Is the Oestrogen pendulum swinging too far?
The past two decades have been plagued by fear of HRT. Largely synthetic hormones or combinations of conjugated equine estrogens and synthetic progestins, later proved to have higher risks (breast cancer, cardiovascular events), left us all scared to take it or to prescribe them.
Now that HRT preparations have thankfully changed, we see an acknowledgment of the safety of human-like / body-identical/ bio-identical hormones, which are more widely available, and this is all good reason to celebrate.
My social media feed has recently been full of videos extolling the benefits of estrogen and encouraging their use as much as possible so I wanted to pause and take stock of our knowledge so far.
Menopause- defined as 12 months after the last menstrual period is the natural consequence of the ovaries having ceased their function. Peri-menopause is the period of time that precedes this. They have been bundled up together in conversations for too long when in fact they can be quite different in their symptoms and biological changes underpinning them.
HRT – as oestrogen replacement therapy- has been studied mostly in women who have ceased their periods and their benefits have been clearly defined. Use of HRT in peri-menopause has rarely been studied.
But first lets’ review the map of menopause transition
Where are you on the map of menopause transition?
This is a simplified timeline of the transition into menopause I adapted from the summary data of the Staging of Reproductive Aging Workshop (https://www.ncbi.nlm.nih.gov/pmc/art-cles/PMC3580996/)
Whilst I agree that estrogens are very important for preserving bone health, cardiovascular health and brain function, and I both take and prescribe estrogen, I believe they can be, at times, “too much of a good thing”.
So, before you put all hopes in that bottle of estrogel, I thought I would stop and review our knowledge and evidence base available currently when it comes to prescribing estrogens.
TIMING is important.
Starting estrogen too late in post-menopause
So far, we know that starting estrogen replacement in the first ten years after the last menstrual period is most beneficial- and this time frame is referred to as a window of opportunity. The same estrogen when started too late (more than 10 years after LMP) seems to lose its protective effects and the risks to the breast and heart disease may be higher. .
Starting oestrogens too early in peri-menopause
The transition into menopause is defined as peri-menopause and can last on average 4 years, although it can last up to 10 years in some cases.
The transition into menopause is often referred to as a decline of oestrogens over time in the preceding years, in spite of accumulating evidence that this is not always true.
A lot of our previous knowledge and assumptions around menopause came from poor quality studies- (limited to women who visited a doctor’s office for help around menopause or studies that did not distinguish between the different stages of the menopause transition).
As such, there is little quality data from randomised controlled trials on the efficacy and long-term safety of oestrogen-based HRT best treatment for peri-menopause. It is well researched and safe later in the transition, when periods have become rare or stopped altogether.
So, what do we know about peri-menopause?
Peri-menopause is in fact a time of huge hormonal fluctuations, the highest to occur in the course of a woman’s life, which until the last decade has been poorly understood and, as dr Prior- the author of this review- summarised
“perimenopause….has been virtually ignored” (https://academic.oup.com/edrv/article/19/4/397/2530801).
Given that the brain is rich in both estrogen and progesterone receptors and sex hormones are also neuro-steroids which interact with our neuro-transmitters, these fluctuations can bring about a large burden of unpleasant psychological symptoms.
The wider the hormones fluctuations, the more severe the symptoms are going to be.
Perimenopause symptoms can be very troublesome and experienced as “NOT MYSELF”
· It can begin when periods are still regular, cycles can be shorter or periods can be heavier
· insomnia, especially waking up at 3-4 am
· irritability,
· anxiety,
· worsening of pre-menstrual syndrome,
· new migraines or headaches
· hot flushes, hotness at the end of sleep
· new onset mental health conditions, which are often poorly understood and respond poorly to the usual strategies, such as anti-depressant SSRIs.
How do we know this?
It wasn’t until some good quality studies done in communities that followed women in midlife over time that we could understand more about the hormonal changes that occur during the menopausal transition.
The Study of Women’s Health Across the Nation (SWAN) enrolled more than 3,000 women living in diverse communities aged 42-52 years old who had an intact uterus and were not taking hormone therapies agreed to take part in a cohort study (a follow up over time study); a subgroup of them had regular hormone testing over the years (in the absence of hormone replacement therapies), which allowed us a better understanding of the hormone fluctuations that occur in peri-menopause.
The SWAN study showed for the first time that:
’NOT ALL MIDLIFE WOMEN HAD THE SAME PATTERN OF ESTROGEN DECLINE’ (https://pubmed.ncbi.nlm.nih.gov/22659249/)
The authors concluded that
· In 31.5% of women had an ESTRADIOL RISE followed by a steep decline pattern (estradiol rose around 5.5 years before the last menstrual period (LMP) and then declined rapidly about one year before the periods stopped)
· 13.1% of women also had a ESTRADIOL RISE followed by a slow decline pattern- estrogen rise for five years, which then decline more slowly over two years before the last period
· 26.9% of women had the familiar slow decline estrogen pattern
· 28.6% had a flat estrogen pattern
Another meta-analysis showed that:
In peri-menopausal women estrogen levels were 20%-30% higher than in women of reproductive age before peri-menopause
ESTROGEN CAN BE HIGHER THAN EVER IN SOME WOMEN IN PERI-MENOPAUSE!(https://academic.oup.com/edrv/article/19/4/397/2530801
My take home points:
Estrogen replacement therapy with bio/body identical hormones - transdermal estradiol and oral micronized progesterone has been studied in menopause but not early phases of peri-menopause (when 50% of women can still have high estrogen)
·Peri-menopause is the time with highest psychological burden – insomnia, brain fog, irritability and worsening of PMS; studies already show that progesterone levels decline first; some evidence suggests progesterone only replacement may be beneficial, however they are limited still and this is not reflected in current national guidance (which advocates use of anti-depressants in early peri-menopause);
Some women may still benefit from estrogen replacement in peri-menopause, although studies show estradiol remains high in at least 50% of women and the addition of estradiol may worsen vaginal bleeding and may not always be well tolerated early in the peri-menopause transition;
·Licensed progesterone preparations are limited to oral micronized progesterone (Utrogestan) 100mg, which is only licensed alongside oestradiol preparations and not on it’s own, although some data exists on the benefits of progesterone only for peri-menopause (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3987489/).
·Maximising lifestyle approaches (nutrition, stress management) in early peri-menopause is crucial and / or hormone balancing therapies, which replace only the hormones that are low or sub-optimal may be an option in early peri-menopause in my opinion.