Time to give IVM a second chance?

The area of assisted reproduction has seen development of a great number of technologies. Some have come and gone, while others have established their importance and have been further developed over the years. And, while it is clear that great steps have been made in the effectiveness of assisted reproductive technology (ART), there are still some key improvements to be made. These include:

-          Reducing incidence of OHSS

-          Reducing psychological pressure

-          Reducing financial pressure

-          Increasing access to treatment

When considering how to make these improvements, we must consider the value of the procedures being offered in clinics today. Are there some that may be being overused? And are some not being used enough? At COGI 2018, we listened as a panel of expert speakers discussed these key questions.

 

Reconsidering IVM

In vitro maturation (IVM) involves the procedure of retrieving early follicles, followed by their maturation in the laboratory. The process was initially developed by Pincus and Enzmann in 1935, with Cha et al the first to successfully deliver a human live birth in 1991. However, in recent years the procedure has been relatively side-lined in clinics.  

Dr. Johan Smitz discussed why this may be. He explained there were two key reasons why IVM remains under-utilized:

-          Follicle heterogeneity - injecting hCG on the small 6-12 mm follicles can cause asynchronous maturation of the oocyte

-          Inappropriate signalling -  IVM can result in spontaneous re-initiation of meiosis

In addition, further issues are associated with IVM. There is a steep learning curve for those undertaking the procedure and a current lack of clear standard operating procedures means that there is a risk that success would not be easily standardised between centres. Also, Dr. Smitz explained that there are certain prejudices related to IVM, with many women believing that the treatment is more painful than IVF. However, this may not necessarily be the truth.

Despite these issues, IVM has a number of significant advantages. When compared with IVF, IVM requires less consultations, monitoring and injections. Dr. Smitz also explained the treatment can be more cost effective and more comfortable.

IVM is also the only ART with zero risk of OHSS. This means that the procedure could be especially suitable for women suffering from Polycystic Ovary Syndrome (PCOS).

 

How can we improve IVM?

Dr. Smitz outlined five key steps to improve the IVM procedure.

Abandon the hCG injection to avoid the issues associated with asynchronous maturation

-          Apply a positive in-vitro maturation stimulus to help to avoid the issues related with inappropriate signalling

-          Give FSH or HO-hMG Priming at 2-3 days

-          Use defining culture media

-          Use a pre-maturation culture

 

Is Capacitation – IVM a step to the future?

Adopting capacitation culture (CAPA) conditions was shown to improve success of IVM. Dr. Smitz shared data from five pilot studies demonstrating that CAPA-IVM can result in high implantation rates and increased number of embryos per oocyte-pickup. The results of these studies remain unpublished at this time however we cannot wait to read the full reports! Further study, improvement and adoption of this procedure can clearly benefit the field and we are excited to see what comes next.

Considering the role of HRT in CHD

Coronary Heart Disease (CHD) is well understood to be one of the major causes of mortality worldwide. Risk factors are generally equal for men and women, except for one main consideration: Menopause.

In an inspiring session at COGI, Prof. John Stevenson explained that women who experience earlier menopause are the most at risk. Indeed, those who experience menopause below the age of 40 are at 2x greater risk of CHD than women who are above 45 years. So, what can be done?

 

An opportunity for HRT?

Prof. Stevenson explained that HRT could provide an answer. Research indicates that estrogen has a clear biological effect on the cardiovascular system, demonstrating beneficial effects on some of the key risk factors of CHD. These include dyslipidaemia, insulin resistance and arterial endothelial function. [1] However, dealing with the problem is not that easy.

The disparagement of HRT in the 2000 Women’s Health Initiative (WHI) study still fuels debate over the benefit and safety of its use for CHD.[2] In addition, some randomised controlled trials (RCTs) have suggested only negligible effects.[3]

While Prof. Stevenson accepted that there is a lack of definitive evidence supporting HRT as a prevention for postmenopausal CHD, he demonstrated that there is a growing number of epidemiological and observational studies supporting its use. One recent Cochrane review studying 40,410 women indicated a decrease in CHD risk for those starting HRT treatment within 10 years of menopause.[4] Similarly a separate study suggested that women <60 years treated by HRT experienced a reduced total mortality.[5] Long term safety has also been demonstrated with even the WHI publishing data showing that in women aged 50-59, treatment with HRT provided in a hazard ratio of 0.65 (CI 0.44-0.96). [6] In older women there was no statistical difference. [6]

 

Timing is key

Time is an essential factor to consider.  Prof. Stevenson explained that to have a beneficial effect, early intervention is needed. In fact, research supporting the use of the HRT as a primary prevention of CHD in postmenopausal women has demonstrated no benefit if the intervention in older women.[3],[7] However, it was stressed that while there was no benefit for late intervention, there was also no evidence of harm.  

There are other considerations to take into account. Benefit may also depend on the type of hormones being administered or the dose of hormones. Prof. Stevenson concluded in stating that HRT should only be used where appropriate and with careful consideration.


Sources:

[1] Stevenson JC. HRT and cardiovascular disease. In Lumsden, MA, ed, Best Practice and Research Clinical Obstetrics and Gynaecology, Vol 23. Elsevier 2009:109–120. https://www.sciencedirect.com/science/article/pii/S152169340800148X

[2] Rossouw JE, Anderson GL, Prentice RL et al.; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–333. doi: 10.1001/jama.288.3.321

[3] Manson JE, Hsia J, Johnson KC et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med2003;349:523–534. doi: 10.1056/nejmoa030808

[4] Boardman HM, Hartley L, Eisinga A et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women.Cochrane Database Syst Rev. 2015:10(3);CD002229. doi: 10.1002/14651858.CD002229.pub4

[5] Salpeter SR, Walsh JME, Greyber E et al. Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis. J Gen Int Med 2004;19:791–804. doi: 10.1111/j.1525-1497.2004.30281.x

[6] Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women’s Health Initiative Randomized Trials. JAMA. 2013;310(13):1353–1368. doi: 10.1001/jama.2013.278040

[7] D.M. Herrington, D.M. Reboussin, K.B. Brosnihan, P.C. Sharp, S.A. Shumaker, T.E. Snyder, et al., Effects of estrogen replacement on the progression of coronary–artery atherosclerosis, N Engl J Med 343(8) (2000) 522–529.

