The Non-Mystery of Chronic Fatigue Syndrome

 
The Non-Mystery of Chronic Fatigue Syndrome

My wife gave me an article from Hadassah Magazine entitled “The Mystery of Chronic Fatigue Syndrome”, by Carol Saline, about the 2017 documentary on Jennifer Brea called “Unrest”.  The film documents her experience with severe chronic fatigue.(1-3)  Jennifer Brea was a previously healthy robust young women until the onset of immune dysfunction with six different infections, followed by debilitating fatigue and brain fog.  The article goes on to state there is no known cause and no known cure for “chronic fatigue syndrome” also called “ME/CFS”.  This has changed. The mystery has been unraveled by a group from Stanford.  Above image courtesy of Jennifer Brea Unrest Movie.

 

Leaky Gut – Incriminating the GUT Microbiome

Dr Montoya’s group at Stanford found elevated pro-inflammatory cytokines in chronic fatigue patients, implicating chronic inflammatory up regulation. (4-5)   In an accompanying editorial in PNAS, Dr Anthony Komaroff  explains it nicely with this quote:(5)

“Another way of incriminating infection in CFS (Chronic Fatigue Syndrome) involves the gut microbiome. Several recent studies have reported dysbiosis accompanied by low-grade inflammation and increased permeability of the gut mucosa. This allows bacterial lipopolysaccharide to enter the circulation, possibly activating innate immunity both systemically and in the brain.”

Notice Jennifer Brea’s story includes six different infections, yet the story says nothing about the antibiotics used to treat these infections.  Many of these patients have history of multiple long term antibiotic use implicating gut dysbiosis and leaky gut.   The use of NSAIDS for fibromyalgia pain worsens the leaky gut pathology as discussed in my previous article.

Leaky gut causes low grade endotoxemia which then upregulates inflammatory cytokines which travel to the brain causing upregulated microglia, depression and HPA (hypothalamic pituitary axis) dysfunction, which then causes adrenal, thyroid and gonadal hormone dysfunction leading to severe fatigue and fibromyalgia.  On top of this there is usually a variable element of mitochondrial dysfunction.

Pre-Existing Genetic Defects and Aggravating Conditions

Symptoms are worse in patients with pre-existing genetic defects in methylation pathways such as MTHFR, or COMT (catechol -o-methl-tranferase), or B12 transport protein defects (detected with elevated MMA levels)   Symptoms are worse if there is an aggravating medical condition such as low thyroid, menopausal transition, gluten sensitivity, stressful workplace or home life etc.

The Mystery Becomes Unraveled

The reason why this disease is a mystery is because the mainstream conventional physician does not bother to test for any of these abnormalities.  Nor do they treat them. We do, and most of our patients eventually get better. That is why Chronic Fatigue/Fibromyalgia is a non-mystery.

Jeffrey Dach MD
7450 Griffin Road Suite 180-190
Davie, Florida 33314
954-792-4663

Book Announcement
Articles with Related Interest
Low Level Endotoxemia, Depression and Endocrinopathy
NSAIDS, Small Bowel Damage and Leaky GUT

Links and References

 see original article:   https://jeffreydachmd.com/2018/04/the-non-mystery-of-chronic-fatigue-syndrome/

Fibrinolytic and Proteolytic Enzymes, Medical Use by Jeffrey Dach MD

 
Fibrinolytic and Proteolytic Enzymes, Medical Use by Jeffrey Dach MD

Sam is a 24 year old with a swollen painful ankle after an injury playing basketball.  Xrays are negative for fracture, but Sam cannot walk and stays at home applying ice packs.  Jim is a 62 year old who sees a Cardiologist for episodes of chest pain, and was diagnosed with “stable angina” and given nitro pills.  Ralph sees a urologist for an enlarged prostate, and was given the diagnosis of BPH (Benign Prostatic Hyperplasia).  Sue has chronic sinusitis and bronchitis with thick mucus.   Neal had two episodes of a “mild” stroke with transient slurred speech.  Left Image sprained ankle courtesy of wikimedia commons.

What do all these patients have in common?

They could all benefit from proteolytic enzymes available at the health food store without a prescription.  Since these are supplements, it is unlikely their doctor would mention it.

The three major enzymes are
1) Serrapeptidase,
2) Nattokinase and
3) Lumbrokinase.

Serrapeptidase is made by the silk worm, and used to digest the cocoon.  Serrapeptidase has anti-inflammatory activity, and has been suggested as a replacement for NSAID anti-inflammatory drugs like Ibuprofen and Indomethacin.   Serrapeptidase is just as effective without the adverse side effects of NSAIDS.

“Serratiopeptidase or serrapeptase is a protein (proteolytic) enzyme isolated from the non-pathogenic enterobacteria Serratia E15 found in silkworms. Serratiopeptidase often prescribed in various specialties like surgery, orthopedics, otorhinolaryngology, gynecology and dentistry for its anti-inflammatory, anti-endemic and analgesic effects . In the research in recent years, exploration illustrated enzyme also plays a vital role in the management of atherosclerosis as it does possess fibrinolytic and caseinolytic properties. ” quote (1)

Blood clots, cysts and arterial plaque are all gradually dissolved. Over 50 clinical trials from Europe and Asia attest to the ability of Serrapeptase to successfully treat conditions ranging from sprains, torn ligaments, post-operative swelling (edema), fibrocystic breast disease, deep vein thrombosis (DVT), carpal tunnel syndrome, ear, nose and throat infections and atherosclerosis. Serrapeptase literally digests inflammatory tissue.”Quote(8)

Serrapeptidase useful for Ankle Sprains

Dr Esch studied ankle sprains in 66 patients finding the use of Serrapeptidase significantly reduced pain and swelling after the injury.(2)

Nattokinase

Nattokinase comes from fermented soy products and a staple of the Japanese diet.  Nattokinase has fibrinolytic effects and thought to be useful in prevention of cardiovascular disease, and is currently undergoing a clinical trial at University of Southern California, Dr Howard Hodis. (70):

“Various animal and human trials have demonstrated that NK improves blood circulation and helps decrease the risk of a variety of cardiovascular diseases without producing any adverse side effects.”quote (22)

 

Lumbrokinase

Lumbrokinase comes from earthworms and is the most potent fibrinolytic enzyme of the three.  It was found effective in improving myocardial perfusion and reducing angina symptoms in patients with coronary artery disease.(1)

Left Image: Improvement in Myocardial Perfusion Scan in Angina Patient after Lumbrokinase. Courtesy of  Kasim 2009. Left column before treatment. Right column alter treatment.  Note perfusion defect between white arrows resolves after treatment.(26)

Lumbrokinase was useful in treatment of  Ischemic Stroke, angina, myocardial ischemia,  deep venous thrombosis, hypertension,  vascular dementia  and hypercoagulation-associated complications.(27)

“serrapeptase is not considered a strong fibrinolytic enzyme and should primarily be used for inflammation and pain association with oral/facial surgeries, sinus infection, arthritis, or chronic airway diseases. Respectively, nattokinase and lumbrokinase would be more suited for patients with mild and severe hypercoagulation or for patients with low and high cardiovascular risks.” Quote from (27)

 
Proteolytic Enzymes Dissolve Biofilms – Assist Antibiotics


A number of studies show that proteolytic enzymes enhance antibiotic effects by breaking up biofilms.  The enzymes are useful add-ons for antibiotic treatment of infectious micro-organisms known to produce bio-films.  Left image Scanning Electron Microscope of BioFilm fibrin strands courtesy of CNN.

Find Lumbrokinase, Nattokinase and Serrapeptidase on Amazon

Jeffrey Dach MD
7450 Griffin Road, Suite 180/190
Davie, Fl 33314
954-792-4663

Links and References

see original article:  https://jeffreydachmd.com/2018/06/fibrinolytic-proteolytic-enzymes-medical-use/

Evolocumab Are You Joking Me ? by Jeffrey Dach MD

 
Evolocumab, Are You Joking Me? by Jeffrey Dach MD

Ralph is a 48 year old divorce lawyer who arrives in my office with a history of familial hypercholesterolemia.  Every lab panel since he was a kid showed a cholesterol of 340.  Other family members had the same genetic abnormality, and some even died of heart attack at early age.  About six months ago Ralph switched to a new doctor whor was alarmed by his high cholesterol.  The new doctor started him on a statin drug which reduced his LDL cholesterol down to 95. However, thinking this was insufficient, the new doctor added Evolocumab, to drive the LDL cholesterol even lower. Header image courtesy of LongevityFacts.com 

FDA Approved in Dec 2017

Amgen’s Evolocumab (Repatha), was recently FDA approved, and requires an injection every two weeks.  At $14,000 a year, Evolocumab is the most expensive cholesterol drug on the market.   A similar PCSK9 inhibitor drug, bococizumab,  under development by Pfizer was discontinued after a failed study.(7)

Lowest LDL in History

After the Evolocumab drug was added to the statin drug, Ralph’s labs showed an LDL cholesterol of 30, the lowest in the history of Western Civilization in a human. I looked at Ralph and asked him if he was all right.  Not exactly, he said.  Ralph has trouble sleeping ever since starting the cholesterol lowering drugs.  He has been experiencing troublesome tingling and burning sensations on his arms at night while trying to sleep.   In a nutshell, Ralph is miserable, and wants to know if he can safely stop the cholesterol medication.

“A Lifesaving Miracle Drug”

Many newspapers and Cardiologists proclaim Evolocumab is a “lifesaving” miracle drug.(1)(27)  Let us see the data showing the number of lives saved.  Here is the data table (below) from Dr Marc Sabatine’s FOURIER study .(2) In this study, 27,500 patients on statin drugs for atherosclerotic heart disease were randomized to either drug (Evolocumab) or placebo.  The drug reduced the LDL-cholesterol by 60%, from 90 to 30 mg/dl.

Below Image Table 2  FOURIER Study  courtesy of Sabatine, Marc S., et al. “Evolocumab and clinical outcomes in patients with cardiovascular disease.” New England Journal of Medicine 376.18 (2017): 1713-1722.(2) Red arrow and circle=drug group.  Green arrow and circle=placebo group.



Cardiovascular Death- No Lives Saved

At the end of the 2.2 year study period there were eleven more deaths in the drug treated group.  There were 251 cardiovascular deaths in the drug group (red arrow and circle), and only 240 in the placebo group (green arrow and circle).  No lives saved.

Death from Any Cause – No Lives Saved

There were 444  deaths in the drug group (red arrow and circle), and only 426 in the placebo group (green arrow and circle).  No lives saved.  Eighteen more deaths in the drug treated group.

Hospitalization for Unstable Angina- No Difference

There were about the same number of hospitalizations for unstable angina in each group.

