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There are many reasons to use
24-hour comprehensive urinary testing in assessing hormones and metabolites in
the steroidogenic pathways, but most practitioners choose comprehensive urinary
hormone testing for the following reasons:
Urinary hormones are a direct measurement of the
active free hormone available to the tissue receptors. In serum, the amount of
hormone available to the tissue receptor is estimated based on binding
calculations and population assumptions.1,2
By testing over a larger time period and
normalizing daily hormone fluctuations, urinary hormone testing prevents false
highs and lows that can show up when testing in more immediate, moment-in-time
methods of detection like serum and saliva.
Urinary hormone testing provides a more in-depth
clinical picture due to the ability to measure hormone metabolites along the
steroidogenic pathway. These metabolites indicate how the primary hormones are affected
by enzymes and cofactors between hormone synthesis and hormone elimination.
This deeper dive into the
clinical utility of urinary hormones and metabolites will be the focus of this
article. As the primary hormones and hormone metabolites move along the
steroidogenic pathway, urinary testing can trace imbalances that are
contributing to common clinical issues by assessing key indicators along the
pathway. The result is a clearer clinical picture and greater ability to
monitor subsequent therapies and lifestyle changes.
This article will describe some
of the benefits of urinary hormone testing and will highlight specific cases
where common clinical findings, (often difficult to identify in serum or
salivary testing) were easily uncovered, and even predicted, by measuring
primary hormones and their metabolites in aging adults.
Why one dose does not fit all
It is a common clinical question when
prescribing progesterone to different patients with similar progesterone
levels; why do some still suffer from anxiety and insomnia, while some are too
sedated or tired, and some respond as expected? The answer lies in the way the
patient metabolizes progesterone. Progesterone metabolizes to 5a-pregnanediol and 5b-pregnanediol at varying
levels. The amount of each is dependent upon the amount of 5-alpha or 5-beta-reductase
activity.3–5 By examining the metabolites
of progesterone and assessing other metabolism pathways of 5-alpha-reductase
activity, practitioners can predict how a patient may respond to progesterone
therapy and can also modify the pathways of progesterone metabolism for the
best clinical response.
Total Estrogen Analysis vs Estradiol Alone
Uncovering estrogen dominance in patients
with low estradiol
Aromatase activity is responsible
for converting androstenedione to estrone as well as testosterone to estradiol.
In younger adults, estradiol is the primary estrogen produced. However, as
patients age, estrone becomes the primary estrogen produced.1 This transition from more estradiol
to more estrone presents an issue when measuring and monitoring estrogen in
aging patients because many practitioners only use estradiol to monitor estrogen
levels and aging patients can falsely appear estrogen deficient when estradiol
is the only estrogen measured. Measuring only estradiol is not advisable when
deciding if premenopausal woman, or even postmenopausal woman, need estrogen
therapy because many aging women with estrogen dominance or elevated estrogens
can still have low estradiol levels. Placing this category of women on estrogen
therapy could potentially lead to worsening symptoms and even endometrial
cancer risk.2,6,7 Additionally, metabolites of estrone
and estradiol can indicate certain risk factors and often have estrogenic
strength as well, so it is important to know the total effect E1, E2, E3 and
their metabolites are having on the target tissues.
Physicians Lab provides a Total
Estrogen Load in each of its urinary hormone testing profiles (Figure 1),
so it is easy to assess total estrogen effect in the patient. Each estrogen is
weighted by its expected binding affinity at the estrogen receptor and is also
presented in a helpful pie chart that compares expected relative levels with
the levels observed in the patient. In
men, estrogen is assessed vs testosterone, and in women, estrogen is assessed
vs progesterone to identify estrogen dominance and uncover any imbalanced
between these metabolic pathways.
Pathways to estradiol and estrone
Aromatase activity converts testosterone
to estradiol or androstenedione to estrone. While increased aromatase activity
can be treated with an aromatase inhibitor, aromatase inhibitors can
dramatically decrease estrogen and result in heart issues as well as declining
brain and bone health.3,7,8 Monitoring and understanding
the pathways of aromatase can assist practitioners in identifying areas of
improvement with or without aromatase inhibitors. Aromatase activity is easily
monitored in urine.
Aromatase to Estradiol
In this male patient (Figure 2), we
can see increased aromatase activity indicated in several areas.
Estradiol is dominating the total estrogen load
and is higher than expected, in relative ratio to the other estrogen components
of the total.
