Wow. This article really is about someone like me. 62, Hashimotos for 12 years- which is in remission- I have cut out a lot of gluten and sugar. However, I gain every time my thyroid meds increase, I have the big middle, a bit of achy joints, sleep issues and low libido, low motivation and a history of heart disease in my family. Feeling ok not great or even good- just ok and muddling through with no motivation to do anything. I had almost given up - but after this article I will reach out to my Doctor and see if we can go down this path. I really want more energy and health.
Katg, what you are describing is so common but can be hard to figure out. Please do not settle for just ok. Bring this to your doctor, ask for the full workup, and keep me posted. Rooting for you!
Thank you for such a thorough article. Love that you mentioned magnesium in relation to vitamin d. I worked in a lab (oncology clinic) for years and so many people were deficient in magnesium. I always found it interesting that mg was not in the chemistry panels but an extra test to add on. Anyway, lovely article.
Thank you for reading! And yes, exactly. Magnesium is a cofactor for the enzymes that convert vitamin D to its active form, so supplementing D without adequate magnesium is working against yourself. Your lab observation tracks with what I see clinically. Most of my oncology patients run low, and you are right that it rarely gets checked because it is not on the standard chemistry panel. Serum magnesium also underestimates the problem since most magnesium lives inside cells, not in blood. Thanks for sharing that perspective from the lab side.
Yes, a huge portion of mag lives in our bones which is my focus now, so you are absolutely right that serum labs can be misleading in the same way serum calcium levels are. So glad I found you this morning. Good alignment!
Thank you for highlighting the importance of objective biomarkers in preventive medicine. As a physician-scientist, I think laboratory tests are most valuable when they help us understand why disease risk is changing, not simply whether a value falls inside or outside a reference range.
That said, no panel of biomarkers can predict an individual’s future health in isolation. The greatest clinical value comes from integrating laboratory data with family history, physical examination, imaging when appropriate, lifestyle factors, and (perhaps most importantly) longitudinal trends. A single measurement is a snapshot; repeated measurements over time tell a much richer story about a person’s biology.
I also think we’re entering an exciting era where traditional laboratory markers will increasingly be complemented by multi-omics, continuous wearable data, and AI-assisted risk prediction. The challenge will not be generating more data, but determining which biomarkers meaningfully improve clinical decision-making and patient outcomes.
Ultimately, the goal of preventive medicine is to use the right biomarkers to identify modifiable risk early enough that we can change the trajectory of disease before symptoms ever develop. That’s where laboratory medicine has its greatest potential.
I would suggest that a 4 point 24 hour cortisol panel would be more informative vs. just AM cortisol with regards to cortisol dominance, cortisol/DHEA dysregulation, and whether the individual is in a catabolic state
Agree! I was trying to stay within the blood work frame of mind, but the shape of the curve and much more important than a single reading. And pairing it with DHEA-S gives you the cortisol/DHEA ratio that tells you whether the patient is breaking down faster than they are building, which is exactly what you want to know before you touch insulin or androgens.
This is SOOOO clinically relevant to the population I serve- midlife, perimenopausal and postmenopausal, women.
I also have started ordering all of these tests.
I had a concierge PCP refer me a patient with an A1c of 6.2 that was “stable, so we’re just watching it”. Fasting glucose 99, insulin was 9, LFTs in the low 40’s. And she’s on a statin and blood pressure medication already, no hormone therapy. Vegan diet.
I was like “wow” this lady is a ticking time bomb! We are actively adjusting her diet, her exercise, her supplements and I’m having her use a CGM. And starting MHT.
Curious about your comment on T gel- they have absorption enhancers, so why is cream better? (What concentration and dose of cream?)
Sounds all too familiar! Those numbers are not stable, but compensated. LFTs in the low 40s with a vegan diet is whispering MASLD
On gels: typical systemic bioavailability is only like ~10% of the applied dose; the enhancers work, and but i think permeation half the battle. Commercially available gel is built for 50 to 100 mg daily and if the patient needs 5, you are asking her to dispense a tenth of a pump every day. Alcohol also flashes off and front-loads the flux, where a lipid cream sits and releases over hours, which forgives shower timing and sweat. I will often use 1% cream, 10 mg/mL, 0.5 mL daily for 5 mg as a starting point. That is the AndroFeme regimen, and the PK behind it shows 5 mg restores premenopausal physiologic levels, but i will treat based on symtoms.