A Lifesaving Drug that Actually Kills More People Than Placebo ?
Perhaps someone can explain to me how this can be called a “lifesaving” miracle drug, when in fact, more people died in the drug group, and no lives were actually saved by the drug?

The Miraculous Benefit of Intensive Lowering of LDL Cholesterol

If one is coldly objective about the data coming in, one might say the PCSK9 drug trials have actually falsified the cholesterol theory of heart disease.  Here we have the lowest LDL cholesterol ever achieved in the history of medicine, yet no lives are saved. Bryan Hubbard says in May 2017:

The PCSK9 drug trials are inadvertently challenging the cholesterol-heart disease theory. The drugs are bringing down ‘bad’ LDL cholesterol to unprecedented levels, and yet similar numbers of people are dying from heart attack and stroke whether taking the drug or a placebo.(20)

Wait Just A Minute, Fourier Showed Reduction in MI’s
The Fourier study data (above) showed 171 fewer Myocardial Infarctions (MI) in the PCSK9 Evolocumab drug group. Isn’t this a real benefit of the drug?   Here is what Dr Harumi Okuyama had to say about that.(55)  The data is biased and faked:

“The composite end point included measures that were less objective; hence, the accuracy of these measures as used across 49 different countries could have been biased, with the exception of mortality. For example, troponin level is known to be elevated after coronary angioplasty, leading to more frequent diagnosis of MI in the placebo group….However, we speculate that the reported data do not substantiate the conclusions made by the original authors, and we recommend against accepting their conclusions as an endorsement of PCSK9 inhibitors.

Heart Attacks Kill People, Don’t They? 

I think we are all in agreement with the statement: “Heart attacks kill people”.  You might ask, how many people?  According to Dr Viola Vaccarino in the New England Journal from 1999, early mortality after myocardial infarction is 16.7 per cent in men and 11.5 per cent in women.(57)  If we have two randomized groups, and one group has more heart attacks, then this should translate into increased mortality for that group. This is just common sense.  The Fourier Evolocumab drug study showed the opposite.  The placebo group had 171 more heart attacks, yet did not show increased mortality compared to the drug group.   Exactly how an FDA committees can overlook this blatantly obvious contradiction is mind boggling.

Effect of Intensive Cholesterol Lowering on Calcium Score

We have made the case for annual calcium score progression as our most important tool in the management of coronary artery disease.  Where is the calcium score data for the FOURIER Evolocumab study?  There is none.  The study neglected to obtain annual calcium scores.
Remember, statin cholesterol lowering drugs were studied with annual calcium score by Dr Paolo Raggi in 2004.  His study showed that 41 of 500 patients on statins had heart attacks over 6 years in spite of cholesterol lowering.  The feature which defined the heart attack group was greater than 15 % annual calcium score progression, not the cholesterol level which was identical for both drug and placebo groups.  Dr Paolo Raggi showed progression of calcium score and myocardial infarction in 41 patients in spite of statin treatment. Will Amgen’s Evolocumab yield similar results?  We await these studies.

Non-Statin Cholesterol Lowering Drugs Abandoned 

Non-statin cholestrol lowering drugs have not fared well in the past.  Statin drugs have the advantage over these newer drugs because statins not only lower cholesterol, they also have pleomorphic effects (anti-inflammatory effects) which some would say provide the real benefit.
High hopes were raised for the non-statin  CETP inhibitor drugs including Eli Lilly’s Anacetrapib and Merc’s Evacetrapib.  Both were highly effective for reducing LDL cholesterol,  yet both failed to reduce the rate of cardiovascular events in patients with high risk cardiovascular disease.  Because of failed clinical trials, both drugs were abandoned and never brought to market.  In retrospect, perhaps the newer non-statin  PCSK9 inhibitor drugs should all share this same fate.(7)  In my opinion,  lack of mortality benefit should have prevented FDA approval of Evolocumab, which was approved anyway, raising the question of behind the scenes political influence.   It is indeed a difficult thing to walk away from a 500 million dollar investment.

Concern for Adverse Neurocognitive Effects 

The FOURIER Evolocumab study reported no adverse effects from intensive lipid lowering. I find this difficult to believe in view of the FDA warning letter asking for a prospective study of neurocognitive adverse effects in the PCSK9 Inhibitor treated group.(29,30)  Neurocognitive effect is a polite way to say loss of ability to focus, think and remember. In other words, drug induced dementia.

Dr Kristopher Swiger wrote an article in 2015 Drug Safety entitled: “PCSK9 Inhibitors and Neurocognitive Adverse Events: ” (31).  He says:

On both theoretical and empirical grounds, concern for adverse neurocognitive effects currently extends to PCSK9 inhibitors.(31) These events  included delirium, cognitive and attention disorders and disturbances, dementia, disturbances in thinking and perception, and mental impairment disorders.(32)

Adverse Psychiatric Reactions with Intensive Cholesterol Lowering

Lower cholesterol level is associated with a number of adverse psychiatric reactions, such as increased risk of suicidal and violent behavior, depression, aggression, and impulsivity  . (35-37)  Dr Eriksen wrote in  Psychiatry Research 2017:

“low cholesterol is a risk marker for inpatient and post-discharge violence in acute psychiatry.”(39) 

People with low cholesterol are more likely to commit violent crimes.(41)  Dr Beatrice Golomb found that low cholesterol was associated with:

“severe irritability homicidal impulses, threats to others, road rage, generation of fear in family members, and damage to property.”(42)

Dr Michael Tatley writes about “Psychiatric adverse reactions with statins, fibrates and ezetimibe.” in Drug Safety 2007(43).  He says:

“The reactions mentioned … include depression, memory loss, confusion and aggressive reactions….The observation that other lipid-lowering agents have similar adverse effects supports the hypothesis that decreased brain cell membrane cholesterol may be important in the aetiology of these psychiatric reactions.”

Dr Repo-Tiihonen investigated “associations between Total Cholesterol levels, violent and suicidal behavior, age of onset of the conduct disorder (CD) and the age of death among 250 Finnish male criminal offenders with ASPD (Antisocial Personality Disorder)”, finding lower cholesterol a  prognostic marker for early unnatural death, and violent crimes. (44)

We Cannot Ignore the Massive Data of Negative Impact

In 2016 Drug Safety, Drs Cham, Koslik, and Golomb reoorted on “Mood, Personality, and Behavior Changes During Treatment with Statins: A Case Series.“   Adverse events related to cholesterol lowering drugs included violent ideation, irritability, depression, and suicide.  These problems resolved when the drug was stopped and recurred when the drug restarted. (45)

Dr Alfonso Troisi says in Neuroscience & Biobehavioral Reviews  2009 :

“we cannot ignore the mass of data showing a negative impact of low cholesterol in some clinical populations or healthy subjects.”(38)

U Shaped Curve Associates Low Cholesterol With Increased Mortality
The finding of increased mortality at low cholesterol levels is not surprising, and  has been known for decades. Back in the 1990’s, accumulated data from multiple studies showed that low cholesterol is associated with increased mortality.(46-53)  The cholesterol data chart reveals U shaped curve in all the cohort studies such as the J-Lit, HUNT-2, and MRFIT.(46-53)  Both left and right arms of the curve show increased mortality.  Dr Petursson from Norway says in 2012:(48)

“Regarding the association between total cholesterol and mortality, our results generally indicated U-shaped or inverse linear curves for total and CVD mortality….Our results contradict the guidelines’ well-established demarcation line (200 mg/dl ) between ‘good’ and ‘too high’ levels of cholesterol. They also contradict the popularized idea of a positive, linear relationship between cholesterol and fatal disease. Guideline-based advice regarding CVD prevention may thus be outdated and misleading, particularly regarding many women who have cholesterol levels in the range of (200-270 mg/dl) and are currently encouraged to take better care of their health….recommendations regarding the ‘dangers’ of cholesterol should be revised. This is especially true for women, for whom moderately elevated cholesterol (by current standards) may prove to be not only harmless but even beneficial.”(48)

In Circulation 1992, Dr Judith Walsh says :

There is an association between low blood cholesterol and noncardiovascular deaths in men and women.  There is no association between high blood cholesterol and cardiovascular deaths in women.”(50)

In 1993, Dr Jacobs speculated on the reason why low cholesterol is associated with risk of non-atherosclerotic death. He says: (49)

“Cholesterol affects the fluidity of cell membranes, membrane permeability, transmembrane exchange,  signal transmission, and other cell properties. Cholesterol is a precursor for five major classes of steroid hormones. It affects gluconeogenesis and immune function; its transport forms, the lipoproteins, also serve as vehicles for fat-soluble vitamins, antioxidants, drugs, and toxins. Thus, cholesterol plays general, fundamental, and highly specific roles in the economy of the body.  …Several authors have recently suggested caution in the pursuit of low Total Cholesterol,  recommending against Total Cholesterol  lowering in persons with Total Cholesterol less than 225 mg/dl.”(49)

Review and Meta-Analysis of PCSK9 Drug Trials

In 2018, Dr Alessandro Battaggia reviewed all the PCSK9 studies and says there was no benefit.  Even in trials recruiting familial hypercholesterolemia patients, there is “tendency to harm” (56) :

“No beneficial relationship was found between LDL-C lowering and cardiovascular events explored by meta-regression; instead, there was a trend toward harm. For any of the other outcomes there was no significant association between LDL-C lowering and risk…..A separate meta-analysis of trials recruiting familial hypercholesterolemia patients have showed a tendency to harm for almost all outcomes….Therefore, at the moment, the data available from randomized trials does not clearly support the use of these antibodies.”(56)

Conclusion:  The lack of mortality benefit reported in the FOURIER study, in spite of the lowest LDL levels in medical history is not surprising, since increased mortality associated with low cholesterol has been known for decades.  In addition, it is clear from both failed CETP inhibitor drug trials, and the PCSK9 drug trials, that lowering cholesterol with a non-statin drug is a futile exercise which provides no health benefit.   I would agree with Dr Alessandro Battaggia’s report, that intensive cholesterol lowering with expensive non-statin drugs has a “tendency to harm”.(56)  This is a medical practice that should be halted immediately.

Articles with Related Interest:

Coronary Calcium Score benefits of aged Garlic
Calcium Score Paradigm Shift in Cardiology
Statin Denialism on the Internet
Autopsy Studies and Cholesterol No Correlation
Familial Hypercholesterolemia and Statin Drugs

Jeffrey Dach MD
7450 Griffin Road
Suite 180/190
Davie, Florida 33314
954-792-4663

Links and References

see original article at: https://jeffreydachmd.com/2018/06/evolocumab-are-you-joking/

Dr Antonio Bianco Rattles Cages in Mainstream Endocrinology by Jeffrey Dach MD

Dr Antonio Bianco 
Rattles Cages in 
Mainstream  Endocrinology

by Jeffrey Dach MD
 
Dr Antonio Bianco asks a very important question, “Does a normal serum TSH indicate adequate treatment in patients given levothyroxine (T4-only) medication?” His answer, published in the Oct 2016 Endocrinology and Metabolism, may rattle a few cages, and is in agreement with what we have been writing for many years now.