This means that aromatase activity is
predominantly aromatizing testosterone to estradiol
His elevated testosterone/estrogen ratio with decreased
metabolism to downstream metabolites shows that testosterone is metabolizing
toward estradiol more often and with more preference than downstream
metabolites of testosterone
Testosterone must be metabolized
and eliminated. There are essentially two pathways for this: the 5a-reductase pathway
(creating testosterone metabolites) or the aromatase pathway (creating
estradiol). When testosterone is elevated, often aromatase activity will often increase,
and the level of expected testosterone metabolites will decrease (which is the
case with this patient). When this happens, the ratio between testosterone and
estrogen will indicate estrogen dominance. This means that aromatase activity
is creating an imbalance between testosterone and estrogen. Aromatase activity
and 5a-reductase activity are
often negatively correlated, because when 5a-reductase
goes up, there is less testosterone available for aromatase activity, and vice
versa. However, this is not always the case. Sometimes when 5a-reductase activity is
low, testosterone will start to pool and appear elevated due to the inability
to metabolize downstream and the excess testosterone will not aromatize. Therefore,
we examine the ratios of testosterone to estrogen and testosterone to its
downstream metabolites in order to determine which endpoint of testosterone is
Symptoms of estrogen dominance
Although the testosterone is elevated, the
patient is struggling with symptoms that mimic testosterone deficiency because
estrogen is having a greater effect at the tissues. This is common in patients
with estrogen dominance.
Not every male with elevated
aromatase activity will have high levels of testosterone with elevated estrogen
(like the patient described here), so it is important to have multiple measures
with steroid pathway metabolites when interpreting and assessing aromatase
By examining the pathways and
measuring multiple points along these pathways of hormone synthesis and
metabolism, it becomes clear where certain pathways may have accelerated and
others may have decreased.
Aromatase to Estrone
In a similar example, aromatase
activity to estrone is the conversion of androstenedione to estrone (instead of
testosterone to estradiol), so there is a different mechanism to examine when
aromatase activity results in increased estrone. Androstenedione originates
from DHEA and progesterone pathways of metabolism. As mentioned previously,
estrone is the dominant estrogen in aging men and women; but what mechanisms
cause estrone to increase and estradiol to decrease in aging patients?
Testosterone to estradiol
conversion happens at the sex organs in younger adults whereas androstenedione conversion
to estrone happens in adipose tissue and adrenals as well as the sex organs.9 As patients age, the ovaries
and testicles decline in function causing lower testosterone production, increased
androstenedione production and increased conversion of androstenedione to
estrone vs. testosterone.8 Androstenedione is the predominate steroid
hormone produced by the postmenopausal ovary in women and aging patients often
have inflammatory responses and other issues causing the adrenals to produce
more androstenedione as well. The presence of more androstenedione is not the
only reason for increasing levels of estrone – the declining expression of
certain enzymes required for testosterone production in the steroidogenic
pathway pushes metabolism of androstenedione directly to estrone instead of
Androstenedione is primarily a
product of DHEA but can also be created from progesterone, so when increased
aromatase activity results in estrone, it is important to check both DHEA and progesterone
levels (especially in patients taking DHEA or progesterone supplementation).
When deciding how to treat
patients with increased aromatase activity, there are several options to
consider. Assessing the multiple markers along the pathway, as well as
examining which pathway of metabolism seems to be predominant, is crucial. Increasing
testosterone, decreasing testosterone, increasing DHEA, decreasing DHEA,
decreasing progesterone, or inhibiting aromatase activity are all options.
However, choosing the best options requires an understanding of the pathway of
Hypothyroidism and Estrogens
Linking aromatase activity, thyroid activity and
The conversion of androstenedione
to estrone opens the topic of how hypothyroidism affects estrogen levels. Hypothyroid
decreases the rate of metabolism to androstenedione, thereby decreasing the amount
of estrone produced.11,12 This can cause irregular
periods in premenopausal women and can dramatically reduce the total estrogen load
in postmenopausal women who primarily produce estrone from androstenedione so
hypothyroidism can decrease estrone production. Did you know that
hypothyroidism is often caused by estrogen excess/dominance? The human body
relies so much upon maintaining balance that excess estrogen can cause
hypothyroidism, which then has the ability to reduce estrogen production. This
is one of many mechanisms that reminds us how crucial balance is, how the body
tries to correct itself and why it is so important to know which pathways of
metabolism are being affected before attempting to achieve and maintain balance
When examining urinary hormones
in the HPA-Axis, low metabolism of cortisol is a good first indicator of
hypothyroidism.11 As you can see in the same male
patient from Figure 2, estrogen dominance is combined with low metabolism of
cortisol (Figure 3). While estrogen dominance is not the only thing that can
cause hypothyroidism, we can certainly see that this patient’s elevated
testosterone, low testosterone/estrogen ratio, and decreased 5a-reductase activity are
clear indicators of increased aromatase activity. This pattern is almost always
associated with the reduction in cortisol metabolism, which indicates
hypothyroidism, and shows why elevated aromatase activity is almost always
associated with insulin resistance.13 Simply reducing testosterone
and prescribing an aromatase inhibitor may benefit the patient as long as all
of the balancing measures are closely monitored during treatment.
