Menopause, Oestrogen and Covid – what is going on?

And just when we start to get some respect for menopause, along comes Long Covid, bearing very similar symptoms and affecting more women than men.  And if that isn’t bad enough, it is confused with Menopause and women are, once again, feeling as though they are in a revolving door with no exit.

In truth, distinguishing between Long Covid and Menopause is tricky because oestrogen does more than just organise our menstruation.  It also plays a role in infection and autoimmune diseases.

Menopause

Some of the most common symptoms of menopause include: ‘brain fog' and memory issues, difficulty sleeping, fatigue, hot flushes and joint aches, to name a few.

Perimenopause is the time from the start of menopausal symptoms until after the last period. During perimenopause, oestrogen levels fluctuate, become unpredictable and eventually, fall to a low level.

Perimenopause and menopause usually occur between the ages of 45 and 55 years of age and in the UK, the average age for a woman to reach menopause is 51.

Oestrogen

Oestrogen has long been known to have protective effects against certain illnesses and infections for pre-menopausal women.  Generally speaking, as a result of oestrogen, pre-menopausal, adult females mount stronger innate and adaptive immune responses than males. This equates to faster clearance of pathogens and greater vaccine efficacy in females compared to males. 

Unfortunately, there is a flip side to oestrogen’s protective actions.  This honed inflammatory response tends to lead to an increased susceptibility to autoimmune diseases (aka. immune responses against self).  Indeed, autoimmune diseases occur more frequently in women compared to men; an extreme example of this is Systemic Lupus Erythematosus (SLE), an autoimmune disease in which 90% of patients are females of reproductive age, and oestrogens are considered important pathogenic players.  

Covid and Oestrogen

In terms of acute SARS-CoV-2 infection in women under the age of 50, data shows that oestrogen is capable of boosting a woman’s ability to neutralise SARS-CoV-2 whilst also modulating the immune response to infection, keeping the dreaded cytokine storm at bay.  Indeed, COVID-19 is less severe in pre-menopausal women when compared to men, but the protective effect declines after menopause.  That is unless the post-menopausal woman is taking Hormone Replacement Therapy (HRT).  In a review of studies on inpatient women with COVID-19 who used HRT, it was found that they had a lower risk of both mortality and prolonged hospital stay than non-HRT users. 

Furthermore, emerging data indicate that autoimmunity is a characteristic of Long Covid and women are 50% more likely to develop Long Covid, compared to men, again, up until around age 60, when the risk level becomes similar.  One study that looked at the difference in autoantibody profiles in men and women found that whilst SARS-CoV-2 directly triggers autoantibody development in both sexes, autoantibody profiles differed between men and women.  In particular, they speculate that the profile for asymptomatic women may represent the persistence of self-reactive immunity with implications for post-acute chronic immune-driven disease states.  In other words, this particular autoimmune profile in women may be behind some of the Long Covid symptoms. The caveat here: this was one study, and more research is needed to support and clarify this data.

COVID-19 is also known to affect menstrual cycles.  In a recent review of studies examining the effect of SARS-CoV-2 infection on menstrual cycle changes, approximately 20% of infected women experienced some alteration in their cycle, independent of the severity of the infection.  Furthermore, SARS-CoV-2 exerts its effect by binding to angiotensin-converting enzyme 2 (ACE2) receptors, which are found on many tissues in the body, including ovaries.  Autopsy studies have confirmed SARS-CoV-2 infection in, among other tissues, the ovaries.  This infection could alter the functioning of the ovaries, producing fewer hormones and thus resulting in altered menstrual cycles or possibly bringing about more severe or potentially premature perimenopause/menopause.  The authors note that the research on this topic is still too scarce to draw definitive conclusions, and there is a need for further research to distinguish the effects of coronavirus in the different sexes.

Long Covid or Menopause

Symptoms of Long Covid (brain fog, fatigue, sleep disturbance, reduced stamina, headaches and muscle fatigue) are similar to perimenopausal and menopausal symptoms.  Indeed, it would be easy for any clinician examining a woman of around 50 years of age to be confounded as to the cause of these symptoms.  They are symptoms that are common to other illnesses, too, including hypothyroidism (fortunately, there is a blood test for this). 

