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Download the Estrogen Interpretive Guide here

By: Clifford Morris, Ph.D.
Chief Chemist and Research Scientist

Introduction

The largest failure of the biomedical research enterprise over the past 50 years has been its inability to adequately address Alzheimer’s disease. There are currently four FDA-approved medications for the relief of Alzheimer’s symptoms; three of which are acetylcholine esterase inhibitors, and the other is memantine. However, there exists no pharmaceutical intervention that arrests or reverses the disease. Moreover, a meta-analysis recently revealed that patients diagnosed with Alzheimer’s receiving acetylcholine esterase inhibitors showed an increase in cognitive decline compared to placebo.1 Since 2003, every disease-modifying agent has failed in Phase II or III trials.2 Alzheimer’s is the sixth leading cause of death in the United States, afflicting more than 5.8 million Americans.3 Between 2000 and 2017, heart disease mortality dropped nearly 9%, while Alzheimer’s mortality increased 145% (all ages).3 Taken together, this data reveals a grim outlook for the future of progression towards traditional disease-modifying therapies. For these reasons, Alzheimer’s risk reduction and prevention efforts have gained traction. Current Alzheimer’s prevention protocols seek to reduce the area under the curve of a function of Alzheimer’s risk factors. We can think of Alzheimer’s risk as being a function of certain variables, some of which are modifiable while others are non-modifiable. Modifiable risk factors include insulin resistance, obesity, inflammation, and smoking, whereas non-modifiable risk factors are age, sex, and family history. The figure below is meant to depict the difference between an at-risk individual who has taken measures to reduce his/her risk for Alzheimer’s versus one who has not.

The Interplay Between Hormones and Alzheimer’s Disease

One of the most notable non-modifiable disease risk factors is sex: women are two times more likely to die of Alzheimer’s than are men.3–5 Estrogen depletion in postmenopausal women is thought to be associated with this risk.4,5 In 2002, The Cache County Study revealed that women who have used hormone replacement therapy (HRT) for 10 years or more are no more likely to develop Alzheimer’s then are men. However, there was no suggestion of risk reduction if used for less than 10 years.6 These findings highlight the importance of identifying at-risk individuals and starting treatment early. More recently, some studies have suggested that long term use of hormone replacement therapy may actually increase Alzheimer’s risk in women.7 Thus, the story here is complicated, and there is still much to uncover. However, the majority consensus is that hormone replacement therapy may reduce Alzheimer’s risk for certain individuals.6,8,9 Estrogen has been found to play many roles in the human body, most notably in females. It has a unique property of being synthesized directly in the brain; this leads to many of its neuroprotective and neurodegenerative effects. It also plays a role in growth, differentiation, and sexual development.10 Most recently, Estrogen has been implicated with hormone replacement therapy in an attempt to treat Alzheimer’s.10–13 Although HRT can involve many hormones, the ones that most seem to be implicated in impacting Alzheimer’s disease are estrogen and progesterone. The reason for estrogen and progesterone having such a large implication in Alzheimer’s is their perceived sex bias. It has been suggested, although not all studies agree, that women are more likely to develop Alzheimer’s, and it is likely that Alzheimer’s dementia-inducing and deteriorating effects also occur more rapidly in women. There are numerous reasons for this, but perhaps one of the more pronounced ones is the gene APOE-4. APOE-4 is known to be a huge risk marker for Alzheimer’s and plays a role in the development of amyloid plaque deposition. However, it has been shown that being positive for APOE-4 plays a much larger role in cognitive decline in women than it does in men.  This could be due to the extra amounts of estrogen in women, and that is why HRT has been viewed as a possible way to help treat Alzheimer’s. The two most common forms of HRT used for Alzheimer’s are estrogen-only therapy and estrogen in combination with progesterone. Studies have found that younger women (aged 50-63 years) who had undergone hormone therapy were significantly less likely to develop Alzheimer’s, while HRT showed no such effect for older women.10,12 However, in the Women’s Health Initiative trial, women who were on active treatment with estrogen plus progesterone had nearly a twice as likely chance of getting Alzheimer’s with serious dementia, while the women on only estrogen were nearly half as likely to get Alzheimer’s with full-fledged dementia. Data like this has led to a hypothesis known as the critical window hypothesis, where HRT (especially estrogen and progesterone) are only effective for a short amount of time in post-menopausal women. This seems to indicate that the critical window for estrogen therapy would be starting younger and using for a longer amount of time. This window, however, does differ from the window associated with HRT that combines estrogen and progesterone. Women using combination HRT for under a year revealed an elevated risk, but women using combination HRT for between 1-3 years had a lower risk. This not only backs up the critical window hypothesis but also seems to suggest that it changes depending on which hormones are used. That being said, women are not the only ones effected by Alzheimer’s; men also are, but generally at a lower rate. If estrogen decline was found to be a large factor in the development of Alzheimer’s, then that may help explain why men are not affected as much. Serum estrogen rates have actually been found to be higher in elderly males than in post-menopausal women. This is because men constantly make testosterone and then convert that testosterone (albeit at a low rate of 0.2%) to estrogen, providing them with what may be increased protection. Further, another reason that men might be more well protected is the drop-off found in women’s estrogen levels post menopause is not nearly as severe for elderly men despite reduced testosterone production. While it has been shown that estrogen effects Alzheimer’s, it is unknown in exactly what way it does. While HRT may be a promising field that can help with Alzheimer’s, finding out what the critical window is for each person and which set of hormones to use remains a challenge. In the future, a more appropriate form of treatment may be personalized HRT based on the patients’ medical history combined with genetic testing to see if they have an increased risk for Alzheimer’s disease. Physicians Lab offers comprehensive urinary hormone testing to help assess hormone levels and biomarkers that may be critical in developing a therapeutic solution for Alzheimer’s disease prevention.