Male Testosterone Pellet Therapy Issues
Avoiding 2nd and 3rd
pellet disappointment in men
How many times do male patients
feel a significant improvement in energy, libido and overall wellbeing after the
first testosterone pellet, only to be faced with declining benefits in the 2nd
and 3rd pellet insertion? Monitoring
testosterone in serum can show misleading moderate testosterone results and
tracking estrogen levels in serum can mask increased aromatase activity. The
male patient described had this experience due to elevated levels of
testosterone and elevated levels of aromatase activity. The patient was experiencing
symptoms of low androgens, even though the testosterone levels were adequate in
serum. The patient insisted that he was ready for a higher dose of testosterone,
and when the practitioner measured serum the testosterone levels justified a
slight increase. Unfortunately for this patient, the free testosterone levels in
urine would have indicated elevated testosterone, but the calculated serum testosterone
levels (not a direct measurement of free) indicated room for more therapy. This
patient already had some symptoms of testosterone excess such as acne, hair
loss, irritability and aggression, but the patient was more concerned about the
reoccurrence of other symptoms like erectile dysfunction, depression, anxiety,
fatigue, and weight gain which he associated with low testosterone. In fact, these
additional symptoms were associated with excess estrogen caused by increased
aromatase activity. What appeared to be declining effects of testosterone,
turned out to be increasing effects of estrogen with symptoms of testosterone
excess. Additionally, the increased aromatase activity triggered lower cortisol
metabolism (associated with hypothyroidism) accompanied by hypothyroid symptoms,
which can also mimic low testosterone. Although the serum testing and the patient’s
symptoms appeared to warrant higher levels of testosterone therapy, urinary
hormone testing showed that this patient needed a different approach to reach
and maintain balance between testosterone and estrogen for the best clinical
Using an aromatase inhibitor to reduce the
amount of estrogen produced and help with energy levels and sexual function.
Supporting Phase I and Phase II detoxification
of estrogens to help eliminate excess estrogen down the most favorable pathways
of metabolism and mitigate the risks associated with elevated levels of
estrogen in men.
Reducing testosterone therapy addressing acne,
hair loss, and mood.
The reduction in aromatase activity and
detoxification of excess estrogen should improve the sluggish cortisol metabolism
and help reverse the signs of hypothyroidism. However, a healthy-thyroid
lifestyle and/or thyroid support will also help the transition back to balance
Metabolic Syndrome, Type II Diabetes and the
Addressing imbalances in metabolic pathways
As already mentioned, low
metabolism of cortisol is a good first indicator of hypothyroidism. This makes
sense when you consider the connection between cortisol, insulin resistance and
thyroid. However, when we see elevated cortisol metabolism, we experience
insulin resistance issues as well.13,14 For example; this patient appears
to have low cortisol levels throughout the day with an unexpected increase in
the bedtime sample (Figure 5). We
confirm, through cortisone results, that the cortisone has a similar trend but
at higher levels than cortisol, which is a first clue of increased metabolism. When we look at the cortisol metabolites,
they appear elevated and the cortisol:cortisol metabolite ratio appears low.
That indicates high cortisol metabolism, so we can see that even though the
cortisol levels appear predominantly low, the adrenal glands are pumping out
cortisol and this patient is metabolizing that cortisol at elevated rates. This
pattern is very typical of someone who is at a high risk of Type II diabetes.13 In fact, new studies indicate
that the pattern of elevated cortisol metabolism combined with an evening
increase in diurnal cortisol was used to predict the onset of Type II diabetes
over the course of 9 years with over 70% accuracy (refs supporting these
We know that abdominal obesity is
linked to both Type II diabetes and elevated cortisol metabolism. We also know
that Type II diabetes is one of the qualifiers for metabolic syndrome, so it
makes sense that a the warning signs of type II diabetes, insulin resistance
and metabolic syndrome can all be identified by examining the cortisol
metabolites and the anabolic:catabolic ratio. It should also make sense that if
we can identify these warning signs in urine, there are likely other metabolic
issues that can be addressed by measuring, achieving and maintaining the
delicate balance between the anabolic and catabolic metabolism pathways.