Dr Antonio Bianco found levothyroxine (T4) treated patients had difficulty converting T4 into T3, were more likely to be overweight, taking anti-depressants and statins, and had low thyroid symptoms in spite of levothyroxine. Dogmatically clinging to the TSH reference range, and to T4 levothyroxine as the only acceptable thyroid medicine is the error and tragedy of mainstream endocrinology. Dr Bianco’s report has freed endocrinology from the shackles of this false medical dogma. We have written for many years that natural dessicated thyroid (Naturethroid from RLC labs) is a better choice compared to T4 monotherapy with levothyroxine, and that in some cases, suppression of TSH below the reference range is required for relief of symptoms.

Antonio Bianco MD, is an endocrinologist and past president of the American Thyroid Association (ATA) at Rush Medical School in Chicago.  His article is entitled :  Is a Normal TSH Synonymous with “Euthyroidism” in Levothyroxine Monotherapy?  Left image Dr Antonio Bianco Courtesy of the NIH.


Dr Antonio Bianco studied 469 patients treated with levothyroxine (T4 only) for hypothyroidism, and compared to normal controls.  He found:

1) Levothyroxine (T4) treated patients ” had higher serum free T4 and lower serum free T3 than healthy or matched controls.”
My comment: T3 (tri-iodothyronine) is the active thyroid hormone, so a lower serum T3 means these patients are having difficulty converting T4 into T3 and may be suffering from low thyroid symptoms in spite of  levothyroxine (T4).

2) Levothyroxine treated patients were more likely to be overweight despite consuming less calories,
My comment: Weight gain is a common symptom of the low thyroid condition caused by slow metabolic rate, and failure to convert calories to energy.  Instead, consumed calories are stored up as weight gain.
3) Levothyroxine patients were “more likely to be taking anti-depressants, and anti-cholesterol (statin) drugs compared to matched controls.”  
My comment: Lack of energy, fatigue and depression are common symptoms of the low thyroid condition, all relieved by providing adequate thyroid dosage.  Many publications, including the Hunt Study, showed that elevated serum cholesterol is a symptom of the low thyroid condition.  Providing a higher dosage of thyroid medicine is the correct treatment. This will suppress the TSH,  reduce serum cholesterol and prevent heart attacks.   Instead of giving thyroid medicine, the proper medication, the conventional doctor will commonly prescribe a statin anti-cholestrol drug which will reduce serum cholesterol without treating the low thyroid condition.  This is the terrible tragedy and error of mainstream medicine.

Dr Bianco Speaks Out

Dr Antonio Bianco’s study reports that levothyroxine dosage based on the TSH reference range does NOT necessarily provide symptom relief for many patients.(15-17)  That’s because dosage based on TSH range may be inadequate, and higher dosage with suppression of TSH may be needed for complete relief of low thyroid symptoms.

Suppression of TSH May be Needed For Symptom Relief

We have found that suppression of TSH below the reference range is frequently needed for complete symptom relief in the low thyroid patient.  Although endocrinology dogma  opposes TSH suppression, in actuality, endocrinologists commonly suppress the TSH long term with thyroid medicine in two groups of patients, the post thyroidectomy patients and the thyroid nodule patients.  Numerous published studies show no adverse effects of TSH suppression in both groups.  For more on this see: TSH Suppression Benefits and Adverse Effects

The Low Thyroid Condition – Case Report

Mary is a 57 year old female with chronic fatigue, dry, brittle hair, dry skin, muscle aches and pains, and depression, all obvious symptoms of a low thyroid condition. Mary has been to a number of endocrinologists, primary care doctors and even sought advice from her hair stylist. Her latest doctor prescribed a thyroid pill called Levothyroxine (50 mcg) which has done little to relieve her symptoms. In addition, she has depression, and her psychiatrist prescribed an SSRI antidepressant, called Zoloft. She also takes Xanax for bouts of anxiety and insomnia. Mary came into the office frustrated with her conventional medical treatment which was not helping her.

Routine Thyroid Panel

Our routine evaluation includes a full medical history, physical examination and lab panel. Mary’s baseline lab panel showed a TSH of 5.2, a Free T3 of 260 and a Free T4 of 1.4. TPO antibodies were very elevated (1,100) indicating Hashimoto’s Thyroiditis. Her spot urinary Iodine level was 47 mg/dl indicating iodine deficiency (based on World Health Organization Guidelines).

Switching from Levothyroxine to Natural Thyroid

Mary was switched from Levothyroxine to Naturethroid from RLC labs and within a week reported improvement in clinical symptoms. Six weeks later Mary’s Naturethroid dosage was gradually increased to Two and a Half Tablets every day (Using one grain tablets of 65 mg each) . Mary reports improvement. She has tapered off her antidepressants, as she no longer needs them.

Going to the OB/Gyne

Ten weeks later, Mary goes to see her OB Gyne doctor for her annual Pap smear and pelvic exam which included a TSH blood test, with a low result (0.1 which is below the reference range RR).

Her OB/Gyne doctor looks at the TSH test result and tells Mary she is taking too much thyroid medicine and needs to cut back. Mary then calls me at my office to relay this information. Two doctors are telling her different things and Mary doesn’t know who to believe. This scenario plays out in my office with a different patient each week.

The reality is that Mary is on the proper dosage of thyroid medication, and we expect to see a low or suppressed TSH result when this occurs.

In Part One of this series, we discussed how treatment of the low thyroid condition with natural thyroid is superior to Levo-thyroxine (also called Synthroid a T4 only medication).

In our office we use Nature-throid from RLC labs. (Disclosure: NONE, I have no financial relationship with RLC labs, the manufacturer of Nature-Throid NDT – natural dessicated thyroid pills) .
Natural Thyroid which contains both T3 and T4 is a more robust and safer thyroid medication when compared to T4 only medications such as levothyroxine and Synthroid. This is my assessment, based on 10 years of clinical experience prescribing Naturethroid. In addition, we have found that patients who have converted from Synthroid to Natural Thyroid are much happier with their treatment program. The mainstream medical literature is also in agreement.

In part one of this series, we also discussed how the TSH test is not a reliable indicator of adequacy of treatment.(2) In other words, when the patient is taking the proper dosage of natural thyroid medication with complete relief of symptoms, the TSH will typically fall below the lab reference range, also called a suppressed TSH.

In other words, the TSH will be quite low, and this will disturb the mainstream clinician who mistakenly believes the patient is taking too much thyroid medication. The issue can be settled simply by running a Free T3 test which will show that the Free T3 in the normal range, thus excluding any possibility of a “hyperthyroid state”. Unfortunately, most conventional docs do not have the knowledge to order a free T3 test, and have limited understanding of the thyroid patient.

Suppressive Dose Needed –The TSH Test is Not a Reliable Monitor

Many patients do quite well on Synthroid. However about 20% (one fifth) of patients on T4 only medications like Synthroid do not do well, and have continued symptoms of a low thyroid condition.(3) Why is that? A miniscule amount of T4 medication such as 50-88 mcg of Levothyroxine may be sufficient to drive down the TSH, and the endocrinologist will then consider treatment dosage adequate. It is not adequate. This is explained by Dr D.S. Oreilly in his articles (4-5), and by Dr. Henry Lindner in his detailed article highlighting why TSH suppression below the lab reference range is needed for adequate treatment for the low thyroid condition. (6)

Japan in Agreement

In agreement is another article, this time from the Center for Excellence in Thyroid Care, Kuma Hospital, Japan in which the authors state that :

“TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy “(9),

Again, knowledgeable physicians are finding that TSH suppression below the lab reference range is required for adequate treatment of the low thyroid condition. In this Kuma Hospital study, doctors found TSH-suppressive doses of Synthroid were needed in post-thyroidectomy patients to achieve the same normal Serum T3 levels which were present on pre-operative labs.

Natural Thyroid

When Natural thyroid medication is used, and the dosage gradually adjusted upwards from 1/2 tab daily to the maintainance dose of two to three of the One Grain (65mg) Tabs daily (usually done over 6 weeks), the lab panel at this time will typically show a TSH which is below the normal reference range, and a free T3 which is in the upper end of the normal range 350-420. The low TSH is to be expected, is not disturbing, and is not indicative of a hyperthyroid state.

Why Has Endocrinology Mismanaged  the Low Thyroid Condition for Fifty Years?

The answer is obvious. Follow the money trail. Synthroid is the fourth most prescribed drug in America with 70 million prescriptions. Abbot labs, the makers of Synthroid, uses the massive profits to finance and fund Endocrinology Groups and Societies, their meetings, and clinical research grants. They also fund the key opinion leaders to give lectures at meetings in support of Synthroid and the TSH test. This is all done in spite of the obvious clinical inferiority of T4 only medications such as levothyroxine, and the unreliability of the TSH test to monitor adequacy of treatment. For many decades now, mainstream endocrinology has been completely corrupted by huge cash infusions from Big Pharma. Welcome to America. It’s a great country.

Disclosure: NONE: I have no financial relationship with the makers of natural desiccated thyroid tablets.