Social freezing - A debate

 Traditionally oocytes were only frozen for the purpose of fertility preservation, including for women who may be undergoing chemotherapy.

However, in recent years the concept of social freezing has flourished, where oocytes are frozen for non-medical reasons. This decision to delay conception and pregnancy may be taken for a number of different reasons. Indeed overall, research suggests that both age of marriage and pregnancy are generally rising in high economic countries.

At COGI we were treated to an engaging debate on the key discussions surrounding social freezing, considering whether it truly is a benefit or whether it should be seen as a purely commercial function.

Dr. Ana Cobo opened the discussion, explaining that social freezing can provide effective results in younger women. Oocyte quality is affected by age, therefore the younger the age when the oocyte frozen, the better the chance of a positive clinical outcome later on. However, Dr. Cobo discussed that the majority of patients desiring social freezing were over 35 years old. 16% were 40 years or older. She explained that the outcomes in older women were significantly reduced and that the quality of the oocytes would be severely impacted.

Even in younger healthy women, there is not a complete success rate, with survival failure still a risk. Dr. Cobo shared data from a cohort of younger women which also demonstrated that after a single cycle failure, risk of a second cycle failure was 4x greater. It is therefore important to manage expectations and provide clear information to all women desiring to undertake social freezing.

 

Is social  freezing a purely commercial product?

In his presentation, Dr. Norbert Gleicher reiterated the importance of providing women with accurate and evidence based information in order for them to make an informed decision before undertaking social freezing.

He argued that social freezing can be seen as a purely commercial product. In the US, misinformation and aggressive advertising results in misunderstanding that oocytes can be frozen at any age and will be able to be used to deliver a healthy child when desired. Dr. Gleicher explained that social freezing is often advertised as an insurance, when in fact the success of the process is much less certain.

We must also consider the low number of returning women to actually use the frozen oocytes. In one framework, Dr. Gliecher discussed that only 12% women actually returned. With the high upfront costs associated with freezing oocytes, the low level of returning women and the uncertain level of success, we can see why it is so important to understand why ensuring a high level of informed consent and transparency is so important.

 

Is social freezing cost effective?

Dr. Zion Ben Rafael closed the debate by arguing that social freezing is not cost effective. He explained that the cost is an estimated $1million per birth and that the process is only cost effective after the age of 37. However, with live birth rates known to be lower in women over 35, while the process may be cost effective there is no guarantee of success. While success rates are higher in younger women, Dr. Rafael explained that the younger a woman is, the less likely it is that they will use their frozen oocytes as it more likely that they will have a natural birth.

Why we should consider epigenetic factors for IVF

 Research has demonstrated that children born through assisted reproductive technology (ART) are at a higher risk of preterm birth and associated morbidity.[1] So, why is? Well, the cause is likely to be multifactorial. There is the potential that IVF techniques could result in obstetric complications that negatively impact the child, or that ovarian stimulation may negatively impact placental development.[1] However, growing evidence suggests that parental characteristics play a crucial role.  

The opening night of the 26th Annual COGI Conference kicked off with a thought provoking exploration of this fascinating area of epigenetics, considering how parental factors can affect the health of an IVF child.  Epigenetics, the speakers explained, is inherently linked to the concept of developmental plasticity. Specific input during development can produce a lasting difference in phenotype.[2] As such, factors including fetal programming, metabolic endocrine disruption and structural change in organs can all significantly affect the birth of the child.

Effectively understanding how parental factors may affect future health outcomes could help us in the drive for increased precision medicine, where we can adapt specific treatments based on individual factors.

 

Caesarean Sections

 

Prof. Giancarlo Di Rienzo explained that IVF is associated with an increased use of Caesarean Section (CS) during birth. He showed that CS is in turn linked to increases in risk of:

-          Neonatal morbidity

-          Auto-immune diseases in the offspring

-          Metabolic disease in the offspring

 

Maternal Obesity and Smoking

 

Maternal obesity was highlighted as an important factor leading to higher risk of pre-term birth. Similarly, maternal smoking was shown to cause significant epigenetic changes. Interestingly, not only does smoking negatively affect the mother and the unborn child, but if the child is a female the smoke could also affect her reproductive cells. Therefore, these epigenetic changes could result in transgenerational negative effects. Indeed, Prof. Rienzo explained how increased risk of both pre-term birth and small for gestational age (SGA) infants has been shown to span multiple generations.

In his presentation, Prof. Nick Macklon also reiterated the role that diet and nutrition has in affecting epigenetic change.  

 

Could a Mediterranean Diet help?

 

Prof. Macklon explained that a Mediterranean diet is often recommended to women preparing for IVF. But is there really a benefit? To answer this question, he shared data assessing whether the diet has any significant positive impact on embryo quality and overall IVF success rate.

While there was some cohort evidence that the Mediterranean diet positively related to clinical pregnancy, Prof. Macklon explained that we must consider the important confounding factors including microbiome and genetics. He demonstrated that the positive impact of the diet, along with other advertised nutritionals on IVF outcomes is very slight, however this may have a greater cumulative effect over time.


Sources:

[1] A. Pinborg, U.B. Wennerholm, L.B. Romundstad, et al; Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis, Human Reproduction Update, Volume 19, Issue 2, 1 March 2013, Pages 87–104, https://doi.org/10.1093/humupd/dms044

[2] Nettle D, Bateson M. Adaptive developmental plasticity: what is it, how can we recognize it and when can it evolve?. Proc Biol Sci. 2015;282(1812):20151005.