The Anabolic vs Catabolic Ratio
Measuring, achieving and maintaining metabolic
balance in the HPA-axis
The anabolic to catabolic ratio
compares HPA-Axis balance between 17-ketosteroids (mostly DHEA metabolites) and
17-hydroxysteroids (mostly cortisol metabolites). The easiest way to understand
the anabolic/catabolic ratio is to view it as a balance between creating
energy (through catabolic processes) and using that energy to build
(through anabolic processes).
In order to build and maintain
tissues, the body requires energy. This energy is created by breaking down
(catabolizing) energy storage sources such as carbohydrates, fats and proteins.15 If the catabolic pathways are balanced with
the anabolic pathways, then we end up with the perfect amount of energy
generated by the catabolic pathway and utilized by the anabolic pathway.16 When the catabolic pathway is
higher than the anabolic pathway, we end up with more stored energy – often in
the form of fat – and run the risk of Type II diabetes and metabolic syndrome.17 Although we focus a large
deal on low anabolic/catabolic ratios where cortisol metabolism and
17-hydroxysteroids are dominating over anabolic metabolism and 17-ketosteroids,
there are plenty of cases where the anabolic pathways dominate the catabolic
pathways as well. While this can be less common, it is in no way less harmful
to the patient. For these patients, they have the ability to build but they
lack the energy to do so. When the anabolic pathway is higher than the
catabolic pathway, patients are often hypoglycemic, underweight, fatigued and
require more caffeine. Due to craving carbohydrates, a percentage of patients
may be overweight with muscle loss because their energy sources are more carbohydrate
and muscle than fat. These are generalizations for understanding the anabolic
to catabolic ratio, but it points out how balance is best.
When cortisol metabolism is
increased, this will often result in elevated 17-hydroysteroids and an
imbalance in the anabolic to catabolic ratio leaning toward catabolic. When 17-hydroxysteroids increase, balancing
the ratio should include slowing the rate of adrenal output – even when diurnal
cortisols appear normal or low, because elevated 17-hydroxysteroids directly
correlate to increased adrenal output. Temporarily increasing DHEA is also a
valid consideration and allows for balance to be achieved between anabolic and
catabolic while the patient works on lifestyle improvements to lower cortisol
production. Increasing DHEA, even just temporarily, often works well because an
imbalance (leaning toward catabolic) can make lifestyle changes, such as weight
loss, nearly impossible due to the fact that elevated cortisol metabolites are driving
energy storage and weight gain. DHEA therapy can also increase 5-alpha-reductase
activity which is often helpful in reducing cortisol metabolism because decreased
5a-reductase is often
associated with increased cortisol metabolism as well. Although increasing DHEA
is not always an option, DHEA replacement is usually a good option when an
imbalance exists due to low 17-ketosteroids and decreased 5a-reductase activity.
Understanding where the decreased
17-ketosteroids are stemming from in the pathway is important in choosing therapeutic
options. To accomplish this, the 17-ketosteroids are displayed in a pie chart
in the report allowing for the comparison between the patient results (actual) and
the expected results in each individual ketosteroid. Through this graphic, accelerated
or sluggish pathway mechanisms can be quickly identified. For example, the
patient in Figure 6 has an anabolic to catabolic ratio that is leaning toward
the catabolic side. The results indicate both elevated catabolic metabolites
and low anabolic metabolites combining to produce an extremely imbalanced
ratio. The root cause of the extremely low 17-ketosteroids is due to low DHEA.
The cause of the increased cortisol metabolites is not obesity (the patient is
only 120 lbs.), but rather metabolism down the 5b-reductase pathway at a much
higher rate than expected, which is also associated with increased cortisol
In these cases, we can often increase
DHEA, which also increases 5a-reductase
activity,7,17 and consider slowing 5β-reductase activity
using licorice.18 One other benefit of licorice is that
it will slow the rate at which back-door androgen metabolism occurs,10 (which is not an issue in this
patient) and will assist in sending DHEA metabolism down the 17-ketosteroid
pathway. We may also see increases in testosterone and estrogen as DHEA and 5a-reductase activity increase. The end result
will be more balance between the anabolic and catabolic in the ratio, both by
increasing the anabolic side through DHEA supplementation and decreasing the
catabolic side by calming the adrenals and reducing 5b-reductase activity.
Physicians Lab’s comprehensive
report was designed to take some of the guesswork out of interpreting results
and treating patients. The totals and ratios are a good start and the dynamic
text contained in these reports can often tell you exactly what is happening
because the text is based on the results of each patient.
Our primary focus is to deliver the most accurate results with the highest amount of clinical information and our comprehensive report containing results-driven text allows us to transfer this information directly to the report as the scientific community gains more insight into these pathways.
