8/22/2011

Menopausal Symptoms And Underlying Mechanism

by Etsuko Ueda, August 2011
Connecting the dots
Over the course of history, women have tried a variety of methods to deal with menopausal symptoms without knowing the exact cause. Today we know they are caused by the withdrawal of ovarian hormones progesterone and estradiol. Ever since chemists have figured out how to make hormones, bio-identical to human's or otherwise, many experiments have been conducted to find the best approach, and women and their doctors have been presented with a wide array of choices. Whatever the choice, it eventually reaches to a point where some form of estrogen supplementation becomes highly desirable and nothing else seems quite satisfactory, pointing to a unique and important role estrogen plays in women's body. As I reviewed in Menopausal symptoms: What are we complaining?, the most common, salient and easy to recognize features of menopausal symptoms associated with estrogen withdrawal are:
  • Brain strain sensation (foggy brain), along with difficulty in concentrating
  • Hot flash (vasomotor symptoms)
  • Feeling of stress, anxiety, irritable, sweating
  • Low energy, easily fatigued
  • Similarities with other withdrawal symptoms (Benzodiazepine, morphine, etc.)
  • Urogenital / Vaginal atrophy and dryness
In my search to figure out the underlying biological mechanism, I could find many studies connecting hormones, neural functions, and hot flashes / vasomotor functions. But I could not find studies on foggy brain or difficulty in concentrating, as I reported else where. It turns out that estrogen's role in cognitive functions including the ability to concentrate has been studied in terms of its role in maintaining the cholinergic system activities. The neurons and synapses in cholinergic system use acetylcholine to transmit the signals, and they are found in such areas as hippocampus, basal prefrontal cortex, and in many areas of neo cortex. The parasympathetic system neurons are also cholinergic, and together with the sympathetic system (partly cholinergic), they form the autonomic nerve system. It is called cholinergic because the neurotransmitter acetylcholine (ACh) is made from choline (one of B vitamins).

Estrogen, Underactive Cholinergic System, And Difficulty In Concentrating

  • Estrogen increases parasympathetic activity through NMDA receptors and reduces sympathetic nerve activities through GABAa receptors.

Estrogen-induced autonomic effects are mediated by NMDA and GABAA receptors in the parabrachial nucleus.  Tarek M Saleh, Barry J Connell, 2003

Although, estrogen seems to have opposite effect on sympathetic nerve activities though GABAa receptors through insular cortex. (Sympathoexcitatory effects of estrogen in the insular cortex are mediated by GABA.  Tarek M Saleh, Barry J Connell, Alastair E Cribb 2005)
    • An underactive parasympathetic system (cholinergic) allows the sympathetic system (adrenergic) to become overactive, when estrogen is lacking. (Estrogen blocks the cardiovascular and autonomic changes following vagal stimulation in ovariectomized rats. T M Saleh, M C Saleh, B J Connell 2001),
      • The overactive sympathetic system can manifest as increased feeling of tension/stress, anxiety, sweating, hot flashes, and chill or "hard to get warm" condition, and estrogen effectively remedies all of them.
      • The underactive parasympathetic system can manifest as commonly seen menopausal complaints of dry eyes, dry mouth, less sexual arousal, weaker digestion, etc., since the parasympathetic system controls the glandular system.
      • This fits well with the observations that anything that can elevate the parasympathetic activity or that can reduce sympathetic activity can ease menopausal symptoms. These benefits can derive from various relaxation techniques such as paced deep breathing, massage, acupressure, and acupuncture, to drugs including Clonidine and others (Pathophysiology and Treatment of Menopausal Hot Flashes. Robert R. Freedman, 2005).
    These characteristics of the cholinergic neurons make it a perfect candidate to explain the underlying neural mechanism of the menopausal symptoms, not only the difficulty in concentrating but also the hot flash and other related menopausal symptoms. The picture emerging from these studies is: Estrogen deprived/addicted brain struggles with an underactive cholinergic/parasympathetic system and overactive sympathetic (adrenergic) activity. It is our common knowledge that when we are upset, anxious, nervous, or fearful - when sympathetic autonomic activity level is high - our performance (cognitive or otherwise) suffers compared to when we are cool, calm, and collected - when cholinergic/parasympathetic neural activity is strong. Menopausal estrogen withdrawal puts the brain in an even more disadvantaged state, and the brain strain sensation or the foggy brain sensation may be the brain's plea for help. Strangely, though, researchers studying cholinergic system and its role in cognitive functions in relation to menopause do not seem interested in menopausal symptoms.

