cancer and may benefit from the decreased risk of endometrial hyperplasia and endometrial cancer associated with COC use.

What about using POC in obese women?

At present no data indicates decreased efficacy of POP in obese women, considering this does not increase VTE and ATE risk in obese women, it is an important and safe option.

Using contraception to prevent unwanted pregnancies is recommended to all women regardless of their weight. POC and IUD have minimal metabolic effect and are effective in obese women so should be tried over use of COC which should only be used if other methods are not acceptable due to its increased risk of VTE and ATE.

Bridging the contraception menopause gap.

Ali Kubba presented us with a case study of a 44 year old women who has been on the progesterone only pill (POP) for four years and had begun noticing some changes; her period is heavier and she’s suffering from vaginal dryness and painful sex. She’s looking for non-contraceptive benefits from her pill as she wants her treatment to address all the symptoms she’s experiencing.

To start, Ali looked at the symptoms she’s suffering from.

-          Could her symptoms be phsycho-sexual related to stress and responsibility of life?

-          Is she suffering from any other menopausal symptoms she’s embarrassed to raise?

-          Could it be the POP that’s the cause of her vaginal dryness?

-          Do we need to do a hormone test?  

-          What are the reasons she is not on the COC pill?

He then discussed, the options available to his patient;

-          Could we change her POP?  Dependent on her pill-type, could we move her to a lower dose pill?

-          Could an IUD be a viable option? This could help with heavy menstrual bleeding

-          Is the Copper IUD an option? This may impact her bleeding schedule but is non-hormonal so may remove vaginal dryness

-          Could she use a COC/patch/ring? COC has a number of additional benefits which are even more significant to women over the age of 40.

-          Could he suggest barrier contraception? This could be an option, if she and her sexual partner are comfortable with this method and familiar with it.

-          What about DMPA? – Ali noted this should be the  last choice, due to concerns of links to bond density and CVD markers

What questions did she have?

-          Am I too old to use COC? No, age alone is not a contraindication to anything!

-          When do I stop contraceptive treatment? Under the age of 50 she must use contraception for 2 years after diagnosis of menopause, over the age of 50, she must use contraception for 1 years after diagnosis.

As she is presenting symptoms of estrogen deficiency, it could also be possible to combine the POP with MHT or combine her POP with a local estrogen or lubricant. Moisturisers and lubricants can hydrate the vaginal tissue, remove sensitivity and reduce pain and discomfort but only have a short term effect.

How would we diagnose menopause?

To diagnose menopause we need to look for the presence of amenorrhea and key symptoms. If a patients is using a contraceptive we need to carry out FSH and LH twice, 6 weeks apart. Whilst tests can be done if a patient has an IUD or is on the POP, patients must stop COC for a cycle and stop DMPA for testing. When diagnosing, it’s important to think about the opportunities for screening and education. Discuss cervical screening, breast self-testing, osteoporosis risk, ovarian cancer, diabetes and incontinence, talk about symptoms and risk factors that increase with age.

So what would be the desirable features of a contraception taken up to/during climacteric?

-          Sufficient efficacy

-          Improved sex life

-          Control of climacteric symptoms

-          Control of “normal” menstrual cycle

-          Decreased risk of gynaecological pathology and hysterectomy

-          Provide protection against osteoporosis

-          Avoidance of systemic side effects

Ali believes that COC is an appropriate choice for women at 50 as it regulates anovulatory cycles and the cardiovascular risk is small. Data from the RCGP study in over 46,000 women has shown that OC use is even associated with a 20% reduction in risk of colon cancer, a 34% reduction in endometrial cancer and a 33% reduction in ovarian cancer.  IUD is also an option, if it’s fitter after the age of 40 it can be kept till menopause.

Perimenopause is a time of; opportunity, risk, confusion and optimism. Ali suggests to use this time to discuss with the patient and get them thinking about what is best for them from a contraceptive and overall health perspective, it’s important to remove concerns around age and myths around treatment options! 

 

Non-oral hormone contraception

Luis Ignacio Leta Lasa followed on from Kristina’s presentation looking at the potential use of non-oral hormone contraception. Non-oral hormone contraceptives can be separated into two groups; combined hormonal contraceptives which are short acting reversible contraceptives (SARCs) such as the transdermal patch, vaginal ring and injectable and progestin only contraceptives which are long acting reversible contraceptives (LARCs) including the implant and LNG-IUS.

SARCs vs LARCs

SARCs can provide a number of advantages when used including; provision of good cycle control, cyclic bleeding that mimics natural menstruation, non-contraceptive benefits, protection against some forms of cancer, quick return to fertility and the avoidance of invasive intervention. However disadvantages include; the fact they need high compliance otherwise they are only minimally effective, they present hormonal dependent side effects, are linked to increased VTE risk, women may experience some withdrawal symptoms, they can interact with other drugs and can’t be used by a woman who is breast feeding.

The three different modalities of SARC (patch, ring and injectable) all contain estrogen and progestins but have different methods of administration and regimens. In Luis’ presentation he shared his experience of the vaginal ring in Spain. The TEAM’s study assessed the reasons for women choosing the pill, the patch or the ring. The study found the most popular method was the vaginal ring due its monthly regimen, convenience and lowered probability of non-compliance. The Remo study looked at non-compliance of different modalities, 61% of pill users reported forgetting to take pills, 32% of patch users forgot to take medication whilst only 22% of ring users reported compliance issues. Results suggest non-compliant behaviour is more frequent in users of daily contraceptive methods compared to users of monthly contraceptive methods. The HABITS study looked at the contraceptive modalities used in the general female population compared to HCPs in Spain. The vaginal ring was used by 3% of the general population and by 13% of the HCPs whilst the pill was used by 17% of the population compared to 13% of the HCPs. This study showed that HCPs opt for LARCs because of their effectiveness and safety whilst the general population rely more frequently on the condom and surgical methods.