Articles With Related Interest

TSH Suppression Benefits and Adverse Effects

New Study Shows Natural Thyroid Better than Synthetic

Ann Nicole Smith and Hypothyroidism
Why Natural Thyroid is Better than Synthetic Part One
Why Natural Thyroid is Better Part Two
The TSH Reference Range Wars – Part One
TSH Wars, Part Two

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
www.jeffreydachmd.com
www.drdach.com
www.naturalmedicine101.com
www.bioidenticalhormones101.com
www.truemedmd.com

Links and References

1) http://www.scielosp.org/scielo.php?pid=S0042-96862002000800007&script=sci_arttext
Bulletin of the World Health Organization
Bull World Health Organ vol.80 no.8 Genebra Aug. 2002

dx.doi.org/10.1590/S0042-96862002000800007
Determining median urinary iodine concentration that indicates adequate iodine intake at population level by François Delange,1 Bruno de Benoist,2 Hans Bürgi,1 & the ICCIDD Working Group3

2) www.ncbi.nlm.nih.gov/pubmed/16416346
TSH may not be a good marker for adequate thyroid hormone replacement therapy. Wien Klin Wochenschr. 2005 Sep;117(18):636-40. Alevizaki M, Mantzou E, Cimponeriu AT, Alevizaki CC, Koutras DA. Endocrine Unit, Dept Medical Therapeutics, Alexandra Hospital, Athens University School of Medicine, Athens, Greece.
The objective of this study was to evaluate parameters of thyroid function and indices of peripheral thyroid hormone action (such as SHBG) in patients whose hypothyroidism was considered well controlled under current criteria. 85 – Eighty-five patients with T4-treated hypothyroidism, 28 of whom had athyria, were compared with 114 normal individuals with the same TSH levels. T3 levels were significantly lower in hypothyroidism although mean T4 and fT4 levels were significantly higher. Furthermore, mean SHBG levels were significantly lower in hypothyroidism independently of age. The difference remained when stricter criteria for adequate treatment were applied (TSH < 2.5 microgU/ml). Significant negative correlations were found between logTSH and T3. The slopes of the regression lines of T3 to TSH were significantly different in the control group and the hypothyroid group: thus, for the same TSH levels, T3 levels were lower in the hypothyroid group. “We conclude that patients with T4-treated hypothyroidism have lower T3 levels, lower T3/T4 ratio and lower SHBG than normal individuals with the same TSH, perhaps indicating relative tissue hypothyroidism in the liver. TSH levels used to monitor substitution, mostly regulated by intracellular T3 in the pituitary, may not be such a good indicator of adequate thyroid hormone action in all tissues. The co-administration of T3 may prove more effective in this respect,“ provided novel suitable preparations are developed. Until this is accomplished, substitution in hypothyroidism should aim at low normal TSH, to ensure normal T3 levels.
2011

3) www.ncbi.nlm.nih.gov/pmc/articles/PMC3148220/ .free full text ….
www.ncbi.nlm.nih.gov/pubmed/21829633
Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients (normal TSH). Dr Damiano Gullo MD – Endocrine Unit, University of Catania Medical School, Catania, Italy PLoS ONE 6(8): Published: August 1, 2011
20% of patient on Synthroid (T4) will have abnormal T3/T4 ratios because they are unable to convert T4 to T3. I say: They need a more physiologic treatment such as natural dessicated thyroid. “More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion.”
Context- Levothyroxine monotherapy is the treatment of choice for hypothyroid patients because peripheral T4 to T3 conversion is believed to account for the overall tissue requirement for thyroid hormones. However, there are indirect evidences that this may not be the case in all patients.
Objective – To evaluate in a large series of athyreotic patients whether levothyroxine monotherapy can normalize serum thyroid hormones and thyroid-pituitary feedback. Setting – Academic hospital.Patients- 1,811 patients with normal TSH levels under levothyroxine monotherapy and 3,875 euthyroid controls.
Measurements – TSH, FT4 and FT3 concentrations by immunoassays.
Results- FT4 levels were significantly higher and FT3 levels were significantly lower (p<0.001 in both cases) in levothyroxine-treated athyreotic patients than in matched euthyroid controls. Among the levothyroxine-treated patients 15.2% had lower serum FT3 and 7.2% had higher serum FT4 compared to euthyroid controls. A wide range of FT3/FT4 ratios indicated a major heterogeneity in the peripheral T3 production capacity in different individuals.
The correlation between thyroid hormones and serum TSH levels indicated an abnormal feedback mechanism in levothyroxine-treated patients.
Conclusions- Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients.
2010
4) www.ncbi.nlm.nih.gov/pubmed/20584231
Thyroid hormone replacement: an iatrogenic problem.
Int J Clin Pract. 2010 Jun;64(7):991-4. Dr O’Reilly DS. Department of Clinical Biochemistry, Royal Infirmary, Glasgow, UK.
Abstract Thyroid hormone replacement is one of the very few medical treatments devised in the 19th century that still survive. It is safe, very effective and hailed as a major success by patients and clinicians. Currently, it is arguably the most contentious issue in clinical endocrinology. The current controversy and patient disquiet began in the early 1970s, when on theoretical grounds and without proper assessment, the serum thyrotropin (TSH) concentration was adopted as the means of assessing the adequacy of thyroxine replacement. The published literature shows that the serum TSH concentration is a poor indicator of clinical status in patients on thyroxine. The adequacy of thyroxine replacement should be assessed clinically with the serum T3 being measured, when required, to detect over-replacement.
1986
5) www.ncbi.nlm.nih.gov/pmc/articles/PMC1341585/
Br Med J (Clin Res Ed). 1986 September 27; 293(6550) full text
Are biochemical tests of thyroid function of any value in monitoring patients receiving thyroxine replacement? W D Fraser, E M Biggart, D S O’Reilly, H W Gray, J H McKillop, and J A Thomson
To establish their role in monitoring patients receiving thyroxine replacement biochemical tests of thyroid function were performed in 148 hypothyroid patients studied prospectively. Measurements of serum concentrations of total thyroxine, analogue free thyroxine, total triiodothyronine, analogue free triiodothyronine, and TSH thyroid stimulating hormone, made with a sensitive immunoradiometric assay, did not, except in patients with gross abnormalities, distinguish euthyroid patients from those who were receiving inadequate or excessive replacement. These measurements are therefore of little, if any, value in monitoring patients receiving thyroxine replacement. To stop doing thyroid function tests in these cases would result in considerable savings nationally in the cost of reagents in laboratories using commercial kits.
Article By Henry Lindner MD
6) hormonerestoration.com/files/TSHWrongtree.pdf
Against TSH-T4 Reference Range Thyroidology: The Case for Clinical Thyroidology Henry H. Lindner MD1
The current reliance upon the TSH to both detect hypothyroidism and direct its treatment is illogical and ineffective. Hypothalamic-pituitary function is modified by many known and unknown factors, and is known to deteriorate with age. Even if one could know that a person’s hypothalamic-pituitary response is perfect, one cannot assume that the TSH response to once-daily oral thyroid replacement is identical to the response to continual thyroidal hormone production. The TSH level is only a measure of the hypothalamic-pituitary response to thyroid hormones. It is neither a test of free thyroid hormone levels nor of thyroid hormone effects throughout the body. It is useful for determining the cause of hypothyroidism; not for diagnosing or treating it. The most reliable serum tests of thyroid hormone sufficiency are free T4 and free T3, but their broad laboratory reference ranges are neither optimal nor treatment ranges, and there are marked individual variations. Ultimately, both the diagnosis and treatment of hypothyroidism must be clinical.
7) www.ncbi.nlm.nih.gov/pubmed/11201857
Thyroid. 2000 Dec;10(12):1107-11. Is excessive weight gain after ablative treatment of hyperthyroidism due to inadequate thyroid hormone therapy?
Tigas S, Idiculla J, Beckett G, Toft A. Source Endocrine Unit, Royal Infirmary, Edinburgh, Scotland.
Abstract There is controversy about the correct dose and form of thyroid hormone therapy for patients with hypothyroidism. Despite restoration of serum thyrotropin (TSH) concentrations to normal, many patients complain of excessive weight gain. We have compared weight at diagnosis of hyperthyroidism with that when euthyroid, evidenced by a stable, normal serum TSH concentration, with or without thyroxine (T4) replacement therapy, in patients treated with an 18-month course of antithyroid drugs (43 patients), surgery (56 patients), or 13I (34 patients) for Graves’ disease. In addition, weights were recorded before and after treatment of 25 patients with differentiated thyroid carcinoma by total thyroidectomy, 131I, and long-term T4 suppressive therapy, resulting in undetectable serum TSH concentrations. Mean weight gain in patients with Graves’ disease who required T4 replacement therapy following surgery was significantly greater than in those of the same age, sex, and severity of hyperthyroidism rendered euthyroid by surgery (3.9 kg) (p < 0.001) or at the end of a course of antithyroid drugs (4.1 kg) (p < 0.001). Weight gain was similar in those requiring T4 replacement following surgery or 131T therapy (10.4 versus 10.1 kg). In contrast, ablative therapy combined with suppression of TSH secretion by T4 in patients with differentiated thyroid carcinoma did not result in weight gain. The excessive weight gain in patients becoming hypothyroid after destructive therapy for Graves’ disease suggests that restoration of serum TSH to the reference range by T4 alone may constitute inadequate hormone replacement.
8) www.ncbi.nlm.nih.gov/pmc/articles/PMC143526/
BMJ. 2003 February 8; 326(7384): 311–312. PMCID: PMC143526 full text free
Serum thyroid stimulating hormone in assessment of severity of tissue hypothyroidism in patients with overt primary thyroid failure: cross sectional survey Christian Meier, senior registrar in endocrinology, Peter Trittibach, clinical research fellow, Merih Guglielmetti, statistician, Jean-Jacques Staub, emeritus professor of endocrinology, and Beat Müller, head of division Division of Endocrinology, Department of Medicine, University Hospital, CH-4031 Basle, Switzerland
We found no correlations between the different parameters of target tissues and serum TSH. Our findings are in accordance with a cross sectional study showing only a modest correlation between TSH and the percentage of positive hypothyroid symptoms4 and data showing discordant responses between the pituitary and peripheral target tissues in patients treated with l-triiodothyronine.5 We assume that secretion of TSH is driven by maximal stimulation, with no further increase occurring with greater severity of hypothyroidism. Therefore, the biological effects of thyroid hormones at the peripheral tissues—and not TSH concentrations—reflect the clinical severity of hypothyroidism. A judicious initiation of thyroxine treatment should be guided by clinical and metabolic presentation and thyroid hormone concentrations (free thyroxine) and not by serum TSH concentrations.
TSH suppression required to achieve good result with Synthroid
9) http://www.eje-online.org/content/167/3/373.abstract
TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy by Mitsuru Ito,Akira Miyauchi,Shinji Morita,Takumi Kudo,Eijun Nishihara, Minoru Kihara,Yuuki Takamura,Yasuhiro Ito, Kaoru Kobayashi, Akihiro Miya, Sumihisa Kubota and Nobuyuki Amino from the Center for Excellence in Thyroid Care, Kuma Hospital, 8-2-35, Shimoyamate-Dori, Chuo-Ku, Kobe-City, Hyogo 650-0011, Japan
Objective Thyroidal production of triiodothyronine (T3) is absent in patients who have undergone total thyroidectomy. Therefore, relative T3 deficiency may occur during postoperative levothyroxine (l-T4) therapy. The objective of this study was to evaluate how the individual serum T3 level changes between preoperative native thyroid function and postoperative l-T4 therapy.
Methods We retrospectively studied 135 consecutive patients with papillary thyroid carcinoma, who underwent total thyroidectomy. Serum free T4 (FT4), free T3 (FT3), and TSH levels measured preoperatively were compared with those levels measured on postoperative l-T4 therapy.
Results Serum TSH levels during postoperative l-T4 therapy were significantly decreased compared with native TSH levels (P<0.001). Serum FT4 levels were significantly increased (P<0.001). Serum FT3 levels were significantly decreased (P=0.029). We divided the patients into four groups according to postoperative serum TSH levels: strongly suppressed (less than one-tenth of the lower limit); moderately suppressed (between one-tenth of the lower limit and the lower limit); normal limit; and more than upper limit. Patients with strongly suppressed TSH levels had serum FT3 levels significantly higher than the native levels (P<0.001). Patients with moderately suppressed TSH levels had serum FT3 levels equivalent to the native levels (P=0.51), and patients with normal TSH levels had significantly lower serum FT3 levels (P<0.001).
Conclusions Serum FT3 levels during postoperative l-T4 therapy were equivalent to the preoperative levels in patients with moderately suppressed TSH levels. Our study indicated that a moderately TSH-suppressive dose of l-T4 is required to achieve the preoperative native serum T3 levels in postoperative l-T4 therapy.
10) full text
http://content.karger.com/ProdukteDB/produkte.asp?Doi=339447
Translational Thyroidology / Review
Thyroid Hormone Replacement Therapy: Three ‘Simple’ Questions, Complex Answers
Antonio C. Bianco, Sabina Casula from the Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Fla., USA
Eur Thyroid J 2012;1:88-98
11) http://www.ncbi.nlm.nih.gov/pubmed/22593590
http://jcem.endojournals.org/content/97/7/2256.short
J Clin Endocrinol Metab. 2012 Jul;97(7):2256-71. doi: 10.1210/jc.2011-3399. Epub 2012 May 16.
Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism? Biondi B, Wartofsky L. Department of Clinical and Molecular Endocrinology and Oncology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy.
Levothyroxine therapy is the traditional lifelong replacement therapy for hypothyroid patients. Over the last several years, new evidence has led clinicians to evaluate the option of combined T(3) and T(4) treatment to improve the quality of life, cognition, and peripheral parameters of thyroid hormone action in hypothyroidism. The aim of this review is to assess the physiological basis and the results of current studies on this topic.
We searched Medline for reports published with the following search terms: hypothyroidism, levothyroxine, triiodothyronine, thyroid, guidelines, treatment, deiodinases, clinical symptoms, quality of life, cognition, mood, depression, body weight, heart rate, cholesterol, bone markers, SHBG, and patient preference for combined therapy. The search was restricted to reports published in English since 1970, but some reports published before 1970 were also incorporated. We supplemented the search with records from personal files and references of relevant articles and textbooks. Parameters analyzed included the rationale for combination treatment, the type of patients to be selected, the optimal T(4)/T(3) ratio, and the potential benefits of this therapy on symptoms of hypothyroidism, quality of life, mood, cognition, and peripheral parameters of thyroid hormone action.
The outcome of our analysis suggests that it may be time to consider a personalized regimen of thyroid hormone replacement therapy in hypothyroid patients.Further prospective randomized controlled studies are needed to clarify this important issue. Innovative formulations of the thyroid hormones will be required to mimic a more perfect thyroid hormone replacement therapy than is currently available.
12) http://www.eje-online.org/content/early/2012/11/26/EJE-12-0819.short
Is Pituitary Thyrotropin an Adequate Measure Of Thyroid Hormone-Controlled Homeostasis During Thyroxine Treatment? by Rudolf Hoermann, John E M Midgley, Rolf Larisch and Johannes W Dietrich
Objective. In recognition of its primary role in pituitary-thyroid feedback, thyrotropin (TSH) determination has become a key parameter for clinical decision-making. The present study evaluates the value of TSH as a measure of thyroid hormone homeostasis under T4 therapy.
Design,
Methods. We have examined the interrelationships between free triiodothyronine (FT3), free thyroxine (FT4) and pituitary TSH by means of 1) a retrospective analysis of a large clinical sample comprising 1994 patients either untreated or on varying doses of L-T4 and 2) independent mathematical simulation applying a model of thyroid homeostasis, together with a sensitivity analysis.
Results. Over a euthyroid to mildly hyperthyroid functional range, we found markedly different correlation slopes of log TSH versus FT3 and FT4 between untreated patients and L-T4 groups. Total deiodinase activity (GD) was positively correlated with TSH in untreated subjects. However, GD was significantly altered and the correlation lost under increasing L-T4 doses. 95% confidence intervals for FT3 and FT4, when assessed in defined TSH concentration bands, differed significantly for L-T4-treated, compared to untreated patients. Higher doses were often needed to restore FT3 levels within its reference range. Sensitivity analysis revealed the influence of various structural parameters on pituitary TSH secretion including a preeminent role of pituitary deiodinase type 2.
Conclusion. The data reveal disjoints between FT4-TSH feedback and T3 production that persist even when sufficient T4 apparently restores euthyroidism. T4 treatment displays a compensatory adaptation, but does not completely re-enact normal euthyroid physiology. This invites a study of the clinical consequences of this disparity.
13) Low Thyroid function associated with heart disease risk
HUNT study
14) http://www.ncbi.nlm.nih.gov/pubmed/18443261
Thyrotropin TSH Levels and Risk of Fatal Coronary Heart Disease- The HUNT Study . Norway Arch Intern Med. 2008;168(8):855-860. Bjørn O. Åsvold, MD; Trine Bjøro, MD, PhD; Tom Ivar L. Nilsen, PhD; David Gunnell, MD, PhD; Lars J. Vatten, MD, PhD (Norway) —
70% increased mortality from Heart Disease in higher TSH range (2.5-3.5) In a Norwegian population TSH Levels measured and pts followed over 8 years for death from heart attack 17, 311 women and 8,002 men (without known thyroid or cardiovascular disease or diabetes mellitus at baseline.) Results: In women the hazard ratios for coronary death were 1.41 (95% confidence interval [CI], 1.02-1.96) and 1.69 (95% CI, 1.14-2.52) for women in the intermediate (thyrotropin level, 1.5-2.4 mIU/L) and higher (thyrotropin level, 2.5-3.5 mIU/L) categories, respectively. Conclusions: (TSH) Thyrotropin levels within the reference range were positively and linearly associated with CHD mortality in women. The results indicate that relatively low but clinically normal thyroid function may increase the risk of fatal CHD by 70% .
Antonio C. Bianco M.D.
15) Is a Normal TSH Synonymous with “Euthyroidism” in Levothyroxine Monotherapy? Sarah J. Peterson Ph.D., Elizabeth A. McAninch M.D., and Antonio C. Bianco M.D. Division of Endocrinology and Metabolism, Rush University Medical Center, 1735 W Harrison St; Cohn Building Rm 212; Chicago, IL 60612, USA
Context: Levothyroxine (LT4) monotherapy is the standard of care for hypothyroidism.
Objective: To determine whether LT4 at doses that normalize the serum TSH is associated with normal markers of thyroid status.
Design: Cross-sectional data from the US National Health and Nutrition Examination Survey (2001–2012) was used to evaluate 52 clinical parameters. LT4-users were compared to healthy controls and controls matched for age, sex, race, and serum TSH. Regression was used to evaluate for correlation with serum thyroxine (T4) and triiodothyronine (T3) levels.
Participants: 9,981 participants with normal serum TSH were identified; 469 were LT4-treated.
Results: Participants using LT4 had higher serum total and free T4 and lower serum total and free T3 than healthy or matched controls. This translated to ∽15–20% lower serum T3:T4 ratios in LT4 treatment, as has been shown in other cohorts. In comparison to matched controls, LT4-treated participants: had higher BMI despite report of consuming less calories/day/kg; were more likely to be taking beta-blockers, statins, and anti-depressants; and reported lower total metabolic equivalents. A serum TSH level below the mean in LT4-treated participants was associated with a higher serum free T4 but similar free and total T3; yet those with lower serum TSH levels exhibited higher serum HDL and lower serum LDL, triglycerides, and CRP. Age was associated with serum free T3:free T4 ratio in all participants; caloric intake was associated in LT4-treated individuals.
Conclusions: In a large population study, participants using LT4 exhibited lower serum T3:T4 ratios and differed in 12/52 objective and subjective measures.
16) Hypothyroidism Symptoms Linger Despite Medication Use, Normal Blood Tests. Study questions value of TSH levels as indicator that disease is under control. Released: 12-Oct-2016 12:05 PM EDT
Source Newsroom: Rush University Medical Center
17) Hypothyroidism symptoms linger despite medication use, normal blood tests October 12, 2016 Rush University Medical Center
New research gives hypothyroidism patients—who often feel dismissed and forgotten—evidence that their persistent symptoms are not just in their heads.
Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
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Low Thyroid, Hashimotos and Pregnancy