Undetectable T on gel is not proof of non-absorption. Immunoassay is unreliable at female concentrations and technique accounts for a lot. Cream is more forgiving, not categorically better. Everyone is different and sometimes its a little bit of trial and error before we figure out if creams, gels or pellets work best for you
Homocysteine is not covered by Medicare and may cost up to $300 and is considered “investigational” despite the fact that it is a very essential test among the others. So in place try methylmalonic acid.
Agreed on free T3 alone. It is on the panel to explain symptoms and guide dosing, and not to forecast. The prediction in item 9 comes from TPO antibodies, which roughly double the rate of progression to overt hypothyroidism over 20 years in Whickham.
Can women over 65 begin taking testosterone, estradiol and progesterone if they’ve been in menopause since age 52? I’m 65 and have been told if I didn’t start hormones soon after menopause, it is contraindicated for me to start them now. I am so sad about this. At the time I reached menopause, hormone therapy was strongly discouraged by my doctor. I feel so betrayed.
Yes!! I find so many women in similar circumstances, and there is understandable grief around this, especially for women who went through menopause during the years when hormone therapy was widely discouraged. While starting hormone therapy after age 60 or more than 10 years after menopause requires a more individualized risk-benefit discussion, it is not an absolute contraindication. It may still be worth considering transdermal hormones and seeking out a menopause specialist who can help you weigh the risks and benefits in the context of your individual health history.
Given the critical role of Carbon Monoxide in every type of cancer, why does Dr Malarkey not measure CO via blood, breath or skin? It is the most common form of poisoning and most commonly misdiagnosed as ME/CFS, FM or MCS.
I love that you brought this up. Heme oxygenase 1 is upregulated across many tumors, circulating CO tracks its activity, and there is human colorectal data linking elevated CO to HO-1 over expression and reduced chemosensitivity.
That said, measuring CO in clinic is a different question. COHb and breath CO reflect exposure, are confounded by smoking, hemolysis, cardiovascular dz and inflammation, and have no validated cutoff for cancer risk. This piece covered labs where I have a number and a next step…
I agree, CO poisoning is underdiagnosed, and I order COHb when the history points to it. If you have prospective human data tying COHb to cancer incidence or outcomes, please send it my way bc I am not aware of it
I’m curious about the thyroid testing. How are you treating patients with normal TSH and T4 but the flagging ft3 and Rt3 ratio? What is done with that information? I was trained to always ask before ordering a test ‘what will you do with that information? How will it change your plan of care?’ So I’m curious to know the answer for the thyroid. These posts empower patients to ask for certain tests directly but that doesn’t mean there’s evidence based steps on what to do with the results
Hi Merrily, I am sorry I seem to have missed your question until now, and it's a good one! The honest answer is that reverse T3 is the weakest item on the list. There is definitely insufficient evidence for routine rT3 measurement and I do not disagree... I would definilty not treat a flagged ratio with liothyronine.
Why I order it (sometimes) is to guide me to where I to look next. Elevated rT3 with a normal TSH usually reflects a shift in deiodinase activity, most often from inflammation, significant caloric restriction, or glucocorticoid excess. So it sends me to hsCRP, an AM cortisol, and a thorough intake history.
My point is not to order labs endlessly. It is to order the ones we can act on, with a provider who can interpret them and who will retest to see whether what we changed actually moved anything. The logic of ordering only the tests you already expect to be abnormal is what I am pushing against. The body whispers before it screams, and if we wait for the scream, we have spent the years when the problem was still reversible.
This answered a few of my questions! I am 32 years old with a fasting insulin at 80 an A1C at 4.8. My thyroglobulin antibodies are through the roof, very slightly low t3. My homocysteine is low, dhea very high, and my iron panel is completely out of wack. My ferritin climbed 25 points over the last four months- my iron is high and my iron saturation is high at 77%. I did recently find out I have fatty liver & I have two lesions on my liver that appear to be benign but have had continual pain in my upper right abdomen. Hopefully I can find some answers. I eat very clean and exercise regularly, my sleep is great, but I struggle with chronic fatigue. I am not over weight I have an athletic build and decent muscle mass 🤷🏻♀️🫠
I'm glad it helped. I can't give individual advice here, but one thing stood out to ask your team about is HFE gene testing for hereditary hemochromatosis. Not the only thing that could be going on, but It might also explain the rest. Iron deposits in the liver and pancreas, which produces exactly what you're describing: fatty liver in someone lean who eats well, right upper quadrant pain, and relentless fatigue.
