COGI 2018: 5 key messages

COGI is over for another year. Now we can take time to digest the information from the inspiring and thought-provoking sessions and ask ourselves: ‘what have we learnt?’

In this special edition blog we look back at five key messages and highlights from the three days.

 

1.       Time to consider HRT for primary CHD?

Research suggests that estrogen has a clear biological effect on the cardiovascular system, demonstrating beneficial effects on some of the key risk factors of Cardiovascular Heart Disease (CHD). While there is a lack of definitive evidence supporting HRT as a prevention for postmenopausal CHD, there are a growing number of epidemiological and observational studies supporting its use. In these studies, timing was shown to be a key factor with HRT demonstrating no benefit in older women. However, although there was no benefit there was also no evidence of harm.

 

2.       The role of epigenetics in long term health

Specific epigenetic input during development can produce a lasting difference in phenotype, meaning fetal programming, metabolic endocrine disruption and structural change in organs can all significantly affect the birth of a child.

For example, Caesarean Sections are linked to increases in neonatal morbidity, auto-immune diseases and metabolic disease in the offspring. Maternal obesity and smoking are also shown to be associated with long term negative outcomes for the child. In fact, research suggests that these negative effects may even cross generations.

 

3.       Fertility may be able to be preserved in women with POI

Primary ovarian insufficiency (POI) affects 1 in 100 women at the age of 40. In order to plan the most effective fertility preservation treatment, it is crucial to predict as much as possible whether POI may be imminent. While this is not simple, the condition is hereditary therefore assessing family history may help to provide important insight. Additionally, more research is taking place into the genetic basis of POI, with some evidence suggesting that reproductive health and success may be a marker for identifying POI and health outcomes later in life.  

There are many more options available for treating imminent POI than confirmed POI, including vitrification of oocytes or embryos following ovarian stimulation, freezing of ovarian tissue or a combination of the two. When treating confirmed POI, the options are more complex. While a small number of sufferers may go on to experience a spontaneous pregnancy, researchers are now considering a new technique: in vitro follicle activation (IVA). However, refinement and improvement of the technique is needed for it to lead to an effective strategy for these patients.

  

4.       The freezing debate is definitely not over!

The debate on whether freezing oocytes for non-medicinal reasons is truly beneficial contined at COGI. Speakers argued that social freezing could be seen as a purely commercial enterprise with advertising often aggressive and marred with misinformation. In fact, only 12% women actually return to the clinic and there is a far from certain chance of success.

However, freezing was shown to provide effective results in younger women seeing fertility preservation. In addition, some studies have demonstrated that freezing may be able to reduce risk of OHSS and be beneficial for groups of high responders.

 

5.       ART may be driving rates of pre-term birth

ART is associated with increased incidence of multiple pregnancy. Multiple pregnancy in turn is related with higher risk of pre-term birth and Cerebral Palsy. Using real world data we were shown that incidence of twins born at <32 weeks increased 27-fold from 1987 to 2010, with ART suggested as a main driver.

The genetics of menopause

While the median age of menopause is 51 years, primary ovarian insufficiency (POI) premature menopause can occur at 40 years or younger and late menopause can occur as late as 62 years. We know that POI is related to adverse health conditions including increased risk of CHD, osteoporosis, cognitive decline and mortality.[1] But why does premature menopause occur? Nutritional status is not considered to affect age of menopause. Similarly, menopause shows no decennial or centennial trends. So, what is causing this variation?

 

The genetic impact

Presenting at COGI 2018, Prof. Joop Laven explained that over 50% of the variation in age of menopause is caused by genetic variance.

However, pinpointing the specific genetic variants associated with menopause is complex. Results from genetic studies are often underpowered with inconsistent results. One genome-wide linkage study identified only one variant approaching genome-wide significance (rs6543833)[2], while another study concluded that the genetic architecture related to age of menopause involves a large number of rare, low frequency and common variants.[3]

However, with the advances in next generation sequencing (NGS) there is hope. Prof. Laven shared data from two recent genome-wide association studies (GWAS), which suggest that genes affecting ovarian function seem to play a role in DNA maintenance and DNA repair, particularly in repairing double strand breaks (DSB).[4],[5] Somatic cell ageing is associated with decreased effectiveness of DNA repair and Prof. Laven explained that it is key to understand that these genes therefore affect both somatic cell ageing and germ line ageing.