The freeze all debate: an introduction

Despite IVF technology evolving significantly over the last 40 years, the process is far from perfect. Current research is still incredibly important to study how we can improve live birth rates, patient safety and reduce the time to live birth. [1]

One area of particular debate is whether a freeze all or fresh transfer approach is preferable when transferring embryos. But what is a freeze all approach and why is this discussion important?

What is a freeze all approach?

Following oocyte stimulation, retrieval and oocyte fertilisation, two options for embryo transfer are available. During a fresh embryo transfer a selected embryo can be transferred back to the mother soon after oocyte retrieval. Alternatively, the embryos can be vitrified and stored for transfer later. This is also called the “freeze all” approach, where embryos are then thawed before transfer.[1] 

The freeze all method was initially developed for the purpose of fertility preservation, such as for patients due to undergo chemotherapy. However, there is evidence that it may be a preferred option for all fertility patients. This is in light of data suggesting that staggering oocyte stimulation and embryo transfer allows the endometrium to be better primed for receipt of an oocyte.[2] There is also evidence that it can lessen the risk of ovarian hyperstimulation syndrome (OHSS).[1]

 

Effect of the freeze all method on outcomes in pregnancy, birth and neonate health

A 2014 retrospective cohort study, the largest of its kind, concluded that the use of vitrified thawed embryos did not worsen the outcomes in respect to pregnancy, birth and neonate health in comparison to the use of fresh embryos. The only notable differences were a greater number of interventions and a lower number of urinary tract infections reported with the vitrified oocyte group compared to the fresh oocyte group.[3]

 Further data from the Society for Assisted Reproductive Technology in 2011, found that gestational carriers receiving frozen-thawed embryos had 7-8% higher age-adjusted success rates than non-gestational carrier comparators receiving fresh embryos.[2]

 

The programmed endometrium 

There is evidence to suggest that ovarian stimulation can cause irregular endocrine milieu which could hinder embryo implantation during a fresh IVF cycle. Whereas, the freeze all method allows thawed embryos to be transferred at later cycles when the endometrium is programmed to be more receptive to freeze-thawed embryos.[1]

 

Risk of OHSS

There is evidence that the risk of developing OHSS is greater during fresh IVF cycles as oocyte development, retrieval and embryo transfer occur around the same time. It has been suggested that staggering oocyte stimulation by using the freeze all method could reduce this risk. Robust randomised controlled trials are underway to determine if the freeze-all method could lessen the risk of OHSS without reducing successful treatment outcomes.[1]

 

The debate continues at COGI

The World Congress on Controversies in Obstetrics, Gynecology & Infertility (COGI) congress will be held in London on 23rd-25th November, with key discussions including a debate on social freezing and a presentation titled ‘the end of freeze all?’. We will be attending to provide you with the latest updates from the conference, including research highlights and key messages.

Sources:

1.       Niederberger, C., Pellicer, A. and Cohen, J. et al. Forty years of IVF. Fertil Steril. 2018; 110 (2), 185-324.

2.       Society for Assisted Reproductive Technology. 2010 and 2011 SART fertility success rate report. Available at: http://www.sart.org/SART_Success_Rates.

3.       Cabo, A., Serra, V., Garrido, N. et al., Obstetric and perinatal outcome of babies born from vitrified oocytes. Fertil Steril. 2014; 102 (4), 1006-1015.

HRT to treat symptoms of menopause

Menopause is an event that naturally occurs in all women from around the age of 40 onwards. It is characterised by the lack of periods and concurrent reduction of oestrogen and progesterone levels in the blood, which has a wide range of effects on the body.

How is menopause diagnosed?

Symptoms of menopause can include hot flushes, night sweats, joint aches and headaches, all of which can be particularly bothersome in day-to-day life. Menopause is typically diagnosed retrospectively based on the presence of these symptoms, the patient’s age and frequency of periods. However, the US Food and Drug Administration (FDA) has recently permitted the marketing of the first diagnostic kit that can identify patients who are entering their menopausal transition. The technology uses declining levels of anti-Müllerian hormone concentrations in the blood as a marker, thus allowing treatments to be administered promptly.[1]

What is the current treatment landscape for menopause?

Lifestyle changes such as healthy eating, reducing alcohol intake and regular exercise can sometimes help to alleviate menopausal symptoms. In some cases, hormone replacement therapy (HRT) may be prescribed to top-up oestrogen and/or progesterone levels, aiming to restore the hormonal balance. HRT for menopause is a key area of interest and has been the focus of recent major randomised controlled trials (RCTs).[2]

What do the experts say on HRT?

In theory (and in practice), HRT has the potential to reverse the symptoms of menopause. However, there have been some concerns on the side effects associated with this type of treatment. Although both the North American Menopause Society (NAMS)[3] and European Menopause and Andropause Society (EMAS)[4]  consider HRT to be the most effective treatment for vasomotor symptoms, genitourinary syndrome of menopause and preventing bone loss and fracture, they do highlight the risk of cardiovascular events, endometrial hyperplasia and certain cancers associated with HRT. To tip the benefit-risk balance in our favour, the appropriate dose, formulation and route of administration should be all individualised to the patient at treatment initiation and adapted throughout treatment where necessary. [2]

How is the field of HRT evolving?

Following the publication of initial findings from an RCT by the Women’s Health Institute (WHI) there were fears that HRT increases the risk of breast cancer and cardiovascular disease. As a result, the use of non-FDA-approved compounded hormone therapy in the US increased and FDA-approved hormone therapies declined.[5] However, subsequent detailed analyses showed that these fears were misrepresented and the risks were only applicable to a small subset of patients. Since then, it has been an upward battle to turn the field around and encourage HCPs and women to consider the evidence and opt for approved therapies, rather than taking non-approved compounded therapies with unknown risks.

The change is upon us, slowly but surely

The US has recently seen the approval of the first bioidentical combination HRT containing 17β-estradiol and progesterone (chemically-identical to those found in the body) for the treatment of moderate to severe vasomotor symptoms associated with menopause in women with a uterus. The REPLENISH trial demonstrated that the frequency and severity of vasomotor symptoms were significantly decreased with the combo therapy compared with placebo and no endometrial hyperplasia events were reported over the 12-month trial period.[6] This approval marks a milestone in the field of HRT and could be the turnaround needed to ensure women receive the most appropriate treatment for their menopause.