    The link between menopausal symptoms and cognitive impairment
    According to some research, nearly 90% of women experience menopausal symptoms (Bresilda Sierra, et.al. 2005). They start about 2 years before the final menstrual period, and lasts for many years. Nearly 50% of all women reported vasomotor symptoms 4 years after their final menstrual period, and 10% of all women reported symptoms as far as 12 years after final menstrual period, 1 year following the final menstrual period (late perimenopause) seems the most difficult time in terms of bothersome symptoms (Revisiting the Duration of Vasomotor Symptoms of Menopause: A Meta-Analysis. Mary Politi, Mark Schleinitz, Nananda Col 2008).

    • Since hot flash is a big part of menopausal symptoms, you would expect some kind of correlation between the hot flash severity and the cognitive deficit, if menopausal cognitive impairment should have anything to do with the severity of menopausal symptom. It was only when the number of hot flashes were measured objectively, a significant correlation with "delayed verbal memory" performance emerged (Objective hot flashes are negatively related to verbal memory performance in midlife women. Pauline Maki, et. al., 2008).
    The discrepancies seen among these studies probably are due to the sensitivity of the tasks and measures used. Less sensitive measures can demonstrate the menopause effect only when the symptoms are overwhelmingly strong, and more subtle impairments would go undetected.

    Menopause and Cognitive Decline
    Decline of mental capacity in old age is everyone's concern, and menopausal hormone withdrawal and supplementation has been investigated in that context. The initial effects of menopausal hormone withdrawal seem transient and reversible by hormone supplementation, although there is a possibility that the severity of the symptoms may be a reflection of the damage already done (Glucocorticoids and the ageing hippocampus. C Hibberd, J L Yau, J R Seckl, 2000, Impact of the Hypothalamic-pituitary-adrenal/gonadal Axes on Trajectory of Age-Related Cognitive Decline. Cheryl D Conrad, Heather A Bimonte-Nelson, 2011, Longitudinal Analysis of the Association Between Vasomotor Symptoms and Race/Ethnicity Across the Menopausal Transition: Study of Women’s Health Across the Nation. Ellen B. Gold, et. al. 2006).

    It's been also suggested that after a long term estrogen/progesterone deprivation, suffering through all those symptoms, structural changes or damage may set in through various mechanisms, and it may not be reversible (A cross-sectional study of hormone treatment and hippocampal volume in postmenopausal women: evidence for a limited window of opportunity. Kirk I Erickson, et. al. 2010). The degenerative changes in the brain can be examined through a variety of methods: psychological tests to measure cognitive performance, or by using brain imaging, inspection of actual brain tissues, or chemical analysis to assess the integrity of brain structure and activity patterns. Most current research measures the physical integrity of the brain in terms of the white or gray matter volume, the neural fiber density in certain areas or overall, the number of neurons of certain category, the metabolic tracer densities, or the blood flow volume.

    The Women's Health Initiative (WHI) studies showed a higher risk of dementias for women receiving estrogen in a form of 0.625 mg/day conjugated equine estrogens (Premarin) with or without 2.5 mg/day medroxyprogesterone acetate (Provera) as progesterone substitute (it's chemical structure is not identical to real human progesterone). The detrimental effect of those hormone drugs on blood clot risk has been known and WHI studies could not escape from it.

    The WHI follow-up analysis indicated that those hormone drugs were particularly detrimental to women who had a sign of cognitive decline or of high blood pressure at the start of the study (Postmenopausal hormone therapy and regional brain volumes: the WHIMS-MRI Study. S M Resnick, et. al., 2009; Relationship of hypertension, blood pressure, and blood pressure control with white matter abnormalities in the women's health initiative memory study (WHIMS)-MRI trial., Lewis H Kuller, et. al., 2010). Abnormal white matter lesion volumes were also associated with the hormone drugs used in the WHI study (Relationship of hypertension, blood pressure, and blood pressure control with white matter abnormalities in the women's health initiative memory study (WHIMS)-MRI trial., Lewis H Kuller, et. al., 2010). That is exactly what can be expected from the blood clot risks both drugs have been know for (see Hormone: Does and Don'ts).