He suggested the following paradigm: The ageing of the soma as a result of inefficient DNA repair may be responsible for loss of ovarian function. This means that somatic ageing could be seen as a primary driver of POI.

 

Reproductive success, menopause and longevity

Interestingly, Prof. Laven also explained that genetic factors involved in DNA repair and maintenance are also common between reproductive performance, age of menopause as well as longevity.[5] He discussed that good reproductive health seems to be linked to good physical condition of the soma. As such, decreased fertility appears to be strongly associated with reduced health status.

So, what does this mean? Well, perhaps decreased fertility may be able to be used as a predictor of general health in later life to further support the future of individualised, precision medicine.  


Sources:

[1] The timing of the age at which natural menopause occurs. Obstet Gynecol Clin North Am. 2011;38(3):425-40.

[2] Sonya M. Schuh-Huerta, Nicholas A. Johnson, Mitchell P. Rosen, et al; Genetic variants and environmental factors associated with hormonal markers of ovarian reserve in Caucasian and African American women, Human Reproduction, Volume 27, Issue 2, 1 February 2012, Pages 594–608, https://doi.org/10.1093/humrep/der391

[3] Perry JRB, Murray A, Day FR, Ong KK. Molecular insights into the aetiology of female reproductive ageing. Nat. Rev. Endocrinol. 2015;11:725–734. doi: 10.1038/nrendo.2015.167.

[4] Jiao, X., et al. (2018). "Molecular Genetics of Premature Ovarian Insufficiency." Trends Endocrinol Metab 29(11): 795-807.

[5] Laven, J. S. E., et al. (2016). "Menopause: Genome stability as new paradigm." Maturitas 92: 15-23.

 

Barriers to the HPV vaccine

In an inspiring session at COGI 2018, four experts discussed the human papillomavirus (HPV) vaccine; its safety, efficacy and some of the key barriers to a successful vaccination programme.

Since the introduction of the HPV vaccine around 10 years ago, the UK has developed a largely successful vaccination programme. Dr. Elmar Joura shared data demonstrating that coverage rates are almost 90% and prevalence of HPV16 and HPV18 have in turn reduced by 75% and 86% respectively. However, in other countries coverage rates are much lower. Dr. Joura explained that Japan has a rate of just 0.6%. A 2016 study showed Italy, Netherlands, Norway and Spain also have coverage rates under 60% while France has a rate of just 20%.[1]

The efficacy of the vaccine has been established, Prof. Jorma Paavonen explained, with Phase III trials demonstrating protection against persistent HPV infections, a range of precancers and genital warts (HPV6/11). Safety of the vaccine has also been carefully studied.  Research indicates that the HPV vaccine does not have adverse effects on pregnancy outcomes or cause the onset of autoimmune diseases.[2],[3] In addition the World Health Organisation (WHO) have investigated a number of rare conditions that have speculatively been associated with the vaccine. It concluded that there was no increased risk in outcomes after vaccination.

So, with the efficacy and safety of the vaccine supported by extensive research, why are attendance rates so variable?

 

The path to vaccine hesitation

Dr. Pauline Paterson explained that vaccine hesitancy should be considered as a continuum. While there are individuals that refuse all vaccines, some only delay vaccination and others comply but with hesitation or caution.

There are three main drivers of hesitancy, explained Dr. Paterson.

-          Complacency – This can lead people to perceive a lack of value or need for the vaccine. No visibility of disease threat or misinformation over the seriousness of a disease can all contribute.

-          Convenience – Poor access to the vaccine can prevent people from attending vaccinations

-          Confidence – People may lack trust in vaccines, healthcare providers or scientific truths.  

It is these hesitant groups that can more easily be affected by rumours, stories and case histories that may be expressed in the media. In today’s digital world, the internet allows for rapid global spread of misinformation that exacerbates mistrust and hesitancy over vaccination programmes.