Clean eating and good sleep do not fix a genetic iron loading disorder.
I'm interested to read your recommendations about mineral balance. There are a t least half a dozen pairs of micro- & macro- minerals that are surely either necessary for or precursor of the magic molecules of the hormone class, that the blood work you described here is evaluating.
Absolutely. Mineral balance is an area that deserves much more attention, especially in the context of cancer and overall metabolic health. Many minerals act as cofactors for enzymes involved in hormone production, thyroid function, immune signaling, and energy metabolism, so looking at them in isolation often misses the bigger picture.
I’ll definitely be writing more about this soon, including which minerals I find most clinically useful to evaluate, how I think about their interactions, and where the evidence is strongest. Thanks for the suggestion!
The SHBG section is the one I keep coming back to.
Framing it as a proxy for insulin sensitivity that almost nobody orders is the reframe I wish more panels used, especially the self-reinforcing loop where high insulin suppresses SHBG and low SHBG leaves fewer free androgens available.
When you catch that cycle early, do you get more durable movement breaking it at the insulin node first, or do you usually have to push androgens up in parallel before body composition responds?
I focus on Insulin first, almost every time. Pushing androgens while insulin is high treats the symptom and suppresses SHBG further. Bring insulin down through visceral fat loss, training, low-glycemic intake, sleep, and metformin or berberine, and SHBG climbs on its own while lower aromatization lets endogenous testosterone recover. I would say the rise can lag the metabolic fix by a cycle or two… of course severe hypogonadism or true testicular failure is a different story
Wow. This article really is about someone like me. 62, Hashimotos for 12 years- which is in remission- I have cut out a lot of gluten and sugar. However, I gain every time my thyroid meds increase, I have the big middle, a bit of achy joints, sleep issues and low libido, low motivation and a history of heart disease in my family. Feeling ok not great or even good- just ok and muddling through with no motivation to do anything. I had almost given up - but after this article I will reach out to my Doctor and see if we can go down this path. I really want more energy and health.
Katg, what you are describing is so common but can be hard to figure out. Please do not settle for just ok. Bring this to your doctor, ask for the full workup, and keep me posted. Rooting for you!
Thank you for such a thorough article. Love that you mentioned magnesium in relation to vitamin d. I worked in a lab (oncology clinic) for years and so many people were deficient in magnesium. I always found it interesting that mg was not in the chemistry panels but an extra test to add on. Anyway, lovely article.
Thank you for reading! And yes, exactly. Magnesium is a cofactor for the enzymes that convert vitamin D to its active form, so supplementing D without adequate magnesium is working against yourself. Your lab observation tracks with what I see clinically. Most of my oncology patients run low, and you are right that it rarely gets checked because it is not on the standard chemistry panel. Serum magnesium also underestimates the problem since most magnesium lives inside cells, not in blood. Thanks for sharing that perspective from the lab side.
Yes, a huge portion of mag lives in our bones which is my focus now, so you are absolutely right that serum labs can be misleading in the same way serum calcium levels are. So glad I found you this morning. Good alignment!
Thank you for highlighting the importance of objective biomarkers in preventive medicine. As a physician-scientist, I think laboratory tests are most valuable when they help us understand why disease risk is changing, not simply whether a value falls inside or outside a reference range.
That said, no panel of biomarkers can predict an individual’s future health in isolation. The greatest clinical value comes from integrating laboratory data with family history, physical examination, imaging when appropriate, lifestyle factors, and (perhaps most importantly) longitudinal trends. A single measurement is a snapshot; repeated measurements over time tell a much richer story about a person’s biology.
I also think we’re entering an exciting era where traditional laboratory markers will increasingly be complemented by multi-omics, continuous wearable data, and AI-assisted risk prediction. The challenge will not be generating more data, but determining which biomarkers meaningfully improve clinical decision-making and patient outcomes.
Ultimately, the goal of preventive medicine is to use the right biomarkers to identify modifiable risk early enough that we can change the trajectory of disease before symptoms ever develop. That’s where laboratory medicine has its greatest potential.