1. Roos J, Johnson S, Weddell S, et al.
Monitoring the menstrual cycle: Comparison of urinary and serum reproductive
hormones referenced to true ovulation. Eur J Contracept Reprod Heal Care.
2. Maskarinec G, Beckford F, Morimoto Y,
Franke AA, Stanczyk FZ. Association of estrogen measurements in serum and urine
of premenopausal women. Biomark Med. 2015;9(5):417-424.
3. de Ronde W, de Jong FH. Aromatase
inhibitors in men: Effects and therapeutic options. Reprod Biol Endocrinol.
4. Starka L, Hampl R, Bicikova M, Jelinek R,
Doskovil M. Observations on the biological activity of epitestosterone. Physiol
5. Hiipakka RA, Zhang HZ, Dai W, Dai Q, Liao
S. Structure-activity relationships for inhibition of human 5α-reductases by
polyphenols. Biochem Pharmacol. 2002;63(6):1165-1176.
6. Lu LJW, Cree M, Josyula S, Nagamani M,
Grady JJ, Anderson KE. Increased urinary excretion of 2-hydroxyestrone but not
16α- hydroxyestrone in premenopausal women during a soya diet containing
isoflavones. Cancer Res. 2000;60(5):1299-1305.
7. McCann SE, Edge SB, Hicks DG, et al. A
pilot study comparing the effect of flaxseed, aromatase inhibitor, and the
combination on breast tumor biomarkers. Nutr Cancer. 2014;66(4):566-575.
8. Leder BZ, Rohrer JL, Rubin SD, Gallo J,
Longcope C. Effects of aromatase inhibition in elderly men with low or
borderline-low serum testosterone levels. J Clin Endocrinol Metab.
9. Strauss JF. Some new thoughts on the
pathophysiology and genetics of polycystic ovary syndrome. Ann N Y Acad Sci.
10. Fiandalo M V., Wilton J, Mohler JL. Roles
for the backdoor pathway of androgen metabolism in prostate cancer response to
castration and drug treatment. Int J Biol Sci. 2014;10(6):596-601.
11. Hoshiro M, Ohno Y, Masaki H, Iwase H, Aoki
N. Comprehensive study of urinary cortisol metabolites in hyperthyroid and
hypothyroid patients. Clin Endocrinol (Oxf). 2006;64(1):37-45.
12. Taniyama M, Honma K, Ban Y. Urinary
cortisol metabolites in the assessment of peripheral thyroid hormone action:
Application for diagnosis of resistance to thyroid hormone. Thyroid.
13. Westerbacka J, Yki-Järvinen H, Vehkavaara
S, et al. Body Fat Distribution and Cortisol Metabolism in Healthy Men:
Enhanced 5β-Reductase and Lower Cortisol/Cortisone Metabolite Ratios in Men
with Fatty Liver. J Clin Endocrinol Metab. 2003;88(10):4924-4931. doi:10.1210/jc.2003-030596
14. Declue TJ, Shah SC, Marchese M, Malone JI.
Insulin resistance and hyperinsulinemia induce hyperandrogenism in a young type
B insulin-resistant female. J Clin Endocrinol Metab.
15. Mueller MB, Tuan RS. Anabolic/Catabolic
balance in pathogenesis of osteoarthritis: identifying molecular targets. PM
R. 2011;3(6 Suppl 1):S3-S11. doi:10.1016/j.pmrj.2011.05.009
16. Tzanis G, Dimopoulos S, Agapitou V, Nanas
S. Exercise intolerance in chronic heart failure: The role of cortisol and the
catabolic state. Curr Heart Fail Rep. 2014;11(1):70-79.
17. Ueshiba H, Shimizu Y, Hiroi N, et al.
Decreased steroidogenic enzyme 17,20-lyase and increased 17-hydroxylase activities
in type 2 diabetes mellitus. Eur J Endocrinol. 2002;146(3):375-380.
18. Ferrari P, Sansonnens A, Dick B, Frey FJ.
In vivo 11β-HSD-2 activity: Variability, salt-sensitivity, and effect of
licorice. Hypertension. 2001;38(6):1330-1336. doi:10.1161/hy1101.096112
Co-authored by Clifford Morris, PhD and Thomas Kent
Paradigm of Artificial Intelligence
Technology moves only in one direction—forward. In general, the observation of this fact is welcome. After all, the ability to develop and apply technology is a defining aspect of our species. This fact becomes unwelcome when outcome-driven industries trade their lots for technological efficiency. In medicine, the efficiency economy has resulted in doctors spending less time with patients. This is highlighted by an average first appointment time of only twelve minutes.1 Before we continue, it is important to acknowledge that the gains we have made in efficiency are important to total patient outcomes, as more efficiency equates to more treated patients. Instead, we are concerned with individual patient outcomes.