Based on the recent diagnostic testing and HRT approvals, could it be time to revisit the guidelines? What are the learnings from REPLENISH and other pivotal trials that can be applied to pipeline therapies? What else do we need to do to pull ourselves out of the shadows of the WHI trial? We will be at the COGI Congress to find out more! The congress will be held in London on 23rd-25th November and we will be sharing with you the latest expert opinions and discussions in a special session on “HRT: Where we came from. Where are we going?”. We will also be posting a number of other blogs before, during and after the Congress that will build on the latest clinical and real-world developments in Women’s Health. So stay tuned for more!

 


Sources:

[1] US FDA. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm624284.htm [Accessed October 2018].

[2] Woods NF and Utian W. Quality of life, menopause, and hormone therapy: an update and recommendations for future research. Menopause. 2018 Jul;25(7):713-720.

[3] The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017 Jul;24(7):728-753.

[4] Armeni E, Lambrinoudaki I, Ceausu I et al. Maintaining postreproductive health: A care pathway from the European Menopause and Andropause Society (EMAS). Maturitas. 2016 Jul;89:63-72.

[5] American College of Obstetricians and Gynecologists. Compounded bioidentical menopausal hormone therapy. Committee Opinion No. 532. Obstet Gynecol 2012;120:411–5.

[6] Lobo RA, Archer DF, Kagan R et al. A 17b-Estradiol–Progesterone Oral Capsule for Vasomotor Symptoms in Postmenopausal Women. Obstet Gynecol. 2018 Jul;132(1):161-170.

Preventing bleeding in pregnancy

Postpartum haemorrhage (PPH) is a significant cause of maternal deaths, accounting for around 25% of maternal deaths worldwide (1). A high percentage of the deaths from PPH occur in low- and middle-income countries, a clear demonstration of the unfortunate difference in healthcare infrastructure that we see in the world today. In this blog we discuss what PPH is, the current guidance for managing the condition and whether it could be time to re-evaluate this guidance.

 

What is PPH?

PPH is characterised by significant blood loss at childbirth and associated with serious maternal morbidities including multiorgan failure. It is defined as blood loss of more than 500 mL from the female genital tract after delivery of the foetus (or >1000 mL after a caesarean section) (1).

Why does PPH occur?

During childbirth, a woman’s womb muscles contract in order to limit the bleeding following detachment of the placenta. PPH occurs when these muscles do not contract strongly enough or if the placenta has been left in the womb, resulting in significant blood loss.

Managing PPH – is time to update the guidance?

Naturally healthcare professionals’ preference will be to try and prevent PPH from occurring. Identifying factors that may pre-dispose a woman to PPH, for example placenta praevia or uterine fibroids is key to ensuring that clinicians can plan ahead and make available the necessary resources (1).

When managing PPH, the World Health Organisation (WHO) recommend oxytocin as the first choice, first line treatment (2). However, there are several alternatives. Ergometrine, ergometrine/oxytocin combinations, misoprostol and the newer uterotonic drug carbetocin have all been shown to be efficacious in preventing cases of PPH (3).

With this wide choice of first line treatments available, new research has aimed to answer the question: Do the current recommendations need to be updated?

One recent randomised control trial suggests that a change in guidance could be required. The researchers ask whether in resource-poor countries, oxytocin is the best choice? After all, oxytocin requires special storage conditions to remain stable and effective. This cold chain storage required to transport and store oxytocin may not be available or reliable, causing an increased risk in emergency settings (4). With the majority of cases of PPH occurring in low- and middle-income countries, there may be an need to recommend alternative treatments in a first instance.

Of course, while storage and transportation of a drug is important, efficacy and safety must also be considered. This has been studied in a recent Cochrane review, which suggested that oxytocin in isolation may not be the optimal choice for preventing PPH when compared with alternative treatments (3).

However the debate is not over. At the COGI congress held in London on 23rd-25th November, a special workshop is being held on ‘the prevention and management of bleeding in pregnancy: all about PPH’. Here data from the recent CHAMPION and iMOX clinical trials will be discussed alongside data from the Cochrane review and expert opinions.

We will be there to share with you the very latest in this fascinating discussion, providing a roundup of the key data and conclusions. We hope you are as excited as we are!

 

Sources:

  1. Chandraharan Edwin, Krishna Archana. Diagnosis and management of postpartum haemorrhage. BMJ. 2017; 358:j3875

  2. World Health Organisation. WHO Recommendations for the Prevention and Treatment of Postpartum Haemorrhage. World Health Organization. 2012.

  3. Gallos ID, Williams HM, Price MJ, et al. Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis. Cochrane Database of Systematic Reviews. 2018; 25(4).

  4. Widmer M, Piaggio G, Nguyen T, et al. Heat-Stable Carbetocin versus Oxytocin to Prevent Hemorrhage after Vaginal Birth. N Engl J Med. 2018; 379(8):743-752

40 years of IVF – key breakthroughs

2018 marks the 40th year since the birth of the first IVF baby. This remarkable technological advance changed the world and millions of children are alive today that could not have been born before the development of IVF.

Here we will discuss some of the key breakthroughs in the history of IVF and what advances we may be able to look forward to in the future.

 

1.       The evolution of gonadotropins

The evolution of gonadotropins has been instrumental in improving IVF live birth outcomes.  Early attempts to extract preparations from animals, human cadavers and human urine encountered issues with purity and risk of disease. However, over the decades dedicated research striving for purer, safer and more efficacious gonadotropins have led us to where we are today. Now, availability of recombinant hFSH, recombinant hLH and recombinant hCG allow clinicians to develop individualised protocols for each patient. Coupled with personalised and precise dosing, we can now see both improved patient safety and increased live birth rates. And with more research currently taking place into developing oral active FSH antagonists and agonists we hope to see this evolution continue.

