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.

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.

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.