For too long, medicine, enabled by
the worst aspects of technological advancement, was trending in the direction
of cookie-cutter solutions to the unique needs of individual patients. When
pondering how to rehumanize medicine, AI is often the last thought on one’s
mind. Yet, the current data may lead one to the opposite conclusion. AI seems
to be able to give us this lost time back, allowing for doctors to give
patients the time they truly need. The extra human interaction time is not just
beneficial for the patients, but for the physicians as well. A study conducted at
the University of Colorado showed that taking the computer out of the exam room
and supporting doctors with human medical assistants significantly reduced
burnout rates.2 If AI could use its data-processing
ability to help with the more clerical work nurses do, it could permit nurses
more time with both doctors and patients. The placement of AI in a clinical
setting may facilitate more one on one time between doctors and patients,
leading to a reduction in nosocomial infections and hospital readmissions as
well.1,3 This could save the health care
industry millions, while providing superior patient care. All that is needed is
for someone to commit to the first push.
The Role of AI in the Clinical Lab Field
Although AI may not be prevalent in
the clinical laboratory sector of medicine yet, saying that it is non-existent
altogether is far from the truth. For example, AI is already prevalent in the laboratory
setting. A great example of this is AI in the Liquid Chromatography Mass
Spectrometry (LC-MS) field.4 LC-MS is a great tool used to measure
various compounds in the human body, including everything from hormone levels to
trace metals. One of the ways AI has already integrated with LC-MS is how it
cuts down on the rate limiting steps of LC-MS, which more often than not are
sample prep and LC separations. One system that Physicians Lab has made use of is parallel processing using SCIEX
MPX 2.0 High Throughput System. This system can couple parallel runs with one
LCMS instrument, resulting in twice the speed with no loss to accuracy. It can
do this by staggering two runs either using the same method, or different
methods entirely. What really makes this system great is its ability to automatically
detect carryover and inject solvent blanks to clean the instrument. The system
will then continue its analyzing, while automatically reinjecting samples that may
be affected by the carryover. It will also flag high concentration without user
input, allowing for easy detection of possibly faulty samples. This allows it
to operate without users from startup to shut down. Some of the other ways that
it can be used to increase efficiency are by using integrated
network features to work on anything from streamlining management to increased
throughput. Physicians Lab is also
taking advantage of AI systems by incorporating the ASCENT software from Indigo
Bioautomation. This software uses smart algorithms and machine learning to
automatically integrate the LCMS peaks and turn them into results – a tedious
job normally done by people. A major issue in laboratories using LC-MS is that
the result interpretation of peaks is highly user-subjective and dependent on
their attention, training, and behaviors.5 Using ASCENT eliminates user-to-use variability, improves workflow speed,
and allows the users to focus only on problematic result interpretations. The
result is a highly dependable and consistent result interpretation system, as
well as a better utilized staff. Finally, just about every process from plate
and sample vial changing to gradient formation can be automated, allowing for
fast and accurate results. AI has allowed all of these changes, and it has
shown what the power of a machine that can adjust to new circumstances can do.
These features can almost double lab work speeds in some cases, allowing
doctors to diagnose quicker and attack the problems faster.
AI has played a large role in advancing LC-MS instrumentation, but that is not the only aspect of clinical laboratory life that AI has enhanced. All AI-based lab software works through a term known as “computational pathology”. This means that through the use of visuals and machine learning, the AI makes the product of the data more useful and easily understood for practicing physicians. One of the ways this is achieved is through wearables that can measure blood glucose levels, heart rate, and temperature, as well as other factors. This data can be uploaded to a mass cloud. Another way AI could easily influence lab settings is through tumor detection.4 Tumor detection is generally achieved by analyzing set genes that are already associated with tumor growth, and comparing the genes that are mutated in patients with tumors. This allows for personalized therapy, depending on what tumors the patient has. AI will use machine learning along with traditional techniques for more accurate tumor identification and diagnostic process. Also, the ability to integrate pre-existing algorithms with machines gives them the ability to have a greater pattern recognition than even the best doctors.
The Greater Extent of AI in Healthcare.