Low Thyroid, Hashimotos and Pregnancy

by Jeffrey Dach MD

Today is a happy day for Susan.  She just delivered a healthy baby girl, and mailed me a cute photo of the baby from her hospital bed,  Six months before, Susan was weeping in my office, recounting her story of repeated miscarriages and fertility problems.  Her lab panel showed a borderline low thyroid status and elevated anti-thyroid antibodies indicating Hashimoto’s Autoimmune Thyroiditis.  Upper Left Image courtesy of wikimedia commons.
After a complete evaluation, we started Susan on our usual program including natural desiccated thyroid One and a Half Grains per day, selenium 400 mcg/day, iodine 450 mcg per day and a good prenatal multivitamin.  That must have done the trick, and Susan’s thank you card has the “pitter patter of little feet” on the cover.

A Common Scenario

Since ten to twenty per cent of all women of reproductive age have elevated anti thyroid antibodies, we see this scenario quite often.
There are literally thousands of low thyroid Susans ignored by mainstream medicine, left to suffer through repeated miscarriages and other fertility problems, representing yet another tragic error by conventional endocrinology.  Left image mother and baby courtesy of wikimedia commons.

Dr Peter Taylor Makes a Plea

Dr Peter Taylor made exactly this point at a recent Endocrine Society Meeting when he said that more pregnant women would benefit from thyroid hormone treatment to prevent miscarriages and stillborn babies.(8)  His pleas to screen all pregnant women were ignored, as they have been for many years.(9)  Further studies show that many women with thyroid anti-bodies have better pregnancy outcomes when treated with thyroid hormones.(10,11)


The New York Times Gets the Story Right

A few years back in 2009,  Dr Alex Stagnaro-Green gave the New York Times an accurate accounting of the role of thyroid in pregnancy. (1) These are Dr Green’s points:

1)  Pregnancy is like a stress test for the thyroid. increasing thyroid hormone requirement by 50%

2) Hypothyroidism during pregnancy is linked to miscarriage (5), and preterm delivery. (5)  Compared to aged matched controls, children of hypothyroid mothers have lower I.Q.s by seven points on average when tested  seven to nine years later. (3)  Nineteen per cent of these children had IQ’s of 85 or less.(3)

3) Even though thyroid hormone levels may be completely normal, the presence of Hashimoto’s anti-thyroid antibodies is associated with a 200-300% increase of miscarriage.