A clear example of this is in Japan. Following several years of a successful HPV vaccination programme with attendance rates of around 70%, a Japanese social media scare caused widespread national public concern over the safety of the vaccine. As a result the Japanese government stopped proactively recommending the vaccination and even provided compensation to one individual leading to mass one sided media coverage. Dr. Paterson explained how the internet allowed fears raised in Japan to spread globally, as far as Kenya, Colombia and the UK.  

 

How can we combat vaccine hesitation?

Combating vaccine hesitation is essential for maintaining good public health. When addressing the issue it is important to remember that while healthcare providers remain the most trusted influencer of vaccination decisions, they need more support to address public questioning over vaccines.

Dr. Paterson suggested that strategies addressing hesitancy should be multi-factorial, combining mass media, social mobilization and communication training for healthcare professionals. When considering how to improve HPV vaccination attendance, she indicated four key steps to consider:

-          Ensure the programme is gender neutral

-          Provide a school-based programme

-          Ensure gynecologists keep patients informed, and HCPs keep healthcare professionals continue sharing key factual information

-          Implement organised HPV screening

 

There are many challenges to overcome in addressing vaccine hesitation and the barriers to attendance. However, evidence demonstrates that the HPV vaccine is both safe and effective. We hope that in the future we can combat these barriers to vaccination and work towards effective eradication of HPV.


Sources:

[1] Uhart M, Adam M, Dahlab A, Bresse X. Loss of chance associated with sub-optimal HPV vaccination coverage rate in France. Papillomavirus Res. 2017;3:73-79.

[2] Scheller NM, Pasternak B, Mølgaard-Nielsen D, Svanström H, Hviid A. Quadrivalent HPV vaccination and the risk of adverse pregnancy outcomes. N Engl J Med. 2017;376(13):1223–33.

[3] Lehtinen M, Eriksson T, Apter D, et al. Safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in adolescents aged 12-15 years: Interim analysis of a large community-randomized controlled trial. Hum Vaccin Immunother. 2016;12(12):3177-3185.

Fertility preservation in women with POI

Primary ovarian insufficiency (POI) is a clinical syndrome defined by loss of ovarian activity before the age of 40 years. It is also known by the term premature menopause and can be characterised by menstrual disturbance with raised gonadotropins and low estradiol. While incidence of POI depends on ethnicity, generally the risk is 1 in 1000 at age 30 and 1 in 100 at age 40.

The consequences of POI are unfortunately long term and severe including:

-          Cognitive dysfunction

-          Cardiovascular Disease

-          Autoimmune diseases

-          Osteoporosis

-          Increased mortality

-          Infertility

Presenting on the final day of COGI 2018, Prof. Claus Andersen explained that there is a key focus on providing women with POI the option of fertility preservation. So, what are the available treatments?

 

Approaches for fertility preservation

In order to plan the most effective fertility preservation treatment, Prof. Andersen stressed that it is important to predict as much as possible whether POI may be imminent. How can we do this? Well, often the condition is hereditary. In fact, Prof. Andersen suggested that around 10-15% of women with POI would have a first degree relative who has been affected. Similarly, if a woman has a mother or older sister affected this leads to an approximately 6x higher risk.

There are many more available options for treating women with imminent POI than confirmed POI. Therefore, it is essential women are informed about symptoms and risks. It is also essential that health care professionals understand this increased risk and consider it when diagnosing a potential case.

At COGI we were shown data suggesting that a quarter of women waited over five years for a correct diagnosis, with over half seeing more than three clinicians.  Unfortunately, there is no definitive test for predicting POI, however we can hope that this could be developed in future.