 

2.       Advanced embryo culture systems

Culture media has come a long way since the simple salt solutions developed nearly 150 years ago. IVF laboratories are now using complex optimised media, standardised and regulated to promote consistency and a high level of quality. And as we know, a high quality media is just one factor to consider when culturing embryos. The development of closed culture systems has provided embryologists with a stable environment helping to shield the embryo from outside stresses and increase both efficiency and efficacy.

 

3.       Cryopreservation

In 1971 the field of embryology changed as the first cleavage-stage mouse embryos were frozen. This led the way for cryopreservation of human embryos at all embryonic stages. Improvements in cryopreservation technologies mean that embryo survival rates are now nearly 100% and provided women with the choice to freeze eggs for fertility preservation as well as for medical reasons. Research continues into this area, and the debate on whether a ‘freeze all’ approach should be applied is still being hotly debated.

 

4.       ICSI

Early pioneers in IVF encountered a frustrating issue. Often couples could not partake in IVF programmes due to a low number of mobile sperm and there were no techniques to effectively address this problem. A breakthrough came with the development of intracytoplasmic sperm injection (ICSI) which allows individual sperm cells to be carefully selected and injected into the embryo. ICSI can almost be considered as much of a breakthrough as IVF itself, greatly extending the success of infertility treatments. ICSI technology is here to stay and is expected to play a pivotal role in the future treatments of male infertility including stem cell therapy and extended germ culture.

 

5.       Time-lapse technology

Equipment in the IVF laboratory has dramatically evolved over the decades. Advances in engineering have provided ever more effective options for creating stable and controlled culture environments for embryos. A recent breakthrough has been the availability of time-lapse technology which allows embryologists to follow development of the embryo frame by frame, allowing for an even better understanding of developmental timing and morphology.

 

These are just a few of the many key developments in the history of IVF. And the future is even brighter with key research and advancements still being made in the field of reproductive medicine. At this year’s COGI conference on November 26-28, experts will be discussing some of the key controversies and sharing their latest research. We will be attending to provide you with the highlights so stay tuned for the most up to date insights in this remarkable area.

 

Sources:

Niderberger C, Pellicer A, Cohen J, et al. Forty years of IVF. Fertil and Steril. 2018; 110(2):185-324.e5

Menopause: At work, rest and play (British Menopause Society)

The British Menopause Society arranged a Saturday morning session outlining some of the health and lifestyle changes that can affect many peri- and post-menopausal women. It is important to highlight that many menopausal changes have far reaching effects: altering confidence in the workplace, impeding sleep and reducing sexual desire.

Menopause in the workplace - Kathy Abernethy

Kathy, a nurse specialist and co-leader of a menopause clinic, opened the session with the question:

How does menopause affect women in work?

Sally Davies, the UK's Chief Medical Officer, has recently put together a report specifically looking at the health of women - 51% of the British population, constituting nearly half of the workforce. Sally highlighted that menopause should be discussed at work just as with any other topic; conversations around mental health are becoming increasingly talked about but menopause remains a taboo.

The evidence assessing the impact of menopause on the workplace is mixed - there are reports of both positive and negative effects. However, surveys directed at women in the workplace provide key insights. 72% of women reported little support at work for menopause, and 10% even seriously considered giving up work.

Additional surveys support these findings. It was very common for women to call in sick rather than reporting the issue. Women in lower-paid, manual jobs experienced reduced flexibility and lower satisfaction than those earning higher salaries. Additionally, only 1/4 of women talked to their managers about the problems at work caused by menopause.

In 127 HRT users, 58% reported that work was one of the reasons for choosing therapy and 12% only decided to take HRT to cope at work.

Kathy argued that a more supportive environment should be fostered in the workplace. An improved awareness amongst managers should be encouraged, women should be offered a more flexible working environment, and supportive policies should be introduced. This should be coupled with robust educational programmes supported by legislation.

Sleep through the menopause - Heather Currie

It is well-known that sleep disturbances effect women more than men - not just from menopause but from early stages. In this talk, Heather sought to establish the extent to which menopause influences sleep, what the proposed mechanisms may be and what management may be available.

Sleep is of utmost importance to health. As mentioned in a previous post, the 'best' sleep is non-REM 3 - lack of which has been linked to detrimental effects including CVD risk, poor mental health and cognitive decline. In regards to the peri-menopause, sleep disturbances are commonly reported and have negative impacts on a woman's quality of life. Figures illustrating the extent of sleep disturbances in menopausal women show a large range - with between 28 - 63% of women experiencing disturbances.

Heather highlighted the difficulty in assessing sleep deprivation as subjective and objective measurements demonstrate inconsistencies in epidemiology. There have been conflicting arguments relating to the aetiology of poor sleep in mid-life to older women - some argue it is age-related and others support menopausal causes.

Data has demonstrated that key indicators in peri- and post-menopausal women are poor sleep status prior to menopause and the presence of VMS. Both of these subjectively correlate to poorer sleep but objective measurements of VMS disagree. Sleep apnoea, depression and anxiety have also been implicated. Melatonin, the circadian rhythm regulating hormone, is partly modulated by oestrogen and progesterone. As such, melatonin may have a role in menopause and it has been shown that it's levels decrease in the peri-menopause.

What about management?

HRT has been shown to improve menopause-related sleep disturbances. However, this is a consistent benefit that is only demonstrated in those with VMS symptoms. Use of HRT may not be beneficial in all women. Other treatments include CBT, exercise and alternative therapies such as isoflavones and yoga. Limited studies have shown some improvement with melatonin but it seems that more research is required here.

Improving sex at menopause – is testosterone the answer? - Nick Panay

Healthy young women produce 3-4 times more testosterone than oestrogen. The androgenic hormone modulates sexual desire, arousal and orgasm through dopaminergic pathways. It also affects other aspects of female physiology, including general well-being, energy and mood.

Free testosterone levels decline with age, but insufficiency can be seen following surgical menopause, EOI, adrenal insufficiency and iatrogenic treatments.