Dr. Roberto Negro from Italy published a study in 2006 of women who were thyroid antibody-positive.  Treatment of these women with thyroid hormone resulted in a dramatic reduction of stillbirths and preterm deliveries.(4)  Upper left image courtesy of wikimedia commons.

How to Make Smarter Babies

As mentioned above, children born to hypothyroid mothers, have lower IQ when tested 7-9 years later.  Giving thyroid hormones to the mother makes smarter babies.(3)  In addition, maternal iodine deficiency is associated with reduced educational outcomes in the offspring.(14)  This is precisely why we screen women for iodine levels, and make sure they have adequate iodine supplementation. In  Hashimotos patients, we use low-dose iodine supplementation of 225-450 mcg per day which is a safe level.
Hypothyroid MOM

Perhaps the one person most dedicated to getting this message out is Dana Trentini who runs HypoThyroid Mom.  (left image courtesy of Dana Trentini Hypothyroid MOM.
After suffering through a miscarriage herself, she discovered the importance of thyroid in pregnancy,  and has been a tireless advocate ever since.   Regretting her misplaced trust in doctors who failed to treat her low thyroid condition, HypothyroidMom now encourages all women to take charge of their thyroid health.  The EcoFeminist Blog run by Aimee picks up and amplifies this message in her article,  hypothyroidism and miscarriage.
Conclusion: Another tragedy of modern endocrinology is the manner in which the hypothyroid mom is ignored, leading to unnecessary suffering.  All pregnant women should be screened for thyroid antibodies and more pregnant women should be treated with thyroid hormones which will result in reduction in miscarriages, reduction in preterm infants, and improvement in IQ and educational outcomes in the newborn
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Fl 33314
954-792-4663

Articles with Related Interest
Why Natural Thyroid is Better than Synthetic
TSH SUppression Benefits and Adverse Effects
How to Make Smarter Children with Iodine Supplementation
The Unreliable TSH Part One
The Unreliable TSH Part Two
Hashimotos, Iodine and Selenium

Links and references

1)  http://www.nytimes.com/ref/health/healthguide/esn-hypothyroidism-expert.html?pagewanted=all
Pregnancy and the Thyroid New York Times  3/13/2009
By INGFEI CHEN  Dr. Alex Stagnaro-Green is a professor of medicine and obstetrics and gynecology at Touro University College of Medicine in Hackensack, N. J. He was a member of an international panel of experts convened by the Endocrine Society that issued a clinical practice guideline in 2007 on managing thyroid dysfunction during pregnancy and after childbirth.
It turns out that pregnancy is like a stress test for the thyroid: the amount of thyroid hormone that needs to be released during pregnancy is increased by about 50 percent, and that’s because of some of the hormones related to pregnancy. If there is a dysfunction with the thyroid, it has been linked — especially hypothyroidism — to miscarriage, preterm delivery, and also with decreased I.Q. in the unborn child when tested at 7 to 9 years old. Furthermore, if a woman has Hashimoto’s disease with antibodies, but with the thyroid hormone levels still being normal, that’s also been associated with a two- to threefold increase of miscarriage. So that’s why all this is very important.
But the women who were antibody-positive who didn’t get the thyroid hormone had a miscarriage rate that was four times higher.
First I educate her that about 50 to 60 percent of women who have thyroid disease and are on thyroid hormone replacement therapy will need an increase in the hormone very early in the first trimester. I explain that this is extremely important so as to prevent complications like miscarriage. And therefore we try to adjust the thyroid hormone level before a woman gets pregnant so that she’s clearly in the normal range.
Secondly, as soon as they get pregnant, I have my patients call me immediately to get thyroid function tests so that I can modify their dose as early as possible in the pregnancy. Bottom line is that as soon as a woman knows she is pregnant she should be tested and see her doctor.
2) https://www.ncbi.nlm.nih.gov/pubmed/2118190
JAMA. 1990 Sep 19;264(11):1422-5.
Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies.
Stagnaro-Green A1, Roman SH, Cobin RH, el-Harazy E, Alvarez-Marfany M, Davies TF. Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029.
We screened 552 women who presented to their obstetrician in the first trimester of pregnancy using highly sensitive enzyme-linked immunosorbent assays for the presence of thyroglobulin and thyroid peroxidase autoantibodies and found an incidence of positivity of 19.6%. The tendency to secrete detectable levels of thyroid autoantibodies was significantly correlated with an increased rate of miscarriage. Thyroid autoantibody-positive women miscarried at a rate of 17%, compared with 8.4% for the autoantibody-negative women. Individual levels of thyroglobulin and thyroid peroxidase autoantibodies were similarly related to this increased miscarriage rate, with no evidence of autoantibody specificity in the relationship. Furthermore, the increase in miscarriages could not be explained by differences in thyroid hormone levels, the presence of cardiolipin autoantibodies, maternal age, gestational age at the time of maternal entry into the study, or previous obstetric history. We conclude that thyroid autoantibodies are an independent marker of “at-risk” pregnancy.
3) https://www.ncbi.nlm.nih.gov/pubmed/10451459
N Engl J Med. 1999 Aug 19;341(8):549-55.
Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child.
Haddow JE1, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, O’Heir CE, Mitchell ML, Hermos RJ, Waisbren SE, Faix JD, Klein RZ.
When thyroid deficiency occurs simultaneously in a pregnant woman and her fetus, the child’s neuropsychological development is adversely affected. Whether developmental problems occur when only the mother has hypothyroidism during pregnancy is not known.
METHODS:In 1996 and 1997, we measured thyrotropin in stored serum samples collected from 25,216 pregnant women between January 1987 and March 1990. We then located 47 women with serum thyrotropin concentrations at or above the 99.7th percentile of the values for all the pregnant women, 15 women with values between the 98th and 99.6th percentiles, inclusive, in combination with low thyroxine levels, and 124 matched women with normal values. Their seven-to-nine-year-old children, none of whom had hypothyroidism as newborns, underwent 15 tests relating to intelligence, attention, language, reading ability, school performance, and visual-motor performance.
RESULTS:The children of the 62 women with high serum thyrotropin concentrations performed slightly less well on all 15 tests. Their full-scale IQ scores on the Wechsler Intelligence Scale for Children, third edition, averaged 4 points lower than those of the children of the 124 matched control women (P= 0.06); 15 percent had scores of 85 or less, as compared with 5 percent of the matched control children. Of the 62 women with thyroid deficiency, 48 were not treated for the condition during the pregnancy under study. The full-scale IQ scores of their children averaged 7 points lower than those of the 124 matched control children (P=0.005); 19 percent had scores of 85 or less. Eleven years after the pregnancy under study, 64 percent of the untreated women and 4 percent of the matched control women had confirmed hypothyroidism.
CONCLUSIONS:Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses; therefore, screening for thyroid deficiency during pregnancy may be warranted.
4) https://www.ncbi.nlm.nih.gov/pubmed/16621910
J Clin Endocrinol Metab. 2006 Jul;91(7):2587-91.
Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications.
Negro R1, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H.
Euthyroid women with autoimmune thyroid disease show impairment of thyroid function during gestation and seem to suffer from a higher rate of obstetrical complications.
OBJECTIVE:We sought to determine whether these women suffer from a higher rate of obstetrical complications and whether levothyroxine (LT(4)) treatment exerts beneficial effects.
DESIGN:This was a prospective study.
SETTING:The study was conducted in the Department of Obstetrics and Gynecology.
PATIENTS:A total of 984 pregnant women were studied from November 2002 to October 2004; 11.7% were thyroid peroxidase antibody positive (TPOAb(+)).
INTERVENTION:TPOAb(+) patients were divided into two groups: group A (n = 57) was treated with LT(4), and group B (n = 58) was not treated. The 869 TPOAb(-) patients (group C) served as a normal population control group.
MAIN OUTCOME MEASURES:Rates of obstetrical complications in treated and untreated groups were measured.
RESULTS:At baseline, TPOAb(+) had higher TSH compared with TPOAb(-); TSH remained higher in group B compared with groups A and C throughout gestation. Free T(4) values were lower in group B than groups A and C after 30 wk and after parturition. Groups A and C showed a similar miscarriage rate (3.5 and 2.4%, respectively), which was lower than group B (13.8%) [P < 0.05; relative risk (RR), 1.72; 95% confidence interval (CI), 1.13-2.25; and P < 0.01; RR = 4.95; 95% CI = 2.59-9.48, respectively]. Group B displayed a 22.4% rate of premature deliveries, which was higher than group A (7%) (P < 0.05; RR = 1.66; 95% CI = 1.18-2.34) and group C (8.2%) (P < 0.01; RR = 12.18; 95% CI = 7.93-18.7).
CONCLUSIONS:Euthyroid pregnant women who are positive for TPOAb develop impaired thyroid function, which is associated with an increased risk of miscarriage and premature deliveries. Substitutive treatment with LT(4) is able to lower the chance of miscarriage and premature delivery.
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5) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229690/
Maternal Subclinical Hypothyroidism, Thyroid Autoimmunity, and the Risk of Miscarriage: A Prospective Cohort Study
Liu Haixia, Shan Zhongyan, Li Chenyan, Mao Jinyuan, Xie Xiaochen, Wang Weiwei, Fan Chenling, Wang Hong, Zhang Hongmei,
Han Cheng, Wang Xinyi, Liu Xin, Fan Yuxin, Bao Suqing, and Teng Weiping.  Thyroid. November 2014, 24(11): 1642-1649.
ABSTRACT Background: Increasing data suggest that subclinical hypothyroidism (SCH) and thyroid autoimmunity (TAI) are associated with adverse pregnancy outcomes, but there are limited data on the association of these conditions in early pregnancy with subsequent miscarriage.
Methods: In this prospective cohort study, we screened 3315 women at low risk for thyroid dysfunction at four to eight weeks’ gestation from iodine-sufficient areas of China between January 2012 and September 2012. Thyrotropin (TSH), free thyroxine (fT4), and the autoantibodies thyroid-peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) were measured. Based on these results, women were divided into four groups for comparison: euthyroidism (ET), isolated SCH, isolated TAI (positive TPOAb or/and TgAb), and SCH with TAI (SCH+TAI). The SCH group was stratified into two subgroups (SCH 1 and SCH 2) on the basis of the level of TSH (2.5≤TSH<5.22 or 5.22≤TSH<10 respectively). Accordingly, the SCH+TAI group was also stratified into two subgroups (SCH+TAI 1 and SCH+TAI 2). The outcome of interest was miscarriage, defined as spontaneous pregnancy loss prior to 20 weeks.
Results: Compared to women with ET, the risk of miscarriage was significantly higher among women with SCH 2 (7.1% vs. 2.2%, aOR 3.40 [CI 1.62–7.15]; p=0.002), isolated TAI (5.7% vs. 2.2%, aOR 2.71 [CI 1.43–5.12]; p=0.003), SCH+TAI 1 (10.0% vs. 2.2%, aOR 4.96 [CI 2.76–8.90]; p=0.000), and SCH+TAI 2 (15.2% vs. 2.2%, aOR 9.56 [CI 3.76–24.28]; p=0.000). The gestational ages of 110 women at miscarriage were lower among women with subclinical thyroid abnormalities compared to ET (11.13±3.21 weeks with subclinical thyroid abnormalities vs. 9.33±1.71 weeks with ET; p=0.024). In parallel with the higher TSH levels, there were earlier gestation ages at miscarriage between subgroups of SCH and SCH+TAI (SCH 1 vs. SCH 2: 10.79±1.77 vs. 9.70±1.47 weeks, p=0.039; SCH+TAI 1 vs. SCH+TAI 2: 9.59±1.97 vs. 8.88±1.24 weeks, p=0.031).
Conclusions: Women with SCH and TAI are at an increased risk of miscarriage between four and eight gestational weeks. Women with a combination of SCH and TAI were found to have the highest risk and earlier gestational ages of miscarriage.