AI in the lab will also help doctors design more accurate treatment paths
by analyzing real-time data. The data constructed from laboratories are
generally broken up into three sectors: patients about to be diagnosed,
patients previously diagnosed who are responding to treatment, and patients who
have been diagnosed that are not responding to treatments. If one could take
this data and integrate it into AI, you could get more effective treatments to
patients in a shorter time span. For example, instead of going with a primary treatment
that works 80% of the time, AI may catch something that would instead recommend
a less-used course of action that would be more effective. So instead of going
through a trial and error of multiple treatments, AI could help find the better
solution. As well, if the first line therapy fails, this could provide a faster
way to reach the second line therapy. In order for AI to truly reach its
maximum potential, there must be a shift in thinking. Instead of relying solely
on past data, doctors would be able to rely on real-time, ever-changing data to
get the best results possible.
So with AI becoming prevalent in the clinical lab, how does this translate into doctor-to-patient interaction? Theoretically, the AI would use one of two ways to treat a patient in a clinic.1 The first being the flowchart method. This is where a doctor would essentially transfer all of their data from past interviews of patients and the results into the AI. The AI would then have this knowledge, and be able to ask patients questions and form conclusions in an “If x, then y” format. There are two main issues with this method, the first being the sheer amount of data that needs to be integrated. The second is the AI’s inability to detect when patients may be hiding something. For example, someone lying to get painkillers. This could be where cohesiveness steps into play, as you could have the AI ask questions, with the doctor overriding some of the patients answers. The second method is known as database learning. This requires the machine to be shown the same image over and over again, until it can memorize that image. This could be useful if a doctor sees a mole that he’s not sure is a melanoma or not. The doctor could then go to the computer for a second, and possibly more accurate, opinion. Some of this AI is already here. There is already basic flowchart AI, robotic surgical systems, AI therapy, and AI scheduling programs. AI is bound to be even more integrated into clinical medicine as time marches on. One example of this is Stanford University’s Program in AI-Assisted Care (PAC). One of these programs allows seniors who live alone to be able to reach immediate help if needed, along with monitoring behavioral and movement patterns to spot irregularities. Other examples of future AI in the medical field involve “Molly”, a virtual nurse that can monitor and follow up with patients. This could free up an immense amount of doctors’ time. Not to mention that although certain AI has already been able to help schedule, there are more advanced AI’s which will be able to adapt to the struggles of a busy ward, freeing up more time for nurses.
Although AI may be originally thought of as a bane to physicians and the remaining human aspect of medicine, this is far from the truth. Throughout the continued advancement of AI in the clinical lab, and the newer yet fascinating use of AI in the clinic itself, medicine has a chance to regain its once human form. The abilities of AI to help with anything from scheduling to diagnostics should reduce the combination of doctor’s stress levels, burnout, and hospital readmission rate. This, in turn, should give the doctors much more one on one time with patients, drastically increasing the quality of patient care. The re-humanization of medicine starts not with man, but with the machine.
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medicine: the convergence of human and artificial intelligence. Nat Med.
Wright AA, Katz IT. Beyond burnout
– Redesigning care to restore meaning and sanity for physicians. N Engl J
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Naugler C, Church DL. Automation
and artificial intelligence in the clinical laboratory. Crit Rev Clin Lab
Sci. 2019. doi:10.1080/10408363.2018.1561640
Workman TE, Hirezi M,
Trujillo-Rivera E, et al. A Novel Deep Learning Pipeline to Analyze Temporal
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Gaona García PA, Montenegro Marin
CE, Gaona García EE. Model of Learning Objects Exchange between LCMS Platforms
through Intelligent Agents1. Ing y Univ. 2015.
Patient education. We all know it’s important, we’d like to
do more of it, but it’s time consuming and, frankly, some of us aren’t good at
it. Some patients like a lot of it, while some patients feel overwhelmed and
are turned off. And when you add to this the fact that we are asking for saliva,
blood, urine, stool and money, it’s no surprise patients may feel that this
type of medicine is not for them and decide to just double up on their
I ask myself “what is my job here, with THIS particular
patient?”, and the answer is always –help them feel better physically,
mentally, and emotionally. This almost never works when we overwhelm them with
information that is confusing without actionable steps for improvement.
So, what I’ve learned after a lot of trial and error is to
not over-do it with labs in the beginning. Order what will give the most
valuable and actionable information first. Let the patient see the value in the
tests you pick and how much better they feel with the treatment plan you
customized based on those labs and symptom profile they present with.
Physician’s Lab 24 Hour Urinary Metabolite test is one of
the labs with the most valuable information I do on my patients. But we’ve all
heard, “I went to another office for hormones and I didn’t have to do this
urine test!” How do we overcome this
push back? Here is one of my little
“We are optimizing your hormones so that you feel better physically, mentally, and emotionally not to mention improve the way you age. We want to do this responsibly because all these hormones need to get broken-down/metabolized. Some of us do this well, and some of us don’t. Certain things happen when we don’t metabolize our hormones well. It could be the reason you don’t feel as great as your friends do on BHRT, and it could even give us an idea of how at-risk you are for breast, uterine, ovarian, or prostate cancer.
