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.

 

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.