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6) http://hypothyroidmom.com/what-every-pregnant-woman-needs-to-know-about-hypothyroidism/
What Every Pregnant Woman Needs To Know About Hypothyroidism
October 8, 2012 by Dana Trentini
The launch of my blog Hypothyroid Mom is intentionally timed this October 2012 during Miscarriage Awareness Month in memory of the baby I lost to hypothyroidism and in dedication to my two boys who beat the odds and made it to the world. This is Part 2 of my 5-part series entitled Miscarriage Awareness Month: The Dangers of Hypothyroidism And Pregnancy.
7) https://theecofeminist.com/2016/08/30/hypothyroidism-and-miscarriage/
Hypothyroidism and Miscarriage August 30, 2016     Eco Feminist
Nov 9, 2016  Peter Taylor
8) https://www.sciencedaily.com/releases/2016/11/161109090353.htm
Giving more pregnant women common thyroid medicine may reduce risk of complications.  Date:    November 9, 2016
Source:    Society for Endocrinology
Summary:    Extending the number of pregnant women given the common drug levothyroxine to boost thyroid hormone levels may lead to a reduced number of stillbirths, early caesarean sections and low-weight babies, according to a new study.
In this study, researchers from the University of Cardiff investigated whether pregnant women with mild hypothyroidism and their babies would also benefit from levothyroxine treatment. They combined data from a thyroid screening study and linked it to routinely collected clinical data to study the effect of correcting borderline thyroid function on obstetric outcomes.
The researchers analysed over 13,000 women who were 12-16 weeks pregnant, 518 of whom had mild hypothyroidism. Of these, 263 women received levothyroxine and the rest received no treatment. They assessed the women’s pregnancy outcomes by measuring stillbirth rates, preterm delivery, length of stay at hospital, birth weight and the number of early caesarean sections.
They found that women with mild hypothyroidism treated with levothyroxine had a lower risk of giving birth to low weight babies and were also less likely to undergo an early caesarean. Untreated women with mild hypothyroidism were more likely to have a stillbirth than women with normal thyroid function and no stillbirths occurred in the treated group. However, there was no significant difference between the other obstetric outcomes or when all outcomes were combined.
“Our work raises the possibility of providing real benefits from using a safe, cheap and well established treatment by simply extending it to the number of pregnant women we treat,” said Dr Peter Taylor, lead author of the study.
Dr Taylor believes more substantial benefits might be found by treating the pregnant women at an earlier stage than used in this study. “We should consider universal thyroid screening in pregnancy as it compares favourably in terms of cost-effectiveness with other conditions that we currently screen for,” he added.
9) http://www.futuremedicine.com/doi/abs/10.2217/whe.15.7?journalCode=whe
Taylor, Peter N., et al. “Should all women be screened for thyroid dysfunction in pregnancy?.” Women’s Health 11.3 (2015): 295-307.
The subject of universal thyroid screening in pregnancy generates impassioned debate. Thyroid dysfunction is common, has significant adverse implications for fetal and maternal well-being, is readily detectable and can be effectively and inexpensively treated. Furthermore, the currently recommended case-finding strategy does not identify a substantially proportion of women with thyroid dysfunction thus favoring universal screening. On the other hand subclinical thyroid dysfunction forms the bulk of gestational thyroid disorders and the paucity of high-level evidence to support correction of these asymptomatic biochemical abnormalities weighs against universal screening. This review critically appraises the literature, examines the pros and cons of universal thyroid screening in pregnancy, highlighting the now strong case for implementing universal screening and explores strategies for its implementation.
10) http://www.endocrine-abstracts.org/ea/0044/ea0044OC6.3.htm
Endocrine Abstracts (2016) 44 OC6.3
Controlled Antenatal ; Obstetric Outcomes
Peter Taylor1, Arron Lacey2, Daniel Thayer2, Mohd Draman1, Arshiya Tabasum1,3, Ilaria Muller1, Luke Marsh1, Arwel Poacher1, Aled Roberts3, Marian Ludgate1, Alex Rees3, Kristien Boelaert4, Aled Rees1, Shiao Chan4,5, John Lazarus1, Scott Nelson6, Bijay Vaidya7 & Onyebuchi Okosieme1
Context: Suboptimal thyroid function in pregnancy is associated with adverse obstetric outcomes but it is unclear whether levothyroxine treatment, initiated during pregnancy is beneficial.
Design & Participants: Retrospective analysis of the Controlled Antenatal Thyroid Screening (CATS) study with obstetric outcomes obtained through data-linkage in the Secure Anonymised Information Linkage (SAIL) databank. We studied 13,224 pregnant women; 12,608 had normal thyroid function, 340 had subclinical hypothyroidism (SCH), 305 had isolated hypothyroxinemia (IH). 518 women with abnormal thyroid function were randomized to receive levothyroxine (N=263) or no treatment (N=255) at the end of the first trimester.
Main Outcome Measures: Composite measure (primary outcome) of stillbirth, neonatal death, preterm delivery <34 weeks, APGAR score at 5 minutes <7, length of hospital stay >5 days. Secondary analyses included early gestational age (<37 weeks), early caesarean sections (<37 weeks).
Results: In individuals with abnormal thyroid function randomized to treatment or control, treatment had no discernible effect on the composite outcome. 29 events occurred in the untreated group vs 22 in the treated. OR (treated) = 0.75 95%CI (0.40, 1.40). Untreated women with SCH had increased odds of stillbirth compared to women with normal thyroid function OR=4.37 (95%CI 1.04, 18.3). No stillbirths occurred in women on levothyroxine. Untreated women with IH had increased odds of an early gestational age at delivery (<37 weeks) than women with normal thyroid function OR=1.58 (95%CI 1.04, 2.50). Women with IH randomized to receive treatment with levothyroxine had reduced odds of early gestational age at delivery OR=0.37 (95%CI 0.14, 0.99) and early caesarean sections (0% vs 4%) p=0.04 than untreated women.
Conclusion: Both SCH and IH were associated with key adverse obstetric outcomes. Although there was no difference in composite outcome there were some benefits observed with levothyroxine therapy. Larger studies are required to confirm the benefits of screening and treatment in pregnancy.
11) http://www.bmj.com/content/342/bmj.d2616
Thangaratinam, Shakila, et al. “Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence.” Bmj 342 (2011): d2616.
This systematic review was conducted with a prospective protocol with widely recommended methods.15
Conclusion The presence of maternal thyroid autoantibodies is strongly associated with miscarriage and preterm delivery. There is evidence that treatment with levothyroxine can attenuate the risks.
What is already known on this topic
Thyroid autoantibodies are relatively common in women of reproductive age
Thyroid autoimmunity might be associated with adverse pregnancy outcomes
What this study adds
In women with normal thyroid function and thyroid autoantibodies the risk of miscarriage is more than tripled and the risk of preterm birth is doubled
Treatment with levothyroxine can halve the risk of miscarriage in women with normal thyroid function and thyroid autoantibodies
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12) http://acb.sagepub.com/content/53/4/421.short
Thyroxine replacement: a clinical endocrinologist’s viewpoint
V Eligar1     PN Taylor1     OE Okosieme1,2⇑     GP Leese3     CM Dayan1  1Thyroid Research Group, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, UK  2Endocrine and Diabetes, Department Prince Charles Hospital, Cwm Taf University Health Board Merthyr Tydfil, UK
3Department of Medicine, University of Dundee, Ninewells Hospital, Dundee, UK
OE Okosieme, University Hospital of Wales Cardiff, UK. Email: OkosiemeOE@Cardiff.ac.uk
Background Hypothyroidism affects 2–5% of the general population. Patients with uncorrected disease suffer significant morbidity and have an increased risk of cardiovascular disease and neurocognitive impairment. Levothyroxine, the treatment of choice, is inexpensive, easy to administer and in most cases restores well-being while normalizing thyroid function. However, 30–50% of individuals on levothyroxine are either over-treated or under-treated and others remain dissatisfied with treatment despite achieving thyroid hormone concentrations within the laboratory reference interval.
Methods This review is based on a systematic search of the literature for controlled trials, systematic reviews, guideline papers and cohort studies addressing best practice in thyroid hormone replacement.
Results Recent decades have seen improvements in patient management strategies driven by a better appreciation of levothyroxine pharmacokinetics. However, aspects of therapy such as the optimal timing of medication, strategies to overcome treatment non-adherence and target thyroid stimulating hormone concentrations in pregnancy and in patients with differentiated thyroid cancer remain challenging. Furthermore, there is now a substantial body of literature on common genetic variations in the deiodinases and thyroid hormone transporters and their role in the local regulation of thyroid hormone delivery. The benefits of combination therapy with liothyronine and levothyroxine are uncertain, and while it is theoretically probable that subsets of genetically predisposed individuals will benefit from combination therapy the existing evidence is as yet limited.
Conclusion Despite the availability of thyroid hormone replacement for more than a century, there are still substantial challenges in practice and opportunities to improve treatment outcomes.
13) http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/thyroid/thyroid_preg.html
Thyroid Hormones: Pregnancy and Fetal Development
Thyroid hormones are critical for development of the fetal and neonatal brain, as well as for many other aspects of pregnancy and fetal growth. Hypothyroidism in either the mother or fetus frequently results in fetal disease; in humans, this includes a high incidence of mental retardation.
Isolated maternal hypothyroidism: Overt maternal hypothyroidism typically is not a significant cause of fetal disease because it usually is associated with infertility. When pregnancy does occur, there is increased risk of intrauterine fetal death and gestational hypertension. Subclincial hypothyroidism is increasingly being recognized as a cause of developmental disease – this is a rather scary situation. Several investigators have found that mild maternal hypothyroidism, diagnosed only retrospectively from banked serum, may adversely affect the fetus, leading in children to such effects as slightly lower performance on IQ tests and difficulties with schoolwork. The most common cause of subclinical hypothyroidism is autoimmune disease, and it is known that anti-thyroid antibodies cross the human placenta. Thus, the cause of this disorder may be a passive immune attack on the fetal thyroid gland.
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14) http://press.endocrine.org/doi/full/10.1210/jc.2012-4249
http://ecite.utas.edu.au/99264
Hynes, Kristen L., et al. “Mild iodine deficiency during pregnancy is associated with reduced educational outcomes in the offspring: 9-year follow-up of the gestational iodine cohort.” The Journal of Clinical Endocrinology & Metabolism 98.5 (2013): 1954-1962.
Iodine is essential for neurodevelopment in utero and in childhood, with deficiency being a major cause of preventable intellectual impairment (1). The serious neurodevelopmental consequences of severe iodine deficiency (ID) on the fetus are well documented and include cretinism, which manifests as motor, cognitive, and auditory defects (2). ID, however, results in a spectrum of disorders with many speculating that even mild maternal ID has subtle impacts on fetal development. Recent reviews are not conclusive as to whether low maternal dietary iodine intake in areas of mild deficiency leads to measurable effects on cognition and neurodevelopment of the offspring (3, 4).
Clinical trials of iodine supplementation in pregnancy in regions of mild ID have typically focused on positive changes in maternal and fetal thyroid function and volumes but have not examined long-term developmental consequences in the offspring. To our knowledge, there are only three studies reporting neurodevelopmental outcomes in offspring after supplementation of mothers with mild ID. Berbel et al (5) reported significantly delayed neurobehavioral performance in children (aged 18 months) if their mothers did not receive iodine supplementation by 4 to 6 weeks of gestation. Similarly, Velasco et al (6) found that children (aged 3–18 months) had higher psychomotor development scores if their mothers were given supplements from the first trimester. Both interventions provide preliminary evidence that even mild gestational ID may have an adverse impact on fetal neurodevelopment and subsequent infant functioning. In contrast, Murcia et al (7) reported that higher maternal intake of iodine-containing supplements was associated with lower scores on the Psychomotor Development Index of the Bayley Scales of Infant Development in their children (aged 1 year).
In addition to gestational studies, there is increasing evidence from observational population studies that less severe cognitive and motor impairment occurs in apparently normal individuals from areas of ID (8). Children without cretinism from iodine-deficient regions of Iran were found to have growth retardation and neurological, auditory, and psychomotor impairments (9). Boyages et al (10) reported impaired intellectual and neuromotor development in apparently normal Chinese children, with a shift in the distribution of cognitive skills to a lower level. Furthermore, randomized controlled trial data show that postgestational supplementation can lead to significantly improved mental performance of children from areas of mild (11), moderate (12), and severe ID (13).
We compared educational outcomes of children (aged 9 years) born to women assessed as being iodine deficient (urinary iodine concentration [UIC] <150 μg/L) or sufficient (UIC ≥150 μg/L) during pregnancy. Gestation occurred during 1999–2001, a documented period of mild ID (median UIC, 77.5 μg/L) in the Tasmanian population (14), with the children subsequently growing up in an environment considered to be replete (14, 15) (median UIC, 108.0 μg/L) after introduction of voluntary iodine fortification (16). We investigate whether mild gestational ID has long-term effects on educational outcomes.
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15) http://www.thyroidmanager.org/question/repeated-miscarriages-in-a-young-woman-with-hashimoto%E2%80%99s-thyroiditis-and-antibodies/
Repeated Miscarriages in a Young Woman with Hashimoto’s Thyroiditis and Antibodies  Last Updated: March 5, 2008 ·   Leslie J. DeGroot, M.D.
Question
This is a 32 yr old female who first saw me 3/7/7 when she was 8 weeks IUP, G4M3. First pregnacy was 5yrs ago FTND. Subsequent 3 miscarriages at 6-8wks IUP. Hypothyroidism diagnosed 3yrs ago, not treated for reasons unclear. 6/06 she was started on LT4 50 mcg, gradually increased to 100mcg by 2/07. When I saw her 3/7/7 – TSH was 6.9 (1st trim N- 0.3-4.5), FT4-1.3, TPO> 1000, TGAb>3000, TSI – 132 (N<125), TBII -30%(n<16%). I increased her LT4 to 112mcg, but she went on to have a miscarriage 5/07 at 12 weeks IUP. Her TSH on f/u post miscarriage was – 0.03, FT41.8, T3 185, TPO> 1000, TGAb1050. I reduced her LT4 back to 100mcg/day.
She also had a tennis ball sized fibroid which was subsequently removed. She has also had extensive testing by her reproductive endo, for etiology for her miscarriages, all which seem negative.
She wants to conceive again.
Since 11/07 her TFT have been normal on LT4 88mcg/day. 2/07 – TSH- 2.87, FT4 1.4, T3-122, TPO>1000, TGAb> 3000.
She weighs 123lbs, and was hyperthyroid on 100mcg LT4.So, I have not changed her current dose.
Is she a candidate for IVIG? Is there anything else I can do from endo standpoint to reduce her risk for miscarriage? What would you advice her?
Radha Reddy, MD
Rancho Cucamonga CA
Response
I am not too familiar with the medical phraseology used in the U.S. when presenting case histories, but I think I understood correctly that this patient has been pregnant 4 times, with three previous miscarriages, and a fourth – and last miscarriage – during her most recent pregnancy in 2007. Obviously, she also has chronic autoimmune thyroiditis, with hypothyroidism diagnosed a couple of years ago. It is not clear to me whether the 3 previous miscarriages took place while she was an untreated hypothyroid patient or whether the obstetrical history occurred before that period (where, by the way, she may also have already been hypothyroid, without a diagnosis). In her most recent pregnancy, the patient received L-thyroxine ‘almost’ from the onset of gestation. However, and despite increasing her l-T4 dosage, the “best” TSH obtained was still clearly suboptimal in the first trimester (6.9 mU/L). After that, she miscarried once again. Finally, the antibody data indicate high titers of anti-Tg (>1000-3000) and anti-TPO (>1000) Abs and a positive TBII value (30% TSH binding inhibition).
Comments:
1) This is the sad – but not unusual – story of those patients who miscarry early (in the first trimester) and repeatedly, who have autoimmune thyroiditis and a not well-controlled thyroid function. Most studies on recurrent abortion in such ‘thyroid’ cases indicate that the best that can be done to help them is to make sure that their thyroid function is perfectly equilibrated before they become pregnant (serum TSH below 2.5 mU/L is probably the best target). In my own practice, I tend to titrate them even ‘higher’, to obtain a serum TSH around 1 mU/L. As soon as they become pregnant (spontaneously or medically-assisted), their thyroid function tests need to be monitored extremely closely to make sure that thyroid function remains entirely normal. This can only be achieved by sequential monitoring (every three-four weeks) of serum free T4 and TSH, with rapid (or even anticipated, as I like to do) increments in L-T4 dosage, and a close follow up until 24 weeks gestation, at least.
2) If this Hashimoto patient also has TSH-receptor antibodies (again from my understanding of the data presented), she may well be one of those rare cases with blocking-type TSHR-Abs. In principle, this should not affect the mother other than enhancing the risk of hypothyroidism, but could constitute a risk for fetal thyroid function during the second half of pregnancy (if she ever gets to that point !).
3) She may well be a candidate for IVIG (in addition to L-T4?). This decision is usually taken by our Ob-Gyn colleagues. The rate of pregnancy success with IVIG in the study by E. Vaquero (Amer J Reproductive Immunology in 2000) was improved (54.5%) but less than with l-T4 administration (81.2%). However, that study was not randomized nor controlled and the number of cases in each branch was small (see my Editorial with this article on pages 202-203).
4) I have followed personally a small number of women with the similar difficult medical conditions. Some have undergone medically-assisted procreation, some have even eventually adopted children, and despite these heavy antecedents, we have witnessed a few (but remarkable) successes since some women finally achieved natural conception and successful outcome of pregnancy (after many failed attempts) by treating adequately their Hashimoto’s disease. Thus, there is still hope since the patient is only 32 years of age, but this of course is not to say that success is obtained in all those cases !!
I hope my comments will be helpful to you.
Prof Daniel Glinoer
University of Brussels