The LARC methods have some important advantages; they are highly effective and don’t require compliance. They often limit or completely reducing bleeding, result in fewer side effects due to the absence of estrogens and have no increased risk of VTE. They also have positive effects on dysmenorrhea, endometriosis and heavy bleeding and have few contraindications. As with SARC methods, there are also disadvantages such as development of an unpredictable bleeding pattern which is the leading reason for leaving the method, androgenic effects, hypoestrogenic symptoms, reduced effect on PCOS, lower user control, requirement for long term family planning and dependency on a provider to stop the method.

Whilst they are all estrogen free the have different methods of administration and regimens either via intrauterine insertion or a subdermal implant. LARCs are also not equal in terms of effectiveness. The implant appears to be the most effective and has a much lower percentage of pregnancies when in use, only 5 pregnancies in every 10,000 women compared to 80 using the copper IUD and 20 using the coil. There are also concerns over ease of implementation, in a discussion between Spanish HCP, 93% said they had issues inserting and IUD and 27% said they had experienced difficulties inserting an implant.

Hormone contraception has more advantages than risks including important non-contraceptive benefits. Non-oral hormone contraception is usually associated with better compliance with LARC methods being the most effective as they are not dependent on the user, considerations such as unpredictable bleeding pattern and dependency on a HCP in order to stop are current barriers to further adoption of this effective method. 

Contraception: a pre-requisite for reproductive health

Kristina Gemzell-Danielsson, kicked off the contraception session on the final day of ESG by discussing the unmet need of contraception and its consequences. She began by emphasising that effective contraceptive methods and safe abortion care are pre-requisites for reproductive health.

There are currently 23-47,000 women dying annually due to maternal deaths in the developing regions. Around 7 million women have also been left with temporary or permanent disabilities.  Maternal deaths have shown to result in a higher neonatal death ratio and are a huge financial burden for women, their families and the health systems. It’s estimated by the WHO that 300 million USD is spent each year on treating the complications. In 2016, Lancet published a report looking into the main causes of maternal deaths that showed 18% were cause by complications of abortion, deaths that are avoidable! In humanitarian settings, unintended pregnancy and unsafe abortion risk is increased due to interruptions to health services and supplies, disrupted family and social structures and loss of livelihoods and assets.

Legality of abortion does have an impact. In Romania, when abortion became illegal there was an increase in maternal mortality but when it became legalised again the rate also dropped.  Data from WHO showed that in regions with more liberal abortion law, abortion rates have declines, whilst in areas where abortion is illegal the numbers are increasing. When abortion is available on request it results in the lowest rate of mortality, in the USA legalisation lead to a 73% decline in maternal mortality.

Key stakeholders need to remember that why there is an inverse link between abortion legality and abortion rate, there is a direct link between use of contraception and abortion. So the only definite way to prevention abortions is through education and contraception. Contraception has been shown to improve women’s welfare and the welfare of their children and society.

But do we need new contraceptive methods?

225 million women lack access to safe and accepted contraceptive methods, more than 50% of pregnancies are unintended. In order to improve uptake and compliance to contraception, we need to dismiss the myths around oral contraceptive. For example the notion that oral contraceptives cause cancer. Hannaford et al. BMJ 2007;335:361 showed in a UK study that women on the pill had a 12% lower cancer risk compared to placebo, with biggest reduction in ovarian cancer.

There are also other benefits of the pill that many women don’t know about which leads to poor adherence. So many women are negatively impacted by their bleeding cycles which could be addressed by the pill. The common trend is for people to want “natural” things, but it is important to consider if this is best. In the natural situation women give birth for the first time at 18 or younger, whereas in Europe on average women have their first child at 29 and only have 1-2 pregnancies with all children surviving compared to 12-15 deliveries in the natural setting, many of which aren’t successful.

The unmet need in contraception

We need to create improved methods for contraception on demand.  More works need to be done on non-hormonal long acting methods, methods for dual protection again STIs, HIV and pregnancy, reversible methods for men and methods with added health benefits.

The American CHOICE study, where women chose their method of contraception, showed that LARC methods were more successful in preventing pregnancy followed by pill, patch and ring but were not the most popular. Studies in Sweden showed that at younger ages, short-acting methods are more popular, with long-acting becoming more popular later in life. Analysis has also shown that if 5% of women would switch to LARC, 3, 5000 unwanted pregnancies would be prevents saving millions of euros a year.

Further work must be done to improve access to safe and effective contraceptive methods and to develop new alternatives.  As the use of modern contraceptive methods increase, abortion rates continue to decline, this is key in preventing unwanted pregnancies. With unintended pregnancies placing a substantial economic burden on healthcare systems (£382 million annually in the UK and $4.6 billion in the US) we need to achieve more widespread use of the most effective contraceptive methods such as LARCs.

In order to be successful in reducing abortion rates and maternal deaths, we need to dispel women’s fear in contraceptive methods, work on reversible male contraception and focus on support and information post-abortion around the use of contraception-more work to be done!