    The French E3N Cohort study on blood clot risk (Postmenopausal Hormone Therapy and Risk of Idiopathic Venous Thromboembolism. Results From the E3N Cohort Study.), on the other hand, indicated transdermal natural estradiol 0.05 mg + natural progesterone were as safe as not using hormone supplementation at all, while all other types and forms of estrogen alone or estrogen + progesterone substitute increased blood clot risk. The blood clot risk can also be demonstrated in healthy women as increased thrombin generation long before any clinical health problem develops (Increased thrombin generation among postmenopausal women using hormone therapy: importance of the route of estrogen administration and progestogens. Pierre-Yves Scarabin,et. al., 2011).

    There is no doubt that removing menopause symptoms using hormones improves mental functioning and quality of life in general even when a wrong form of hormone supplementation is used. That is usually the reason many women start hormone therapy and stay on it. It is also clear that wrong forms of hormone supplementation can raise various health risks in the long run for sure as WHI clinical trials and their follow up studies, French E3N studies, and others have demonstrated. Moreover, if you look at individual cases rather than the statistical results, the harms can sometimes manifest immediately since blood clot incidences can occur within a matter of weeks and cancers can grow within a few months.

    What is not clear is whether the right form of hormone therapy can slow down mental decline or reduce the dementia risk that seems an inevitable part of aging. One study (Early menopausal hormone use influences brain regions used for visual working memory. Alison Berent-Spillson, et. al., 2010) compared those who never used hormones to those currently using or who used in the past for at least for 10 years continuously. The study found the hormone use advantageous. The measures used were a visual memory task performance and the related brain activity measured by functional MRI (visual memory task involves a core function of cholinergic system). Interestingly, the past users tested after 1 to 3 years since stopping hormones maintained the advantage compared to never users, but not as much as the current users. The abstract did not indicate if any of the past users or never users were still suffering menopausal symptoms, although it is well known that stopping estrogen will bring back the symptoms in most cases (Vasomotor symptoms usually reappear after cessation of postmenopausal hormone therapy: a Swedish population-based study., Lotta Lindh-Astrand, et. al. Menopause. 2009), and menopausal symptoms can last more than 12 years for some women.

    Also, this study examined post menopausal women who used a wrong form of hormones (Premarin with or without Provera), but it avoided the health risk issues by eliminating everyone sick or otherwise not healthy at the time of testing. It also excluded plant hormone (soy food?) users. All these exclusions can introduce some unknown biases. The study also did not describe or track any other symptoms of menopause their subjects may or may not have suffered. The results of the study may have been different if they looked into only those (current, past and never users) who did not have any significant menopausal complaints or symptoms. There are so many things that can make this study difficult to interpret, but it is the only functional MRI study done on menopausal hormone therapy so far.

    Epidemiological surveys on Alzheimer's disease (AD) in old age also indicated the advantage of menopausal hormone supplementation that seems to increase with the duration of HRT use. Women who used HRT 10 years or more had AD risk comparable to that of men, and shorter duration was associated with higher risk (Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. Peter P Zandi, et. al., 2002). Unfortunately, because the HRT used was the wrong form of hormones (Premarin with or without Provera), it makes the interpretation rather difficult. How can you make sense out of this data against the WHI clinical trial data that ended up with higher incidences of dementias with longer use? It may simply be indicating that longer the HRT duration the more weaker and vulnerable have passed away, and only those resilient have survived?

    Animal studies have observed a lasting advantage of estrogen-only therapy in ovariectomized rats which persisted at least up to 7 months. (Transient Estradiol Exposure during Middle Age in Ovariectomized Rats Exerts Lasting Effects on Cognitive Function and the Hippocampus. Shaefali P Rodgers, Johannes Bohacek, Jill M Daniel, 2010).
    So far, animal studies as well as human studies indicate that the physical structure of the brain, such as size, number of neurons, or fiber density, either overall or in some critical areas are better preserved when hormones are supplemented, except for a long term use of the wrong forms of hormones by vulnerable women (Effects of hormone therapy on brain morphology of healthy postmenopausal women: a Voxel-based morphometry study. Marina Boccardi et. al. 2006; Application of machine learning methods to describe the effects of conjugated equine estrogen therapy on region-specific brain volumes. Ramon Casanova, et. al., 2011 ).