Completely agree!
I would suggest that a 4 point 24 hour cortisol panel would be more informative vs. just AM cortisol with regards to cortisol dominance, cortisol/DHEA dysregulation, and whether the individual is in a catabolic state
Agree! I was trying to stay within the blood work frame of mind, but the shape of the curve and much more important than a single reading. And pairing it with DHEA-S gives you the cortisol/DHEA ratio that tells you whether the patient is breaking down faster than they are building, which is exactly what you want to know before you touch insulin or androgens.
This is SOOOO clinically relevant to the population I serve- midlife, perimenopausal and postmenopausal, women.
I also have started ordering all of these tests.
I had a concierge PCP refer me a patient with an A1c of 6.2 that was “stable, so we’re just watching it”. Fasting glucose 99, insulin was 9, LFTs in the low 40’s. And she’s on a statin and blood pressure medication already, no hormone therapy. Vegan diet.
I was like “wow” this lady is a ticking time bomb! We are actively adjusting her diet, her exercise, her supplements and I’m having her use a CGM. And starting MHT.
Curious about your comment on T gel- they have absorption enhancers, so why is cream better? (What concentration and dose of cream?)
Sounds all too familiar! Those numbers are not stable, but compensated. LFTs in the low 40s with a vegan diet is whispering MASLD
On gels: typical systemic bioavailability is only like ~10% of the applied dose; the enhancers work, and but i think permeation half the battle. Commercially available gel is built for 50 to 100 mg daily and if the patient needs 5, you are asking her to dispense a tenth of a pump every day. Alcohol also flashes off and front-loads the flux, where a lipid cream sits and releases over hours, which forgives shower timing and sweat. I will often use 1% cream, 10 mg/mL, 0.5 mL daily for 5 mg as a starting point. That is the AndroFeme regimen, and the PK behind it shows 5 mg restores premenopausal physiologic levels, but i will treat based on symtoms.
Undetectable T on gel is not proof of non-absorption. Immunoassay is unreliable at female concentrations and technique accounts for a lot. Cream is more forgiving, not categorically better. Everyone is different and sometimes its a little bit of trial and error before we figure out if creams, gels or pellets work best for you
Homocysteine is not covered by Medicare and may cost up to $300 and is considered “investigational” despite the fact that it is a very essential test among the others. So in place try methylmalonic acid.
Great point! Many direct to consumer labs offer this at a fraction of the cost. Great full break down here - https://mitohealth.com/guide/homocysteine-test-cost
Have shared with my family and friends. Such a great insight and clear explanation
I am glad!
T3 does absolutely nothing to predict your next 10 years. Zero.
Agreed on free T3 alone. It is on the panel to explain symptoms and guide dosing, and not to forecast. The prediction in item 9 comes from TPO antibodies, which roughly double the rate of progression to overt hypothyroidism over 20 years in Whickham.
Can women over 65 begin taking testosterone, estradiol and progesterone if they’ve been in menopause since age 52? I’m 65 and have been told if I didn’t start hormones soon after menopause, it is contraindicated for me to start them now. I am so sad about this. At the time I reached menopause, hormone therapy was strongly discouraged by my doctor. I feel so betrayed.
Yes!! I find so many women in similar circumstances, and there is understandable grief around this, especially for women who went through menopause during the years when hormone therapy was widely discouraged. While starting hormone therapy after age 60 or more than 10 years after menopause requires a more individualized risk-benefit discussion, it is not an absolute contraindication. It may still be worth considering transdermal hormones and seeking out a menopause specialist who can help you weigh the risks and benefits in the context of your individual health history.
Given the critical role of Carbon Monoxide in every type of cancer, why does Dr Malarkey not measure CO via blood, breath or skin? It is the most common form of poisoning and most commonly misdiagnosed as ME/CFS, FM or MCS.
I love that you brought this up. Heme oxygenase 1 is upregulated across many tumors, circulating CO tracks its activity, and there is human colorectal data linking elevated CO to HO-1 over expression and reduced chemosensitivity.