In POI, following surgery, hyposexual desire disorder (HSDD) has been reported in 50% of women and was the second biggest patient concern following fertility. Thus, Nick argued, it is a matter that should be addressed.

Androgenic therapies are recommended in this instance, but the available products are limited. Following androgenic patch therapy in the Instrinsa studies, post-surgically induced menopausal women experienced an improvement in sexual function. Other data have reported inconsistent findings.

What about natural menopause?

Key barriers to using androgens by healthcare professionals are safety concerns. The safety profile of androgens can be supported by the absence of aromatase in the endometrium (limited conversion to oestrogens) and a demonstrated lack of proliferation in the breast tissue following treatment.

What are the recommendations?

NICE recommends considering testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective. This recommendation stands despite the absence of available on-label androgen therapies. IMS guidelines state that androgen replacement should be reserved for women with clinical insufficiency.

To conclude, Nick highlighted that longer-term RCT data is required, including data in high-risk patients e.g. breast cancer. It is clear that there is a lack of available options for androgen therapy. The same cannot be said about sexual function in men.

Menstrual disorders in perimenopause

In this session, the medical and surgical approaches to management of abnormal uterine bleeding were discussed by three leading experts: Steven Goldstein, Risa Kagan and John Sciarra.

Abnormal Uterine Bleeding (AUB)

AUB is the cause of 33% of all gynaecology outpatient visits and more than 70% of the cases are among peri- and post-menopausal women.

PALM-COEIN Classification System for AUB

Previously, there was a general inconsistency in the nomenclature used to describe AUB. To standardise this approach in 2011, the PALM-COEIN Classification System was introduced. The system classifies AUB into either structural (PALM) or non-structural (COEIN) causes of AUB:

Polyp
Ademomyosis
Leiomyoma
Malignancy & Hyperplasia

Coagulopathy
Ovulatory Dysfunction
Endometrial
Iatrogenic
Not Yet Classified

Clinical studies show that 20% of AUB is structural and that 80% is non-structural (COEIN category). Before treating AUB it is critical to firstly perform a proper diagnosis (ruling out any anatomic abnormality), as well as ensuring that there is no pregnancy or malignancy.

Medical treatment

For non-structural causes of AUB, the most appropriate first-line treatment considered should be medical. Combined hormonal contraceptives, such as combined oral contraceptives (COCs), patches, and vaginal rings are ideal for non-smoking women, with no medical contraindications. As well as this, they function as an effective contraception and treat common peri-menopausal conditions.

Progestogens are the first-line therapy for women with contraindications to oestrogens (COCs) and can induce a regular withdrawal bleed. Continuous oral P, LNG-IUS, and DMPA can induce amenorrhea if required. Progestogens can also prevent hyperplasia.

Parenteral oestrogen can be considered in severe haemorrhagic AUB but it is recommended that this is short-term, with patients moving onto COCs for longer-term management. GnRH agonists induce reversible atrophy. Additional treatment options include NSAIDS, the synthetic steroid danazol and tranexamic acid. It should be noted, that the former is contraindicated in women at risk for VTE.

Medical treatments may also represent the most appropriate option for certain structural abnormalities. One of the more recent options available for non-surgical treatment for fibroids are Selective Progesterone Receptor Modulators (SPRMs). The UPA Pearl Trials have demonstrated decreases in bleeding and fibroid volume with SPRM use.

Surgical treatment

John highlighted that before considering surgery, the most like etiology should be evaluated and if possible, medical treatment should be first-line.

Traditional diagnostic tools for AUB include:

  • History and careful pelvic examination
  • Transvaginal ultrasound
  • Office endometrial biopsy
  • Hysteroscopy

John underlined the value of hysteroscopy - the use of modern small diameter endoscopes allows the clinician the ability to differentiate between bleeding secondary to an atrophic endometrium, to benign intracavity uterine lesions such as polyps or submucous fibroids and endometrial adenocarcinoma.

Steven previously outlined the limitations of pipelle catheter - as the sample area is limited - cancers, fibroids or other intrauterine pathologies can be missed.

Diagnostic hysteroscopy and transvaginal ultrasound have the benefits of efficacy and ease - they can be office procedures with no anaesthesia and no cervical dilation.

If medical management has failed, surgical alternatives may offer a therapeutic relief of AU:

  • Hysteroscopic resection
  • Uterine arterial embolization (UAE)
  • Endometrial ablation
  • Ulipristal Acetate (UPA)
  • Hysterectomy

UAE is successfully completed 98-100% of the time and results in an 80-90% relief of menorrhagia. Complications are few but these are occasionally serious. Endometrial ablation is used for heavy menstrual bleeding in a normal size uterus - previously, resectoscope was used commonly but now second generation global endometrial ablation is universal. This method is extremely effective for the control of UAB, especially in those who have failed medical management.

All speakers stressed that medical therapy (COCs, progestogens, NSAIDs) should always be the first options. Although efficacious, endometrial ablation and UAE are not 100% effective. If hysterectomy is to be performed, vaginal and laparoscopic approaches should be preferred.

Meet the expert: Optimising HRT for Cardiovascular Health

Meet the expert: Cynthia Stuenkal

Cynthia opened with a patient case study:

  • A 48-year old woman presents for treatment of bothersome hot flashes.
  • Her last cycle was 6 months ago without irregularity or spotting.
  • At age 46 she was diagnosed with Type-II diabetes.
  • Her glucose control has been normalised on metformin.
  • She is also hypertensive and controlled on a combination of calcium channel blockers and an ACE inhibitor.
  • In spite of her best efforts, her weight remains 90 kg and blood pressure is 150/90.
  • Lipid panel showed low HDL, LDL in upper range and elevated triglycerides.
  • What approach should be taken to treat her menopausal symptoms?

Something to consider is that compared with men, women have a more adverse CVD risk profile - women with diabetes have a 2-fold excess risk of CHD and rates of heart failure are more frequent with higher mortality.

