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:
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.
- Clinical presentation
This is similar to classic features of depression experienced elsewhere in life but with additional menopausal symptoms (e.g. VMS).
- 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.
- 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.
- 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.