Dietary Approaches for Alzheimer’s Disease

As our appreciation for the complexity of Alzheimer’s pathology has evolved, we have begun to view the disease through several different lenses (e.g., the amyloid hypothesis, mitochondrial disfunction, and cerebral hypoperfusion).  An emerging viewpoint is Alzheimer’s as an inflammatory disease.14 Studies have shown that Alzheimer’s patients present with elevated serum levels of inflammatory markers, such as COX, TNF-α, and IL-6.15–18 These inflammatory markers have shown the ability to disrupt amyloid clearance  and combat signaling pathways responsible for cell survival.16,17 Because of the relationship between Alzheimer’s and inflammation, anti-inflammatory drugs show promise in reducing Alzheimer’s risk. Long term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of Alzheimer’s disease.15 Studies suggest that unselective COX inhibitors are more potent than selective inhibitors in terms of risk reduction.19 Further, dietary and lifestyle changes associated with reduced inflammation show promise in Alzheimer’s risk reduction. Specific dietary changes may involve avoiding high-carbohydrate, high-calorie meals that are associated with elevated serum levels of IL-6.15

In regards to lifestyle changes, Matthew Walker has devoted a large part of his career to understanding the relationship between sleep disruption and Alzheimer’s. His findings overlap well with the inflammatory hypothesis and suggest that high quality sleep may be critical in preventing the onset of Alzheimer’s disease.20 Despite many positive discoveries to help with the treatment of Alzheimer’s, a cure still remains unknown. This has led individuals to study other areas outside of traditional pharmacology, such as diet and nutritional supplementation. Although a majority of trend diets come and go, there is evidence to support a few diets that may help reduce the incidence of the Alzheimer’s disease: the Mediterranean diet, DASH (Dietary Approaches to Stop Hypertension), and MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay). Studies have shown that the DASH diet and Mediterranean diet were both effective in reducing Alzheimer’s risk.21 The DASH and the Mediterranean diet were originally designed to help with cardiovascular health, while the MIND diet is actually focused on reducing Alzheimer’s risk. Data shows that the MIND diet has close to a 50% chance of being an effective preventative action in regard to Alzheimer’s disease. These studies make sense as these diets are high in foods known as AGE (advanced glycation end products).2,21 Low AGE foods are considered to be good and include fish, fruit, legumes, and certain carbohydrates. These are foods that are rich in Omega-3’s, DHA’s (docosahexaenoic acid), and EPA’s (eicosapentaenoic acid), as well as B and D vitamins. Low AGE foods tend to be prevalent in the MIND diet, furthering the belief that MIND diet can help prevent Alzheimer’s. Diet is not the only non-traditional means used to combat Alzheimer’s either; natural supplements have also been in the mix as well. There are a lot of supplements that have been tested, but only a few were found to have clinical relevance. Huperzine A, Ginkgo biloba, Coral calcium, Coenzyme Q10, and Caprylic acid were all found to be ineffective by the Alzheimer’s Association. Despite these being touted by celebrities, they have failed to display real evidence in working in phase three trials. However, not all hope is lost as far as alternative therapies go, but larger scale studies will be needed to provide conclusive evidence in Alzheimer’s prevention.