Cynthia suggested an individualised approach to treating menopausal symptoms could be considered. Some women with diabetes, after evaluation of CVD risk, may be candidates for MHT.

Care should be taken to consider the contraindications to HT:

  • Possibility of pregnancy
  • Undiagnosed vaginal bleeding
  • Oestrogen sensitive cancers
  • History of MI or stroke
  • History of DVT or PE
  • Liver dysfunction or disease

From a US perspective, the Endocrine Society and NAMS are aligned in recommending quantifying 10-year CVD risk. Cynthia's approach to the case study, she confirmed, was algorithm-based with a focus on quantification on risks. However, this is not to say that the clinician-experience and knowledge of the patient should be ignored. A synergistic approach could be applied.

Based on the quantification of risk factors, a transdermal oestrogen and micronized progesterone were discussed as a possible therapeutic option. At low doses, transdermal therapies may be preferable for women with co-morbidities such as hypertension, hypertriglyceridemia, obesity, metabolic syndrome and diabetes.

However, as previously mentioned, an individualised approach to HT could be considered - supported by the position statement of the NAMS. Indications and evidence-based treatment goals should be accounted for, as well as a woman's age, personal health risks and preferences. NAMS also promoted balancing potential benefits and risks of MHT vs. non-hormonal therapies.

A new approach: treatment of breast cancer with the fetal Estetrol (E4)

Breast cancer is the most common cancer in women worldwide. Although overall 5 year survival rates are optimistic, one patient still dies from breast cancer every 74 seconds.

Consequently, Carole highlighted, it is critical that research continues in order to develop efficacious compounds that target the malignancy.

High dose oestrogen (HDE) was the endocrine treatment of choice in post-menopausal women with advanced breast cancer since 1944 until tamoxifen entered in the 1970s. Exemplifying this was Haddow's pre-eminent paper, which demonstrated a 30% reduction in tumour size when patients were treated with HDE.

Carole explained that in an unusual phenomenon, oestrogens can stimulate breast cancer, but on the other hand they can also be used to treat the disease. In one study from 1981, 143 patients with advanced breast cancer were treated with either tamoxifen or DES. Although toxicity was higher, patients treated with DES showed greater tumour regression and demonstrated significantly higher long term survival.

Patient selection is crucial:

  • Women with ER+ breast cancer
  • For first-line treatment, women should be at least 5 years post-menopausal
  • For second-line treatment, women should have recorded resistance to endocrine treatment

What is the mode of action?

Several research groups have conducted extensive research to understand the MoA for HDEs. It was found that high doses of oestrogens targeting tumours deficient in the hormone resulted in an increase in apoptosis. However, the issue of in vivo tolerability still persisted.

Of the 4 natural oestrogens, estetrol is a foetal oestrogen that is potentially tolerable with a long half-life, allowing oral dosing.

Estetrol in patients with advanced breast cancer - the ABCE4 study

To investigate this in an in vivo model, Carole and her colleagues are conducting an ongoing combined phase I/II trial to determine the safety and effectiveness of estetrol in advanced breast cancer.

The study has been divided into 2 parts:

  • Phase I: 4 weeks of treatment to assess dose limiting toxicity
  • Phase II: Followed by 8 weeks of treatment to assess initial anti-tumour respons

Although the trial recruited only 6 patients, results reported a tolerable safety profile with no patients experiencing dose-limiting toxicity. Of the 3 patients who reached phase II, 1 patient has demonstrated disease stability after 6 months of treatment.

Investigators are optimistic about the future of this new approach harnessing HT, and Carole informed the audience that she will be meeting with them to discuss next steps in the coming weeks.

The impact of progesterone on weight and sleep

In Friday morning's session - 'Hormone therapy in menopause: Beyond hot flushes', sponsored by EMAS - Petra Stute presented data exploring the impact of progesterone on weight and sleep.

For women aged 55-65 years, weight gain is one of their major health concerns. Worldwide, the prevalence of obesity has more than doubled since 1980. It is not surprising then, that obesity is a major risk factor for chronic non-communicable diseases. Unsurprisingly, this has been one of the over-arching themes at the conference this year.

A key questioned posed by Peta was: Is weight gain at midlife a consequence of menopause or ageing?

Existing literature tends to support the theory that weight gain in mid-life is primarily a result of ageing and lifestyle changes. However, as visceral fat deposits increase in women, combined with a decrease of lean body weight and an increase in weight circumference, Petra argued that it is unlikely that ageing alone can explain this.

What might explain weight gain in the menopause?

Normal physiological sleep is characterised by non-REM and REM sleep stages - the former of which can be classified further into 4 sub-stages. The most crucial stage of sleep (in regards to quality) is non-REM 3 (NREM3).

In NREM3 sleep glucose tolerance is minimal, growth hormone peaks and inhibition of the hypothalamus-pituitary-adrenal axis is high, reducing cortisol levels. This results in low stress levels and reduced glucose uptake.

The metabolic consequences of decreased sleep quality lead to decreased insulin sensitivity, extra energy expenditure, increased hunger and reduced physical activity. Consequently, energy intake exceeds increased energy expenditure - resulting in an increase in body weight. As such, poor sleep increases risk of obesity, diabetes and CVD.

During the ageing process, circadian hormonal secretion changes - cortisol levels increase and growth hormone and melatonin decrease. In menopause, oestrogens and progesterone decrease.

How does progesterone affect sleep?

Progesterone is metabolised to allopregnanolone, promoting a sedative effect via modulation of GABA receptors. It significantly positively correlates with NREM3 duration and treatment with progesterone significantly increases total sleep time and decreases sleep onset latency and awakenings. Importantly, progesterone increases growth hormones peaks at night, triggering NREM3 sleep.

To investigate this further, Petra performed a systematic literature search. Of the 10 results, 3 found a significant impact on body weight. The studies, using oestrogens combined with micronized progesterone, did not demonstrate a change or reduction in body weight in normal weighted post-menopausal women.