    However, what kind of advantage a structural preservation would give in terms of mental functioning is not at all clear. Some researchers seem to suggest that cognitive deficits associated with menopausal symptoms are precursors to the later decline and dementias. This however is not certain. The brain shrinks as part of the normal aging process. However, the pattern of brain shrinkage seen in people with early sign of dementia is abnormal compared to that of normal aging brains (Longitudinal pattern of regional brain volume change differentiates normal aging from MCI. I Driscoll, C Davatzikos, et. al., 2009). Dementia is also associated with abnormal lesion volume (Relationship of hypertension, blood pressure, and blood pressure control with white matter abnormalities in the women's health initiative memory study (WHIMS)-MRI trial., Lewis H Kuller, et. al., 2010).

    Critical window of opportunity?
    Researchers have been trying to find whether there is a critical window of opportunity: meaning that if you miss that window (may be a few years after the last menstruation), the hormone is no longer effective in bringing back normal functioning. Worse, hormone deprivation may initiate the degenerative process.
    Do these studies prove there is a critical window of opportunity? Not so fast. For the cholinergic system to benefit from estrogen, it has to have estrogen receptors (Viral Vector-mediated Delivery of Estrogen Receptor-alpha to the Hippocampus Improves Spatial Learning in Estrogen Receptor-alpha Knockout Mice. Thomas C Foster, et. al., 2008). Since progesterone regulates estrogen receptor expression, it is rather peculiar to see research after research that used estrogen only therapy to examine the critical period hypothesis. The exclusive focus on estrogen in so many studies is misguided. The importance and advantage of proper use of progesterone is shown in various studies:
    In other words, to prove the critical period hypothesis, we need to see studies with the right form of estrogen + progesterone therapies.

    There is also evidence that hormone therapy can be effective even after a long period of hormone deprivation. It has been demonstrated that initiation of progesterone therapy can have effects on bone mineral density long after menopause, even over 80 years of age (Osteoporosis reversal with transdermal progesterone., John R. Lee 1990, see also What Your Doctor May Not Tell You About Menopause, by John R. Lee, M.D. with Virginia Hopkins, 1996). I personally witnessed old women's hair started to grow back when progesterone therapy was initiated for the first time in their 80's.

    Cholinergic system is not the only thing hormones protect
    The cholinergic system has been the main focus of the studies in menopausal cognitive decline. The cognitive tasks that demonstrated the effects of hormones are often characterized as attention processes, executive functions, processing speed, learning, working memory, etc. For example, various versions of cued multiple choice task have been used to assess sustained visual attention, which has emerged as one of the core functions of cholinergic system, especially at hippocampus. The cue is presented only for a brief period in a way if you are not paying attention, you would miss it.

    While others may experience it as memory problem in some other context, the cognitive impairment I have experienced can be best characterized as difficulty in concentrating, and it was particularly noticeable when working on computer screens. Some people may experience it as tired eyes. Maintaining the visual attention on a specific aspect of the display to accomplish the task at hand, without losing the place or the train of thought was very tiring, and I was constantly fighting the urge to close my eyes to rest or catch my attention drifting, and quickly became exhausted. These characteristics fits well to the notion of impaired "sustained visual attention" arising from the underactive cholinergic system. Similarly, a study that examined middle-aged computer terminal operators found that the work-related physical discomfort scores (mainly eyes, but arm, neck, shoulder, hip were also involved) correlate with menopausal symptom scores (Sumika Yoshimura 2007), indicating that the menopausal symptoms may be the underling cause of the discomfort and difficulties.

    I have not examined all the cognitive tasks used in the studies to demonstrate hormone effects, but my impression is that they are tasks that require attention, concentration, or conscious effort, which has higher energy requirements compared to simply accessing established memories and skills, or drifting into daydreaming.
    It is tempting to say the deficit is mainly in cholinergic system, but it may only be a part of the story. The high energy demand aspect of the affected cognitive functions points to the role of hormones in neural energy production (Progesterone and Estrogen Regulate Oxidative Metabolism in Brain Mitochondria. Ronald W Irwin, 2008), and there is no reason to think it only affects cholinergic system.