The Unknown Factors

Another neuropathological feature of Alzheimer’s is oxidative stress. Postmortem examination of the Alzheimer’s brain reveals increased lipid peroxidation, protein and DNA oxidation, and evidence of impaired mitochondrial function.15,22 Alzheimer’s risk reduction with respect to reactive oxygen species (ROS) generation is primarily concerned with mediating homocysteine levels. Epidemiological studies have associated homocysteine, a known ROS stimulator, with the onset of Alzheimer’s disease.23 B vitamins are required to metabolize homocysteine to either methionine or cysteine. In 2007, a double-blind, placebo-controlled trial showed that extended use of vitamin B9 is associated with significantly slower cognitive decline versus placebo.24 It is important to note that a significant fraction of Hispanics and Caucasians may suffer from an MTHFR polymorphism that is linked to hyperhomocysteinemia.25 Such at-risk individuals are important to identify and treat appropriately as early as possible. There are a multitude of unknown and co-dependent factors resulting in the presentation of Alzheimer’s disease. The nebulous mechanisms in which these all act in concert are a testament to the complexity of the disease, and it will take significantly more time and resources until we fully understand these discreet processes.

In Conclusion

We have reviewed some of the most trafficked avenues of Alzheimer’s risk reduction and sought to understand Alzheimer’s as a multifaceted malady. Alzheimer’s risk is a function of many variables, some modifiable and others non-modifiable. Clinical action towards addressing each variable is unique. Some risks may be alleviated with pharmaceutical intervention, while others may require lifestyle and dietary changes.

References

(1)        Kennedy, R. E.; Cutter, G. R.; Fowler, M. E.; Schneider, L. S. Association of Concomitant Use of Cholinesterase Inhibitors or Memantine With Cognitive Decline in Alzheimer Clinical Trials. JAMA Netw. Open 2018, 1 (7), e184080.

(2)        Galvin, J. E. Prevention of Alzheimer’s Disease: Lessons Learned and Applied. J. Am. Geriatr. Soc. 2017, 65 (10), 2128–2133.

(3)        Alzheimer’s Association. 2019 Alzheimer’s Disease Facts and Figures. Alzheimer’s Dement. 2019, 15 (3), 321–387.

(4)        Launer, L. J.; Andersen, K.; Dewey, M. E.; Letenneur, L.; Ott, A.; Amaducci, L. A.; Brayne, C.; Copeland, J. R. M.; Dartigues, J.-F.; Kragh-Sorensen, P.; et al. Rates and Risk Factors for Dementia and Alzheimer’s Disease: Results from EURODEM Pooled Analyses. Neurology 1999, 52 (1), 78–84.

(5)        Medeiros, A. D. M.; Silva, R. H. Sex Differences in Alzheimer’s Disease: Where Do We Stand? J. Alzheimer’s Dis. 2019, 67 (1), 35–60.

(6)        Zandi, P. P.; Carlson, M. C.; Plassman, B. L.; Welsh-bohmer, K. A.; Mayer, L. S.; Steffens, D. C.; Breitner, J. C. S. Hormone Replacement Therapy and Incidence of Alzheimer Disease in Older Women. Health Care (Don. Mills). 2002, 288 (17), 2123–2129.

(7)        Savolainen-Peltonen, H.; Rahkola-Soisalo, P.; Hoti, F.; Vattulainen, P.; Gissler, M.; Ylikorkala, O.; Mikkola, T. S. Use of Postmenopausal Hormone Therapy and Risk of Alzheimer’s Disease in Finland: Nationwide Case-Control Study. BMJ 2019, 364, 1–8.

(8)        Imtiaz, B.; Taipale, H.; Tanskanen, A.; Tiihonen, M.; Kivipelto, M.; Heikkinen, A. M.; Tiihonen, J.; Soininen, H.; Hartikainen, S.; Tolppanen, A. M. Risk of Alzheimer’s Disease among Users of Postmenopausal Hormone Therapy: A Nationwide Case-Control Study. Maturitas 2017, 98, 7–13.

(9)        Seshadri, S.; Zornberg, G. L.; Derby, L. E.; Myers, M. W.; Jick, H.; Drachman, D. A. Postmenopausal Estrogen Replacement Therapy and the Risk of Alzheimer Disease. Arch. Neurol. 2001, 58 (3), 435–440.

(10)      Henderson, V. W. Alzheimer’s Disease: Review of Hormone Therapy Trials and Implications for Treatment and Prevention after Menopause. Journal of Steroid Biochemistry and Molecular Biology. 2014.

(11)      Scheyer, O.; Rahman, A.; Hristov, H.; Berkowitz, C.; Isaacson, R. S.; Diaz Brinton, R.; Mosconi, L. Female Sex and Alzheimer’s Risk: The Menopause Connection. J. Prev. Alzheimer’s Dis. 2018.

(12)      Maki, P. M.; Henderson, V. W. Hormone Therapy, Dementia, and Cognition: The Women’s Health Initiative 10 Years On. Climacteric. 2012.

(13)      Janicki, S. C.; Schupf, N. Hormonal Influences on Cognition and Risk for Alzheimer’s Disease. Current Neurology and Neuroscience Reports. 2010.