Petra argued that further investigation, using progesterone alone is required for more robust results. Perhaps a larger, more focussed trial will yield more valuable insight into this under-explored area of research.

Rediscover HT: Showing the Benefits and Controlling the Real Risks (Sponsored by Mylan)

In the Mylan sponsored symposium, the focus was on HT and how perceptions within the medical community and general public have changed and are continuing to change over time. Themes included the perceived risk vs benefits of HT, the history of HT trials and the potential future of HT.

 Depression in the Menopausal Transition: Role of HT - Pauline Maki

Pauline's presentation was a summary of guidelines (a collaboration between NAMS and the National Network of Depression Centers) for the treatment of depression in the menopausal transition - the product of 2 and a half years of work involving 11 experts.

Here are the main conclusions:

  1. Epidemiology
    The perimenopause is a window of vulnerability for the development of both depressive symptoms and Major Depressive Episodes (MDEs). The risk of depressive symptoms is elevated during the perimenopause even in women with no history of MDD. Most women that experience MDE have experienced a prior episode - the episode represents recurrence. Most importantly, MDD increases in peri- and post-menopausal stages only in women with prior MDD.
  2. Clinical presentation
    This is similar to classic features of depression experienced elsewhere in life but with additional menopausal symptoms (e.g. VMS).
  3. Therapeutic effects of antidepressants
    It is recommended to use the same treatment that was effective in other parts of a woman's life. Antidepressants are the first-line of treatment, most commonly SSRIs and SNRIs.
  4. What about HT?
    HT has only been shown to be effective in peri-menopausal women - the 'window of opportunity'. Some data has supported the use of HT to treat depressive symptoms. Additionally, additional studies have suggested that HT enhances mood and well-being in women who are peri-menopausal, as well as potentially augmenting anti-depressants. The current recommendation is that HT should not be used for depression prophylaxis.
  5. Other therapies?
    Available data is insufficient for recommending botanical extracts, vitamins, alternative medicine etc. for the treatment of peri-menopausal depression.

CVD benefit/risk ratio of HT - what do we need to know in 2018? - Tomi Mikkola

15-years post-WHI, Tomi explained that a big concern surrounding HT is the under-utilisation and under-treatment of women with quality of life reducing symptoms such as hot flashes and night sweats.

Tomi outlined the more recent trends in HT post-WHI:

  • 'The window of opportunity', or as Tomi preferred to use, 'the timing effect'. This is a less discriminate approach and instead advocates that earlier initiation of HT is more beneficial but there is not necessarily a 'cut-off point' where HT becomes detrimental.
  • Preference for estradiol over CEE.
  • Lower dose - many benefits of HT have been studied in higher doses, benefits of lower doses should be explored.
  • The association of some progestogens with harm e.g. MPA.

Using data from the Medicine Reimbursement Register in Finland, one of the most comprehensive registries in the world, the number of CHD deaths in HT users was compared to the expected number of deaths due to CHD.

Data reported that after short term discontinuation, there was an increased risk of cardiac mortality in women younger than 60. This was not observed in the discontinuations following more than a year of HT. As there were suggestions of data-bias, the ratio calculations were replicated. Even after cases of MI following previous HT discontinuation were excluded, data still reported the same outcomes.

The explanation behind this is currently unknown - vasoconstriction and/or inflammation following immediate withdrawal are possible theories but it was clear more research was required. However, the results were of such interest, a placebo controlled trial will soon be conducted on women who discontinue HT therapy.

HT: does the progestogen make the difference? - John Stevenson

CHD is a major disease for women; totality of current data indicates that HRT, when administered appropriately, is beneficial for prevention of coronary events.

However, as Tomi previously outlined, the timing of intervention with HT in relation to menopause onset is important, with the greatest benefits for CHD prevention being seen in those women initiating treatment in the early menopause.

The choice of hormones is critical - different types have differing metabolic effects that impact on CHD risk. In this presentation, the choice of progestogen was of particular focus.

Oestrogens have largely beneficial effects on lipoproteins and lipids in a dose dependent manner. The beneficial increase in HDL cholesterol by oestrogen may be attenuated by androgenic progestogens (e.g. norgesterol, NETA or MPA). Beneficial HDL increases, however, are not modified by non-androgenic progestogens (e.g. dydrogesterone).

In regards to glucose and insulin, androgenic progestogens increased insulin resistance, with opposite effects seen with non-androgenic progestogens. As expected, blood pressure was unaffacted with HRT.

In conclusion, it was clear that different progestogens had different metabolic effects, with more androgenic progestogens tending to display worse effects. By administering appropriate progestogens that synergise effectively with oestrogens, HRT may improve cardiovascular benefits.

The WHI: What Happened? What Can We Believe? What Should We Do now? - Robert D. Langer

Designed in the early 1990s, the WHI HRT trial tested prevention of CHD by HRT in women well past menopause. Prior to this, the prevailing opinion was that HRT was a low-risk intervention providing symptom relief for recently menopausal women.

The WHI HRT trial was designed to test the benefit of - contemporary in 1993 - HRT for the prevention of CHD, the dominant chronic disease in post-menopausal older women. The WHI was not designed to test outcomes of HRT initiated near menopause.

Robert expressed the frustration shared by his colleagues within the medical community when the press release was published. Science was vetted via the press with a focus on non-significant findings that played on women's greatest fear - breast cancer. According to Robert, it quickly became clear to some that the paper largely abandoned the analysis plan stipulated in the protocol and misinterpreted findings.

When data was adjusted for covariates (age of menopause, BMI, pregnancies etc.) VTE and fracture were the significant changes - not breast cancer.

Learnings from the WHI trial are that the effects of HRT on most organ systems vary by age and time since last physiologic exposure to hormones. Importantly, there are differences between regimens.

Adding to this, the primary results paper did not acknowledge that the trial was not designed to study outcomes in recently menopausal women.

In 2018, Robert highlighted that good evidence from 50 years of observational studies and clinical trials suggests that the benefits of HRT outweigh risks for most women when started early.

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.