    Since the cholinergic system is an essential part of normal mental functioning, some form of abnormality in the cholinergic system is always present in dementia brains. That, however, does not necessarily indicate the impairment is cholinergic specific or originated from cholinergic system, either.
    For the prevention of old age dementias, I would count on the protective roles of hormones that have much broader implications on the brain health. For example:
    To settle the issue
    The questions to be answered are:
    • Does every menopausal women benefit from hormone supplementation in terms of cognitive aging and the health in general if they use the right form of hormone therapy (bio-identical transdermal estradiol 0.03~0.05 mg/day + bio-identical transdermal progesterone 10~20 mg/day, continuous regimen)?
    • Can you protect your brain and the rest of the body for that matter, by maintaining hormonal balance all though the adult life, supplementing bio-identical transdermal progesterone when the need arises? And does it reduce the severity of menopausal symptoms?
    The answers should be "yes", "yes", and "yes". The idea originates from the conclusion Ray Peat, Ph.D and late John R. Lee, M.D. reached decades ago based on the research available back then. Their recommendations have been followed by many doctors and women around the world with positive results. Today, there are endless variety of research that demonstrate how bio-identical natural hormones protect women's health or men's. Below are only a small fraction of the studies out there on the neuroprotective role of hormones alone. The evidence is overwhelming. Only lacking are actual studies that are designed to answer these specific questions in humans.

    The WHI clinical trials was supposed to give us enough data to answer many questions surrounding menopausal hormone therapy. Instead, they exposed an entire generation of menopausal women to dangerous drugs, scared and confused consumers and doctors alike, and sent researchers chasing dead-end false leads, all because it used wrong forms of hormone therapy. It's a shame that it happened in the face of the fact that Premarin and Provera or Prempro have been known for a long list of serious side effects, which the pharmaceutical industry and medical establishment have chosen to ignore, if not hide (see The Hormone War is Heating Up).

    Caution for overdose
    It should also be noted that, although estrogen plays an important role in the cholinergic system and many other parts of human body, estrogen is an excitetoxin, so without progesterone's protection, estrogen can make the brain more vulnerable to stress. Estrogen can harm the brain when overdosed, and it can amplify stress hormone responses to psychosocial stress, as indicated in the following studies.

    Overdose of progesterone, on the other hand, in animal experiments as well as in human can pose a different kind of problem due to progesterone and its metabolites' GABAa mediated sedative effects (Pharmacology of endogenous neuroactive steroids., Doodipala Samba Reddy, 2003). You cannot expect any heavily sedated animal (or human for that matter) to perform well on a cognitive task. Researchers who experiment with various dosage levels often find lower doses more effective. (Effects of estrogen and progesterone treatment on rat hippocampal NMDA receptors: relationship to Morris water maze performance. El-Bakri NK, et. al. 2004, Different role of endothelium/nitric oxide in 17beta-estradiol- and progesterone-induced relaxation in rat arteries. H Y Chan, et. al., 2001).

    Note: Premarin + Provera (used in the WHI clinical trials and most commonly prescribed in the US) has been known for low compliance, and many people do not like the way it feels and soon discontinue. Recent studies provided a clue. Provera (a progesterone substitute) shuts down important neural activities (Impact of progestins on estradiol potentiation of the glutamate calcium response. Jon Nilsen, Roberta Diaz Brinton 2002). Consistent with its negative impact on the neural activities, Premarin + Provera (or simply referred as HT or HRT) was observed to worsen some aspects of verbal memory while reducing hot flashes (Effects of botanicals and combined hormone therapy on cognition in postmenopausal women. Pauline Maki, 2009, Effects of the menopause transition and hormone use on cognitive performance in midlife women., G A Greendale,et. al., 2009).


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    Before you post your HRT questions, please try what I think safe and effective for at least 3 months: estradiol 0.025~0.050mg/day patch, with 20~40mg/day progesterone cream (about 1000mg progesterone in 2oz cream). You can also add DHEA 5~10mg /day.
    That is the only recommendation you will get from me.

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