(14)      Bolós, M.; Perea, J. R.; Avila, J. Alzheimer’s Disease as an Inflammatory Disease. Biomol. Concepts 2017, 8 (1), 37–43.

(15)      Schelke, M. W.; Attia, P.; Palenchar, D. J.; Kaplan, B.; Mureb, M.; Ganzer, C. A.; Scheyer, O.; Rahman, A.; Kachko, R.; Krikorian, R.; et al. Mechanisms of Risk Reduction in the Clinical Practice of Alzheimer’s Disease Prevention. Front. Aging Neurosci. 2018, 10 (APR), 1–14.

(16)      Álvarez, A.; Cacabelos, R.; Sanpedro, C.; García-Fantini, M.; Aleixandre, M. Serum TNF-Alpha Levels Are Increased and Correlate Negatively with Free IGF-I in Alzheimer Disease. Neurobiol. Aging 2007, 28 (4), 533–536.

(17)      Hüll, M.; Strauss, S.; Berger, M.; Volk, B.; Bauer, J. The Participation of Interleukin-6, a Stress-Inducible Cytokine, in the Pathogenesis of Alzheimer’s Disease. Behav. Brain Res. 1996, 78 (1), 37–41.

(18)      Heneka, M. T.; O’Banion, M. K.; Terwel, D.; Kummer, M. P. Neuroinflammatory Processes in Alzheimer’s Disease. J. Neural Transm. 2010, 117 (8), 919–947.

(19)      Gasparini, L.; Ongini, E.; Wenk, G. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in Alzheimer’s Disease: Old and New Mechanisms of Action. J. Neurochem. 2004, 91 (3), 521–536.

(20)      Mander, B. A.; Winer, J. R.; Jagust, W. J.; Walker, M. P. Sleep: A Novel Mechanistic Pathway, Biomarker, and Treatment Target in the Pathology of Alzheimer’s Disease? Trends Neurosci. 2016, 39 (8), 552–566.

(21)      Hu, N.; Yu, J.-T.; Tan, L.; Wang, Y.-L.; Sun, L.; Tan, L. Nutrition and the Risk of Alzheimer’s Disease. Biomed Res. Int. 2013.

(22)      Markesbery, W. R. Oxidative stress hypothesis in alzheimer’s disease. Free Radic. Biol. Med. 1997, 23 (1), 134–147.

(23)      Morris, M. S. Homocysteine and Alzheimer’s Disease. Lancet Neurol. 2003, 2 (7), 425–428.

(24)      Durga, J.; van Boxtel, M. P.; Schouten, E. G.; Kok, F. J.; Jolles, J.; Katan, M. B.; Verhoef, P. Effect of 3-Year Folic Acid Supplementation on Cognitive Function in Older Adults in the FACIT Trial: A Randomised, Double Blind, Controlled Trial. Lancet 2007, 369 (9557), 208–216.

(25)      Dean, L. Methylenetetrahydrofolate Reductase Deficiency. Med. Genet. Summ. 2012, No. Md, 1–5.

By: Catherine Chua, DO, FAAFP, FMNM, CPE (Certified Physician Executive)
Chief Medical Officer
Davis Health System
Elkins, WV

While attending courses during my Fellowship training, I distinctly remember an esteemed colleague asking the audience, “How many of you think that women develop a Prozac deficiency when they turn 35?”  We were all somewhat stunned at the question, but we also realized she was absolutely correct.  Fast forward, and I have now been a practitioner of both Family Medicine and Functional and Nutritional medicine for many years.  I have often found that I am the last stop for many frazzled, exhausted, depressed, inflamed, overweight women and men.  These patients have been to multiple doctors – primary care, rheumatology, endocrinology – only to be told that there is “nothing” wrong and that they are just stressed out.  They are often sent out with nothing more than a prescription for an NSAID and an SSRI or SNRI and a pat on the head.  I often hear in my office, “I don’t feel I’m depressed, but I know SOMETHING is wrong.”

Over the years, there has been much debate over salivary vs. urinary hormone testing, and now dried urine spot testing is in the debate as well.  I have pored over the literature during my time as a practicing functional medicine physician, and I still exclusively rely on 24-hour urine testing for my patients for a number of reasons.  I appreciate that with 24-hour testing, the clinician is able to look at all three estrogens as well as their downstream metabolites, and that 24-hour testing removes the problem of variable daily fluctuations in a patient’s hormone levels.  When sitting down with my patients, I explain how when we are younger, we have a lot more circulating estriol and less estrone and that as we age, those ratios shift increasing our risk of breast cancer and causing significant symptoms.   I am able to use testing results to help educate my patients on lifestyle changes, medications, vitamins, and supplements that can help to relieve symptoms as well as improve their overall health risks.  With 24-hour urine testing, I am also able to assess progesterone levels and differentiate between the two types.  That allows me to more effectively treat anxiety, dysmenorrhea, PCOS, peri-menopause, and PMS.  It also allows me to properly treat post menopausal women with a full array of hormones.