 

Imminent POI

For women with imminent POI, Prof. Andersen discussed three main first line approaches:

-          Vitrification of oocytes or embryos following ovarian stimulation

-          Freezing ovarian tissue

-          A combination of oocyte and ovarian tissue freezing

 

Confirmed POI

For those with confirmed POI, treatment is more complex. In some cases, sufferers may experience spontaneous pregnancy. One study of 358 women revealed that a cumulative pregnancy rate of 4.3% at 48 months.[1]

However the alternative is a procedure called in vitro follicle activation (IVA). This involves the removal of an ovary, the preparation of cortical tissue recruiting dormant primordial follicles, freezing and thawing before transplantation back into the POI sufferer. Research is still be undertaken into IVA. However, with refinement and improvement it could lead to a new effective strategy for POI patients to conceive their own genetic children.[2]  


Sources:

[1] M. Bidet, A. Bachelot, E. Bissauge et al. Resumption of Ovarian Function and Pregnancies in 358 Patients With Premature Ovarian Failure. Obstetrical & Gynecological Survey: 2012. 67(4). 231–232. doi: 10.1097/OGX.0b013e3182502238

[2] Kawamura K, Kawamura N, Hsueh AJ. Activation of dormant follicles: a new treatment for premature ovarian failure?. Curr Opin Obstet Gynecol. 2016;28(3):217-22.

ART and preterm birth - What is the link?

Preterm birth is associated with a number of adverse health conditions contributing to increased rates of infant mortality, morbidity and long-term disability.[1] For example, 3-4% of very preterm and very low birth weight babies have Cerebral Palsy. [2]

Speaking at COGI 2018, Prof. Andrew Shennan explained that the issue is considerable, costing the NHS around £1 billion a year.  To be able to effectively tackle the problem, we must understand the key causal factors along with developing and improving management and prevention techniques.

 

Is ART driving premature pregnancy?

The link between ART and increased incidence of multiple pregnancy is well established.[3] In 2014, data from the Centers for Disease Control and Prevention (CDC) indicated that over 20% of all births following ART were multiple births.

Also established is the understanding that multiple pregnancy can result in higher rates of mortality and morbidity both for the mother and child.[2] One of the key complications resulting from multiple pregnancy is pre-term birth. In a thought-provoking session, Prof. Isaac Blickstein discussed why we therefore must consider the major impact that ART could be having on rates of premature pregnancy.

Using mathematical analysis of current preterm and Cerebral Palsy population statistics, Prof. Blickstein demonstrated that out of 100,000 spontaneous births, 2000 twins would be expected, of which 1685 would be very premature and 59 would have Cerebral Palsy.  In contrast, just 10,000 births by ART would be expected to produce 7400 twins, 740 very premature births and 26 cases of Cerebral Palsy.

But how about using real world data? Well, sharing data from a recent population trial, Prof. Blickstein indicated that the incidence of twins after ART born at <32 weeks increased 27-fold from 1987 to 2010 and has not reduced from the peak incidence in the last decade. He suggested that this high level of multiple pregnancy is a key driver of the issue of pre-term birth that we see today.  

 

Managing preterm birth

The speakers agreed that unfortunately there is no clear and definitive strategy to manage pre-term birth, especially in regards to multiple pregnancy. It was discussed that short cervical length is clearly associated with preterm labour and can be used in predicting and preparing for prophylactic intervention. These include:

-          Progesterone

o   While progesterone has been shown to be effective in singleton birth, it has not in multiple pregnancy, even if the delivery is high risk.[4]

-          Cervical Pessary

o   There is no clear evidence to the benefit of the cervical pessary, with some supporting studies and some suggesting no benefit at all.

o   However, Prof. Ben Mol discussed that the treatment could be effective for patients that have a short cervix (25-30mm). He recommended that it may especially be useful for women with multiple pregnancy, as progesterone is not shown to be effective.

-          Cerclage

o   Cerclage needs to be further researched in modern randomised controlled trials. However, Prof. Shennan explained that it could be beneficial in high risk cases.

o   Abdominal cerclage was not recommended as a first line treatment however could be effective for women who had a failed vaginal cerclage.

-          Lifestyle factors

o   Smoking and obesity were outlined as factors increasing risk of complication.

In the UK, Public Health England have announced they will aim to reduce preterm birth to 6% by 2025. While this may not necessarily be reached, it hopefully means that there will be budget available to help future research.