The beauty of this is that even if you are an at-risk person, there are certain things we can do to make us healthier metabolizers and not only reduce our risk of certain cancers, but make your experience with BHRT an amazing one.”
– Prevents bone loss
– Natural antidepressant
– Improves insulin sensitivity
– Decreases fatigue
– Maintains elasticity in arteries
– Increases skin collagen
– Prevents Alzheimer’s disease
– Reduces cataracts
– Maintains memory
– Works as an antioxidant
– Menopausal symptoms
– Heavy bleeding
– Tender breasts
– Cancers: Prostate/Breast/Ovarian/Uterine
So, when I see that a particular patient is not metabolizing their estrogens down the healthier 2-OH pathway, here are some general changes in lifestyle that should be implemented.
1. Decrease exposure to fake estrogens (xenoestrogens).
Avoiding all of these is impossible, but being aware of those we can avoid can make a huge impact on your health. Read your labels! Ingredients to stay away from as much as possible:
(EWG.org makes picking products easier without having to read labels)
– DEA (DIETHANOLAMINE), MEA (MONOETHANOLAMINE), TEA (TRIETHANOLAMINE)
– PARABANS PRESERVATIVES (METHYL, PRPOYL, BUTYL, ISOBUTYL, and ETHYL)
– MINERAL OIL: PETROLATUM, PETROLEUM JELLY (LIQUID PARAFFINUM, PARAFFIN OIL, PARAFFIN WAX, POSH MINERAL OIL)
– Air fresheners, deodorizers, fabric softeners, scented candles, body perfumes
– Fabric detergents, dishwashing detergents, clothing softeners, clothing, cosmetic and personal care products
2. Promote detoxification
– We detox through foods, supplements, exercise, and sleep!
– Fresh, whole, unprocessed, organic, colorful, HIGH FIBER, nuts, seeds, omega 3’s, herbs, fermented products, cabbage, cauliflower, broccoli, high fish consumption (Sardines)
– Soluble fiber and low glycemic load
– Increase green leafy vegetables (10-12 servings)
– Green tea
– Chia seeds
3. Enhance elimination (poop)
Daily bowel movements are essential. We rid our bodies of estrogens when we poop. If you’re constipated, you’ll actually reabsorb the estrogen that was supposed to be eliminated, and it gets circulated again throughout the body, causing more havoc.
4. Decrease insulin stimulation
This means you should eliminate sugars and processed carbs, as well as reduce the frequency of eating. Every time we put something in our mouths, we spike insulin. If we strive to eat 3 (ideally 2) meals a day with no snacking in between, we will stabilize and lower our insulin leading to fat loss and better hormones.
5. Targeted supplementation: Based on individual labs and symptoms
– Reduced glutathione
– Lipoic acid
– Whey protein
– Vitamin C
– Pantothenic acid
– Vitamins Bs 6,9,12
6. Lifestyle modifications
Stress management: healthy levels of cortisol will keep your hormones at happier levels, as well as allow weight loss and detoxification. Stress needs to be managed. Make it a priority. Go out in nature, get natural sunlight, yoga, meditation, exercise, sleep.
7. Address digestion
Optimize gut health with the 5 R program
We know all the benefits of exercise. Get on a
routine that works for you and stick to it. Our lives are more sedentary than
what we were made for. You need to move for proper muscle mass as well as
lymphatic flow (which keeps you healthy and helps prevent cancer)! High
intensity Interval Training (HIT) is what we recommend.
Improve your sleep habits! All of the effort
made to eat the right things and exercise will not pay off unless you get good
quality sleep. This means get in bed
earlier, use blue-light-blocking glasses if you’ll be on your phone or watching
TV, do not eat right before bed, put cell phone on airplane mode or keep out of
the room (EMFs), and bedroom should be as dark as possible (lights from TV,
phone, and window interfere with your production of melatonin, which is needed
for healthy sleep).
10. Mind-body-spirit connection
Whatever your spiritual practice is, make sure you have reconnected and aligned with that.
We are social beings. Connection with friends
and family is of utmost importance in a world where we have replaced the
rewards of real relationships (the “reward” I am talking about is actually
production of feel good hormones that connection and touch provide) with social
media. Put your phones down and reconnect with those you care about.
By: Clifford Morris, Ph.D. Chief Chemist and Research Scientist
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.
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.
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.
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
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.
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