I also appreciate that I am able to get a 4-6 point cortisol and cortisone level.  Most patients who come to see me for functional medicine are completely worn out by the time that they make it through my door.  Using a 24-hour urine test allows me to show the patients the difference between being “sick” and being “well”.  These patients have had bloodwork showing that their cortisol is “normal” and have been told that, therefore, there is no adrenal dysfunction (i.e., they are not sick).  When they see the 24-hour urine results, however, their feelings that they are not “well” are validated.  With the wellness norms established for 24-hour urine testing, I have been able to successfully identify and treat patients with adrenal dysfunction and get them back to their normal lives.

Over the years I have treated many patients with many different issues, including a young woman who had multiple miscarriages and failed fertility treatments.  She came to me because she was tired of having her hormones manipulated, and she wanted to get her “hormones back to normal”.  After 24-hour urine testing, as well as some bloodwork, I found her to have very low progesterone and subclinical hypothyroidism.  When she returned for her follow up four months later, she asked me if the hormones should be causing her to not have a period.  I explained that, no, she should be having more regular menses and asked if she’d taken a pregnancy test.  She became a little perturbed and told me that the whole reason she was there was that she could not get pregnant; that is why she was trying to go back to normal hormone levels.  Her pregnancy test was positive, and that little girl is a feisty 10 year-old today. 

Another case that has occurred more recently was that of a 47 year-old female who presented to a free clinic offered by my facility.  She is a full-time employee in a minimum wage job, and therefore can not afford insurance.  She stated that she was about to have to quit her job, because with her brain fog and fatigue, she could no longer make it through the day at work.  She had put on weight, her periods were long and heavy, her hair was thinning, and overall, she felt like she was dying.  She had not gone through any testing, because she thought she couldn’t afford it.  When I talked to her about the 24-hour urine testing, and the cost of it compared to running a battery of bloodwork, she jumped at the chance to try to find out what was wrong.  When we got the test back, she had very high estrone levels, a low 2:16 ratio, a flat cortisol curve that was below normal levels, and very low progesterone.  I started her on progesterone (at night during the second half of her cycle), DIM and Ashwagandha.  I also discussed lifestyle modifications that would support lowering her estrogen levels and changing her cortisol curve and levels.  She was also started on Armour thyroid at that meeting.  Over the last year, this patient has lost 34 lbs and her blood pressure has come down from 145/80 to 126/80.  She kept her job, and her boss even reached out to thank me for “changing her life”.  She stated that she feels better than she has in years and is excited to start getting out of the house and exercising when the weather gets better. 

Success stories such as these are par for the course for functional medicine.  The information I gain from looking at women’s (and men’s) hormones is yet another very important tool in my doctor bag.  I’m very fortunate, as a provider, that I am able to practice functional medicine even in one of the most impoverished and unhealthy areas in our country.  I am also very fortunate to be able to partner with a state of the art laboratory while actively pursuing optimal wellness for my patients.

Catherine Chua, D.O. completed her Family Practice residency in 2004 and became a fellow of Family Medicine in 2008. She studied Functional Medicine through the A4M in 2009 and became board certified in 2010. Dr. Chua went on to complete the Fellowship in Functional and Nutritional Medicine in 2015. She had a private practice in rural Elkins, WV from 2004 -2013 when she became an employee of Davis Health System. In 2017, Dr. Chua earned the position and title of Chief Medical Officer of Davis Health System and became a Certified Physician Executive in 2018.

By: Stacy Hinz, MS
Director of Clinical Education

Physicians Lab envisions bringing the highest level of clinical relevance and education to practitioners who see the value in personalizing medicine to each patient. We currently have a large number of educational videos, training documents, and one-on-one training opportunities. This year, we continue to focus on superior education tools through our lab reporting engine.

At Physicians Lab, the science, research, diagnostics, and analytics behind the lab results are second-to-none. Our scientists, researchers, and educators have taken great strides to put together laboratory tests that tie together personalized medicine, metabolic pathway mapping, and the epigenetic biomarkers within the steroidogenic pathway. These strides, however, can remain un-tapped resources if the science, data, and lab results are not put together in an easy-to-interpret platform. In other words, we cannot expect our cumulative decades of experience and research to magically make sense to practitioners who are interpreting the lab results.

To address this gap, Physicians Lab is launching a new rules-driven reporting system that will translate what we know onto a personalized patient report. Please review some of the superior tools included in the new report below.

Target Range Graphics:

  • Practitioners can see how their patients compare to population data in easy-to-read graphics.