NICE Guidelines state that if a doctor suspects menopause in a patient, the diagnosis should be based on symptoms.  Given the overlap in symptoms between Long Covid and menopause, and the fact that the average age of women being diagnosed with Long Covid is 49, it is understandable that doctors have difficulty distinguishing. However, in an online study of 460 women, 84% of responders with symptoms of Long Covid had reported that they had not been asked by a healthcare professional about whether or not they could be perimenopausal/menopausal.

A confirmation of the diagnosis of menopause is important because many women would have the opportunity of HRT at this stage.  Supplementation with HRT retains the protective effects of oestrogen lost in menopause – particularly in terms of heart disease, diabetes and osteoporosis.  And, as we have observed, in COVID-19 too.

Long Covid is often likened to Myalgic Encephalitis (ME)/Chronic Fatigue Syndrome (CFS) because they have a striking overlap in symptoms and a large proportion of ME/CFS cases can be traced back to a viral infection.  Women diagnosed with ME/CFS who are going through perimenopause/menopause find that some of their ME/CFS symptoms, especially fatigue levels, cognitive dysfunction/brain fog and problems with temperature regulation get worse.  Treatment with HRT is safe and helpful for this group and may also be beneficial for those with Long Covid in the same position.

Yet, for many women, a diagnosis of perimenopause/menopause still feels like potentially writing-off Long Covid.  The problem here is that there are no definitive tests for Long Covid.  Indeed, there is still difficulty in defining Long Covid, as there are so many symptoms linked to it.  Given that Long Covid could be due to an autoimmune response, or due to reservoirs of the virus hiding in the body, or some other form of continued inflammation, scientists are having to travel up many avenues of research just to try to figure out what is going on.  

Doctors have a test for menopause available to them; a blood test called the Follicle Stimulating Hormone (FSH) measurement, which goes up when oestrogen levels drop.  However, this is not always an accurate test, because FSH levels rise and fall during the course of a menstrual cycle, too.  This test would need to be repeated a couple of times to ensure that the results are in line with symptoms of menopause, but diagnosis is still heavily dependent on symptoms.   Another test sometimes used is the Anti-Mullerian hormone (AMH) test.  This test is used to check a woman’s ability to produce eggs, and is more often used as a fertility test, but can also be used to detect menopause.

Because Long Covid is novel, and symptoms are so varied, no standard protocol exists for assessment.  Since the symptoms also mimic menopause, it is imperative that clinicians, especially in Long Covid clinics, take accurate patient histories, perform clinical examinations, and review comorbidities and social circumstances.  Hence, most investigations are primarily geared towards excluding serious other illnesses. In an article published in the British Medical Journal in September 2022, it is stated “patients may have heard about tests for immunological and clotting function; such tests are the subject of intense research currently, but they do not yet have an established role in clinical practice.”  In other words, at the current time, the key to a correct diagnosis is clear communication between doctors and patients while we await the approval of more accurate tests.

However, don’t lose hope yet about a more objective test for Long Covid.  Scientists are getting there.  In October 2022, a team in Canada announced that they have identified two biomarkers that could be used to classify Long Covid with 96% accuracy.  And, in Sept 2022, a company from the USA was given approval by the European Union regulators to distribute its Long Covid blood test in some European countries.  We await the assessment of the level of accuracy/success of these endeavours.  In the meantime, we have to work with what we have…our voices.

One anecdote in the literature demonstrating the importance of doctors and patients communicating effectively refers to a doctor talking to a patient about her symptoms of brain fog, memory loss, fatigue and headache.  According to the doctor, “After we talked, we realized that her symptoms were due to a fainting spell a couple of months earlier where she whacked her head very hard. She didn’t have long COVID – she had a concussion. But I wouldn’t have picked that up if I had just run a whole battery of tests.”

Talk to your doctor.  If you don’t feel heard, find another doctor.  Long Covid is real, affects millions of people, and will be with us for some time to come.  Science just has to catch up with it.