That said, measuring CO in clinic is a different question. COHb and breath CO reflect exposure, are confounded by smoking, hemolysis, cardiovascular dz and inflammation, and have no validated cutoff for cancer risk. This piece covered labs where I have a number and a next step…
I agree, CO poisoning is underdiagnosed, and I order COHb when the history points to it. If you have prospective human data tying COHb to cancer incidence or outcomes, please send it my way bc I am not aware of it
I’m curious about the thyroid testing. How are you treating patients with normal TSH and T4 but the flagging ft3 and Rt3 ratio? What is done with that information? I was trained to always ask before ordering a test ‘what will you do with that information? How will it change your plan of care?’ So I’m curious to know the answer for the thyroid. These posts empower patients to ask for certain tests directly but that doesn’t mean there’s evidence based steps on what to do with the results
Hi Merrily, I am sorry I seem to have missed your question until now, and it's a good one! The honest answer is that reverse T3 is the weakest item on the list. There is definitely insufficient evidence for routine rT3 measurement and I do not disagree... I would definilty not treat a flagged ratio with liothyronine.
Why I order it (sometimes) is to guide me to where I to look next. Elevated rT3 with a normal TSH usually reflects a shift in deiodinase activity, most often from inflammation, significant caloric restriction, or glucocorticoid excess. So it sends me to hsCRP, an AM cortisol, and a thorough intake history.
My point is not to order labs endlessly. It is to order the ones we can act on, with a provider who can interpret them and who will retest to see whether what we changed actually moved anything. The logic of ordering only the tests you already expect to be abnormal is what I am pushing against. The body whispers before it screams, and if we wait for the scream, we have spent the years when the problem was still reversible.
This answered a few of my questions! I am 32 years old with a fasting insulin at 80 an A1C at 4.8. My thyroglobulin antibodies are through the roof, very slightly low t3. My homocysteine is low, dhea very high, and my iron panel is completely out of wack. My ferritin climbed 25 points over the last four months- my iron is high and my iron saturation is high at 77%. I did recently find out I have fatty liver & I have two lesions on my liver that appear to be benign but have had continual pain in my upper right abdomen. Hopefully I can find some answers. I eat very clean and exercise regularly, my sleep is great, but I struggle with chronic fatigue. I am not over weight I have an athletic build and decent muscle mass 🤷🏻♀️🫠
I'm glad it helped. I can't give individual advice here, but one thing stood out to ask your team about is HFE gene testing for hereditary hemochromatosis. Not the only thing that could be going on, but It might also explain the rest. Iron deposits in the liver and pancreas, which produces exactly what you're describing: fatty liver in someone lean who eats well, right upper quadrant pain, and relentless fatigue.
Clean eating and good sleep do not fix a genetic iron loading disorder.
Thank you so much for your response
Good information. Do you suggest these tests for men also or have another list?
All these, plus a few additional. I’ll wrote up a new male specific guide in the next couple weeks!
I'm interested to read your recommendations about mineral balance. There are a t least half a dozen pairs of micro- & macro- minerals that are surely either necessary for or precursor of the magic molecules of the hormone class, that the blood work you described here is evaluating.
Absolutely. Mineral balance is an area that deserves much more attention, especially in the context of cancer and overall metabolic health. Many minerals act as cofactors for enzymes involved in hormone production, thyroid function, immune signaling, and energy metabolism, so looking at them in isolation often misses the bigger picture.
I’ll definitely be writing more about this soon, including which minerals I find most clinically useful to evaluate, how I think about their interactions, and where the evidence is strongest. Thanks for the suggestion!
Did you do this if so I apologize I haven’t seen it.
So agree. But good luck getting providers to order certain labs just because you want them to.
The SHBG section is the one I keep coming back to.
Framing it as a proxy for insulin sensitivity that almost nobody orders is the reframe I wish more panels used, especially the self-reinforcing loop where high insulin suppresses SHBG and low SHBG leaves fewer free androgens available.
When you catch that cycle early, do you get more durable movement breaking it at the insulin node first, or do you usually have to push androgens up in parallel before body composition responds?
I focus on Insulin first, almost every time. Pushing androgens while insulin is high treats the symptom and suppresses SHBG further. Bring insulin down through visceral fat loss, training, low-glycemic intake, sleep, and metformin or berberine, and SHBG climbs on its own while lower aromatization lets endogenous testosterone recover. I would say the rise can lag the metabolic fix by a cycle or two… of course severe hypogonadism or true testicular failure is a different story
Great article! Thank you for the detailed explanation. 😊