Hormone Pathway Totals vs. Expected:

  • The new report shows individual weights of certain pathway totals and has a visual comparison between patient results and population expectations. These comparisons can pinpoint genetic disruptions and metabolic issues in the steroidogenic pathway. BONUS: these graphics also have rule-driven text describing where deviations from the norm may be modified during patient care.

 Ratio Dials:

  • The new report displays key ratios in graphics that clearly show where the patient falls in each ratio, if the patient is balanced (or imbalanced), and in which direction the patient results are leaning when imbalances occur.

Patient Results-Driven Text:

  • The new report allows for algorithm-driven text and recommendations based on a combination of patient results.

The proper balance between anabolic hormones and catabolic hormones is essential in creating a bio-environment for cell proliferations and tissue health to perform at optimal levels while still allowing for detoxification and responses to stress. The result shown indicates an imbalance between anabolic and catabolic metabolites, with higher catabolic metabolites. This can be due to either elevated cortisol and cortisol metabolites (see causes of elevated 17-hydroxysteroids) or low DHEA and DHEA metabolites (see causes of decreased 17-ketosteroids), and it leads to cascading events when out of balance. Possible causes include chronic stress, obesity, metabolic syndrome, excessive wear and tear, or poor recovery from illness or injury.

Lab Testing History:

  • The new report provides historical data to give practitioners the ability to compare results over time.

Probability of Condition based on Symptoms & Lab Results:

  • The new report assesses patient-reported symptoms from our on-line symptom questionnaire and combines the symptom data with lab results to assess the probability of the conditions listed below.

Updated Graphical Representation of Symptom Questionnaire:

  • This updated graphic displays the specific symptoms reported during the patient questionnaire process and indicates the conditions that could correlate to the symptom. Additionally, this graphic indicates the severity of the patient-reported symptoms (1 green beaker = mild/sometimes, 2 yellow beakers = moderate/often, 3 pink beakers = severe/always).

Physicians Lab was created to serve two purposes: provide state-of-the-art science to a growing number of physicians focusing on preventive medicine and wellness for the aging population, as well as deliver superior solutions to physician practices and patients, who are actively seeking to manage their health through innovations in technology and preventive medicine. Physicians Lab delivers accurate and reliable results, while providing the tools necessary to complete convenient, affordable, error-free, and timely lab testing. For more information, contact (877) 316 – 8686.

Trouble With The Curve:  It’s Not Just a Movie

A practitioner’s approach to the cortisol curve

 By: Benita Phillips, D.O.

 

How many times have you looked at a patient’s cortisol curve and said to yourself:

“That just doesn’t make sense!” 

And you think:

“This person should feel fine…”

Or the contrary:

“How does this patient even get out of bed?”

And then you see it, the dreaded up and down zigzag pattern of cortisol levels all day long, fluctuating faster than gas prices on a holiday weekend. And all the while you’re wondering why their symptoms don’t match the curve – they’re supposed to!

What We Knew

We were taught to treat adrenal dysfunction based on 4 or 5 cortisol levels measured throughout the day, called a diurnal curve.

We were taught to use certain supplements to treat high cortisol levels and certain supplements to treat low cortisol levels.

We were taught to use certain supplements for patients who had a cortisol curve that looked like the rickrack my grandmother sewed onto my homemade clothes as a child.

We learned the symptoms of adrenal dysfunction.

We learned that high cortisol causes things like anxiousness and cravings for sugar and carbs, and we learned that low cortisol causes symptoms like fatigue and salt cravings.

But what can be confusing and frustrating are those cortisol levels that do not explain the symptoms – or worse yet – the patient whose symptoms do not resolve with the supplement designated for their cortisol levels.

What We Know, Now

Enter Physicians Lab and their 24-hour urinary hormone testing.  The report includes not only the standard 5-point cortisol levels and curve but also includes total cortisol metabolites; the cortisol:metabolite ratio and a 5-point cortisone curve (an adrenal game changer!).

Now we can see not only the cortisol curve, but we can also see how each patient metabolizes his or her cortisol.  This is especially important for those patients whose symptoms do not match their cortisol levels.

In addition to studying the individual cortisol values and the diurnal curve, it is very imperative to look at the cortisol:metabolite ratio.  As long as this ratio is in the mid-target range (best being 1), then you know that the reported cortisol levels can be interpreted as is.  Meaning they are true and accurate levels.

However, if the cortisol:metabolite ratio is elevated, then the patient is not metabolizing cortisol well.  He or she has a decreased cortisol metabolism.  This may indicate that the actual cortisol levels could be misinterpreted as the result of increased adrenal production.  The levels may be falsely high.

If the cortisol:metabolite ratio is low, then the patient has increased metabolism of cortisol.  This can cause cortisol levels to be misinterpreted as the product of decreased adrenal production.  The levels may be a false low.