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16) https://www.holtorfmed.com/thyroid-miscarriage/
Subclinical Hypothyroidism and Thyroid Antibodies Increase Risk of Early Miscarriage  .  by Holtorf Medical Group

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17) http://www.stopthethyroidmadness.com/2012/11/28/hypothyroidism-pregnancy-dangerous/
Ladies: Hypothyroidism in pregnancy can be dangerous, says this woman who suffered a miscarriage
November 28, 2012  By Janie Bowthorpe
18) Endocrine Society (2012, June 23). Mild thyroid dysfunction in early pregnancy linked to serious complication. Newswise. Retrieved July 3, 2012 from http://www.newswise.com/articles/mild-thyroid-dysfunction-in-early-pregnancy-linked-to-serious-complications
19) Allan, W.C., J.E. Haddow, G.E. Palomaki, J.R. Williams, M.L. Mitchell, R.J. Hermos, J.D. Faix, R.Z. Klein. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen 2000; 7:127-130. Retrieved from http://171.66.127.126/content/7/3/127.full.pdf
20) Rao VR, Lakshmi A, Sadhnani MD. Prevalence of hypothyroidism in recurrent pregnancy loss in first trimester. Indian J Med Sci 2008;62:357-61. Retrieved from http://www.indianjmedsci.org/text.asp?2008/62/9/357/43122

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21) http://drclark.typepad.com/dr_david_clark/2011/11/thyroid-antibodies-and-risk-of-miscarriage-premature-birth.html
Thyroid Antibodies and Risk of Miscarriage, Premature Birth
TriangleThyroidDoctor.com
Dr. David Clark, DC -Center for Low Thyroid Solutions Durham, NC- explains a hidden cause of why many women suffer miscarriages and premature births.

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Jeffrey Dach MD
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