Sources:

[1] Keelan JA, Newnham JP. Recent advances in the prevention of preterm birth. F1000Res. 2017;6:F1000 Faculty Rev-1139. Published 2017 Jul 18. doi:10.12688/f1000research.11385.1

 [2] Kim Van Naarden Braun, Nancy Doernberg, Laura Schieve, et al. Birth Prevalence of Cerebral Palsy: A Population-Based Study. Pediatrics. Jan 2016, 137 (1) e20152872; DOI: 10.1542/peds.2015-2872

 [3] Multiple pregnancies following assisted reproductive technologies – A happy consequence or double trouble? Seminars in Fetal and Neonatal Medicine, 19(4), 222-227, 2014 doi: https://doi.org/10.1016/j.siny.2014.03.001

 [4] Klein, K. , Rode, L. , Nicolaides, K. H., Krampl‐Bettelheim, E. , Tabor, A. and , (2011), Vaginal micronized progesterone and risk of preterm delivery in high‐risk twin pregnancies: secondary analysis of a placebo‐controlled randomized trial and meta‐analysis. Ultrasound Obstet Gynecol, 38: 281-287. doi:10.1002/uog.9092

Estrogens and Breast Cancer

16 years ago, a Women’s Health Institute (WHI) study was published.[1] This study proved revolutionary. It advised against the use of menopausal hormone therapy (MHT) and resulted in a media storm, causing confusion and a dramatic reduction in the number of prescriptions. Since then, reanalysis of the data and further research has suggested that in fact, for many women MHT is both effective and has a beneficial risk-benefit ratio.[2] As a result, the World Health Organisation have labelled MHT as a purveyor of benefit and not of risk.

Unfortunately, the lack of effective treatment following the WHI study left many women suffering. Speaking at COGI 2018, Prof. Fernand Labrie indicated that treatment of postmenopausal symptoms became a major unmet need. This, he suggested, was mainly due to the fear of estrogens.

 

Do estrogens promote breast cancer?

Dr. Christian Singer explained that exposure to estrogens is a determinant of breast cancer risk. He discussed that estrogens can induce and promote breast cancer, with mechanisms relating to oxidative metabolism in the Catechol pathway and e2 receptor binding leading to altered gene expression. However, recent data has suggested that estrogens alone do not have a significant effect and may even have a positive effect on breast cancer risk or cancer-related mortality.[3]

Further supporting this research, Dr. Herjan Bennink shared fascinating data on lifetime breast cancer risk in females, males and male-to-female transgender persons. Females have a lifetime breast cancer risk of 1 in 8, while males have a risk of 1 in 1000. In order to develop breast tissue, male-female transgender persons must undergo high dose of estrogen treatment for many years. However, risk of breast cancer in these persons remains 1 in 1000. This suggests that alternative factors must play a significant role in the development of breast cancer. Dr. Bennick suggested that these could include an array of considerations including number of menstrual cycles and lifestyle factors.

 

Could estrogens help to prevent breast cancer?

In a special countercurrent lecture, Dr. Bennink argued that while estrogens have a mechanism to promote breast cancer, they may also have some protective effect. As an example, he explained that pregnancy can result in a significant reduction in risk of estrogen-receptor positive breast cancer. We know that pregnancy is associated with a large increase in estrogens. One could hypothesise that this could be protective. However, the specific mechanism of action is not clear and more research is required to fully understand if estrogens could have some protective effects on breast cancer risk.  


Sources:

[1] Writing Group for the Women's Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal WomenPrincipal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA. 2002;288(3):321–333. doi:10.1001/jama.288.3.321

[2] Roger A. Lobo; Where Are We 10 Years After the Women's Health Initiative?, The Journal of Clinical Endocrinology & Metabolism, Volume 98, Issue 5, 1 May 2013, Pages 1771–1780, https://doi.org/10.1210/jc.2012-4070

[3] Marjoribanks J, Farquhar C, Roberts H, Lethaby A, Lee J. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD004143. DOI: 10.1002/14651858.CD004143.pub5

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.