Careful Considerations

At this point, we need to remember that abnormal cortisol metabolism changes only the height of the curve.  It is important to note that an abnormal cortisol metabolism does not change the shape of the curve. The shape of the diurnal curve is still the best way to assess adrenal health and function throughout the day.  Let the shape of the curve guide you in your decision process for supplement use.

We also need to remember that decreased cortisol metabolism is often the first indicator of hypothyroidism.  And, an increased cortisol metabolism (false low curve), indicates that the patient is at high risk for obesity, metabolic syndrome, insulin resistance, and type 2 diabetes.

Supplemental Solutions

Lifestyle changes, as well as carefully chosen supplements, are essential for adrenal health. The following lifestyle changes are imperative for the patient with adrenal dysfunction of any kind, no matter what the trouble with the curve:

  • – Healthy diet with an emphasis on vegetables and some well-chosen fruits. Think berries!
  • – Daily exercise
  • – Stress reduction techniques
  • – Sufficient, quality sleep
  • – Daily supplements – fish oil, multivitamin, vitamin D, probiotic

With so many quality adrenal supplements available at our fingertips to help treat different adrenal issues, below are three of my favorites:

  • – Pure Calm – for truly elevated levels
  • – Pure Lift – for truly low levels
  • – Adapto-Pure – for that zigzag pattern

 

The good thing is that if you have questions about your patient’s results, the friendly folks at Physicians Lab are ready and willing to help interpret results, so you have a clear understanding of what is going on. They can be reached Monday-Friday at (877)316-8686, option 2.

 

 

Benita Phillips, DO received her doctorate of Osteopathic Medicine at Oklahoma State University’s College of Osteopathic Medicine in 2000. She went on to complete her residency in Family Medicine at the University of Oklahoma College of Medicine in Tulsa, where she earned the honor of Chief Resident in back to back years (2002-2003). In 2003, Dr. Phillips became Board Certified by the American Board of Family Practice and was awarded both The Paul E. Tietze Memorial Award for Commitment to Patient Care and the Keeping Up With the Times Award for Research Excellence. She later was presented with the Physician’s Recognition Award by the American Medical Association in 2007. Dr. Benita Phillips is an active member of the fellowship in Regenerative Medicine and the American Academy of Anti-Aging and Regenerative Medicine (A4M). She is also an active member of the American Medical Association and the American Academy of Family Physicians.

Short Communication: Implications of Flaxseed on Urinary Hormone Testing

By: Clifford Morris, Ph.D. Cand., Chief Chemist and Research Scientist

 

Flaxseed and Phytoestrogens

Flaxseed is a powerful plant that has achieved massive interest, yet much of what people know about flaxseed is simply misunderstood. Flaxseed is a popular dietary source of lignans, which are a type of phytoestrogen.1,2 A phytoestrogen is a plant nutrient with structural and biochemical similarity to estrogens. Many plants including soy, sunflower, and sesame contain phytoestrogens. Whole flaxseed is the richest plant source of alpha-linolenic acid (ALA) and the lignan, secoisolaricirescinol diglucoside (SDG).3 Flaxseed also contains a significant number of other macronutrients, fiber, and minerals. ALA is converted to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) which are anti-inflammatory and cardioprotective, while SDG is converted to enterolactone (EL) and enterodiol (ED) which have anti-estrogenic and antioxidant properties.4–6 Phytoestrogen compounds found in flaxseed act closely to estrogen blockers; by modulating the production, availability, and metabolism of endogenous estrogen, specifically 2-methoxyestradiol, estradiol and 17 beta-estradiol.7–10 SDG in flaxseed can lower the production of estradiol by blocking the aromatase enzyme, similarly to aromatase inhibitors, as well as having a higher affinity for estrogen receptors than almost all the endogenous estrogens.11

 

Flaxseed and Breast Cancer

Lignans are the center of the controversy regarding whether it is safe for women with breast cancer to consume flaxseeds. Since the phytoestrogens in flaxseed can act as or block estrogen, this has raised concerns about whether phytoestrogens may not be safe for people with a history of hormone-linked cancers, such as prostate cancer, endometrial cancer, or estrogen receptor positive breast cancer.  In postmenopausal women, lignans can cause the body to produce less active forms of estrogen. This is believed to potentially reduce breast cancer risk.1,7 There is evidence that adding ground flaxseeds into the diet decreases cell growth in breast tissue as well.3,5 Again, this would be the type of change that would be expected to decrease breast cancer risk. Research provides evidence that flaxseed can increase apoptosis. Cell and animal studies have shown that two specific phytoestrogens found in lignans, EL and ED, may help suppress breast tumor growth. Animal studies have shown that both flaxseed oil and lignans can reduce breast tumor growth. 4,6,7,12 Combined, this suggests that flaxseeds may have anti-cancer benefits. It is recommended that human intake should be through diet only, not supplementation. If you plan to add flaxseeds into your nutrition plan, please talk to your doctor first to ensure it is an appropriate choice for you.

