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.

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.