 

Flaxseed and Urinary Hormone Testing

Consumption of flaxseed influences estrogen metabolism, as indicated by both urinary metabolite excretion and serum hormone concentrations. Studies have shown that flaxseed lignans moderately inhibit the enzymes aromatase and 17 beta-hydroxysteroid dehydrogenases, which catalyze the conversion of androgens to estrogens and balance between estrogens, respectively.2,9,10 Flaxseed consumption has also been shown to affect both endocrine and growth factor pathways by modifying steroid hormone metabolism of IGF and EGFR. Since flaxseed alters estrogen metabolism and could change the clinical interpretation of an estrogen profile, it is strongly advised that flaxseed and phytoestrogen consumption be avoided for at least 3 days prior to urinary hormone testing with Physicians Lab.

 

 

References:

(1)         Flower, G.; Fritz, H.; Balneaves, L. G.; Verma, S.; Skidmore, B.; Fernandes, R.; Kennedy, D.; Cooley, K.; Wong, R.; Sagar, S.; et al. Flax and Breast Cancer : A Systematic Review. 2014.

(2)          Brooks, J. D.; Ward, W. E.; Lewis, J. E.; Hilditch, J.; Nickell, L.; Wong, E.; Thompson, L. U. Supplementation with Flaxseed Alters Estrogen Metabolism in Postmenopausal Women to a Greater Extent than Does Supplementation with an Equal Amount of Soy 1 – 3. 2004, No. 1, 318–325.

(3)          Mora, C.; Tomaz, C.; Ana, S.; Gustavo, A.; Costa, V.; Ibrahim, P.; Maria, N.; Costa, B. Comparative Effects of Brown and Golden Flaxseeds on Body Composition , Inflammation and Bone Remodelling Biomarkers in Perimenopausal Overweight Women Q. J. Funct. Foods 2020, 33 (2017), 166–175.

(4)          Lindahl, G.; Saarinen, N.; Abrahamsson, A.; Dabrosin, C. Tamoxifen , Flaxseed , and the Lignan Enterolactone Increase Stroma- and Cancer Cell – Derived IL-1Ra and Decrease Tumor Angiogenesis in Estrogen-Dependent Breast Cancer. 2011, 51–61.

(5)          Gray, S. L.; Lackey, B. R. Optimizing a Recombinant Estrogen Receptor Binding Assay for Analysis of Herbal Extracts. J. Herb. Med. 2018, No. August, 100252.

(6)          Truan, J. S.; Chen, J.; Thompson, L. U. Flaxseed Oil Reduces the Growth of Human Breast Tumors ( MCF-7 ) at High Levels of Circulating Estrogen. 2010, 2, 1414–1421.

(7)          Jelodar, G.; Masoomi, S.; Rahmanifar, F. Hydroalcoholic Extract of Flaxseed Improves Polycystic Ovary Syndrome in a Rat Model. 2017.

(8)          Hutchins, A. M.; Martini, M. C.; Olson, B. A.; Thomas, W.; Slavin, J. L. Flaxseed Consumption Influences Endogenous Hormone Concentrations in Postmenopausal Women. 2001, 39 (1), 58–65.

(9)          Sturgeon, S. R.; Volpe, S. L.; Puleo, E.; Bertone-johnson, E. R.; Heersink, J.; Sabelawski, S.; Kristina, W.; Bigelow, C.; Kurzer, M. S. Effect of Flaxseed Consumption on Urinary Levels of Estrogen Metabolites in Postmenopausal Women. 2010, 62 (2), 175–180.

(10)        Sturgeon, S. R.; Heersink, J. L.; Volpe, S. L.; Bertone-johnson, E. R.; Puleo, E.; Stanczyk, F. Z.; Kristina, W.; Kurzer, M. S.; Bigelow, C. Effect of Dietary Flaxseed on Serum Levels of Estrogens and Androgens in Postmenopausal Women. 2008, 60 (5), 612–618.

(11)        Mccann, S. E.; Edge, S. B.; Hicks, D. G.; Thompson, L. U.; Morrison, C. D.; Andrews, C. A Pilot Study Comparing the Effect of Flaxseed , Aromatase Inhibitor , and the Combination on Breast Tumor Biomarkers Kim Clark and John Wilton. 2014, 66 (4), 566–575.

(12)        Dikshit, A.; Hales, K.; Hales, D. B. Whole Flaxseed Diet Alters Estrogen Metabolism to Promote 2-Methoxtestradiol-Induced Apoptosis in Hen Ovarian Cancer ☆ , ☆☆. J. Nutr. Biochem. 2017, 42, 117–125.