Thyroid Issues? Low Energy Intake Triggers Low T3 / High rT3 Syndrome in Exercising Women >19kcal/kg LBM Avail. Energy Required. Low Carbing Worsens the Impact of ED

It's not your thyroid, but your behavior that's to blame for your low T3 levels, the fatigue and being "unable to lose weight". If you exercised less and ate more, you could fix it without medical intervention or thyroid madness using Lugol's or other junk ;-)

It's something I am facing on a daily basis - on Facebook, in Emails and private messages: Women with self-induced thyroid issue who wonder that their body does everything to conserve lean and fat mass. Women who are working out on a daily basis, dieting like crazy and (in their words) "still not losing weight".

It does not take a thyroid expert to identify the reason for their problems: They are training too much and eating too little. Just like the 27 women in seminal experiment that was conducted at the Ohio University in the early 1990s. A study I am going to elaborate on in today's SuppVersity article, although I personally believe it shouldn't take experimental evidence to convince people (yes, this is true for men, as well) to stop run themselves into the ground.

Low T3 syndrome is also a part of the (Female) Athletes Triad.

Female Athletes' Body Comp Suf- fers From Dieting

Female Athlete's Triad is not ex- clusively female

Female Athlete's Triad - A Vicious Cycle

Female Athlete's Triad - Recovery Part 1/3

Female Athlete's Triad - Recovery Part 2/3

Female Athlete's Triad - Recovery Part 3/3

Said study was conducted by Anne B. Loucks and Edward M. Heath who worked at the Derpartment of Biological Sciences and the College of Osteopathic Medicine at the Ohio University back in 1994. The purpose of their study was to characterize the functional relationship between energy availability and thyroid metabolism to gain insight into the extent of he dietary reform that might be necessary. The scientists expected to find a proportional relationship that would prove the necessity of dietary compensation for exercise energy expenditure to prevent reductions in T3 levels, scientists call "low T3 syndrome".

To this ends, Loucks & Heath recruited 28 healthy, non-obese, nonsmoking women (18-29 years old) with no recent history of dieting or weight loss were recruited from the university and surrounding community. All received a detailed verbal and written description of the study and signed an informed consent document. The participants had to keep a prospective diet records for seven consecutive days a measure that was necessary to determine their baseline energy intake and
Subjects were assigned to four groups in a monotonic experimental design of energy availability treatments.

Figure 1: Overview of the experimental design (Loucks. 1994)

"The experimental manipulation of dietary energy intake, exercise energy expenditure, and, thereby, energy availability (defined as dietary energy intake minus energy expenditure during exercise) is shown in Fig. 1. All four experimental groups expended ~30 kcal kg LBM of energy in daily exercise at 70% of aerobic capacity for four consecutive days beginning on day 2, 3,4, or 5 of the menstrual cycle. All exercise was performed under continuous supervision on treadmill and cycle ergometers in a sequence of 30-min bouts interrupted by lo-min rest periods."  (Loucks. 1994)

During the first exercise bout, heart rate at 70% aerobic capacity was determined by monitoring oxygen uptake. Thereafter, heart rate was monitored continuously by means of a Uniq HeartWatch model 8799 (Computer Instruments, Hemstead, NY) and maintained at the previously measured level by adjusting treadmill speed and slope or cycle work load.

I know you will be asking, but aside from simply eating more there is no way to cure low T3 symptom. In fact the worst thing you can do is to get a script for T4 from your doc, because this will only elevate the inactive thyroid hormone (=break) rT3.

If the heart rate began to drift monotonically, suggesting a thermoregulatory effect, then oxygen uptake was measured directly by gas analysis. Heart rate and Borg scores of per- ceived exertion were recorded at the fourth and fifth minutes of each exercise bout.

Figure 2: Energy intake and expenditure (kcal/lbm) during the study period in all four grous (Loucks. 1999)

As you can see in Figure 2 the amount of available energy ranged from ~10kcal/kg lean body mass (LBM) in the group who had been assigned to the lowest amount of Ensure, a liquid food product that was the only food source the subjects received during the treatment period to ~40kcal/kg lean body mass in the group with the highest intakes.

Table 1: Thyroid hormone concentrations before treatment and changes in concentrations resulting from 4 days of controlled energy availability | Tq, thyroxine; fT4, free T,; T3, triiodothyronine; rT3, reverse T3; ff3, free T3 (Loucks. 1999)

As you can see in Table 1 the thyroid hormone concentration in the two lower groups (10kcal and 19kcal/kg lbm) dropped significantly. With a 10% decrease in free T3 only the changes in the 10.8kcal /kg lbm group were physiologically significant.

Bottom line: In a previous experiment (12), the scientists had been able to show that energy availability, rather than dietary energy intake or exercise energy expenditure separately, is the behavioral factor affecting thyroid regulation in exercising women. It is thus not exactly surprising that 4 days on an energy deficient diet in the study at hand were enough to induce a low T3 syndrome in the female participants of the study at hand.

Figure 3: Mean T3 thyroid hormone levels after 20 days of total fasting, 800kcal diet without carbohydrates and 800kcal diet consisting almost exclusively of carbs (Spaulding. 1976)

In this context it's important to point out that the effect occured only, when the dietary inake fell below 50% of the dietary requirement and that the changes in thyroid hormone levels are restricted to T3 and won't show up on tests that evaluate TSH and T4, only.

In studies of the effects of dietary restriction on thyroid metabolism in sedentary obese patients, T3 levels declined only when dietary energy intake fell below a particular threshold and the carbohydrate con- tent of the diet influenced the location of this threshold. T3 levels fell when energy intake was reduced to 800 kcal/day if carbohydrate content was <200kcal/day. Previous studies also highlight that a reduction of carbohydrate intake, will reduce the amount of free T3 by increasing the conversion of T4 to the inactive thyroid metabolite rT3.

Irrespective of the fact that a high(er) carbohydrate diet can help women maintain normal thyroid function on a diet, studies indicate that there is an energy threshold below the amounts of carbs in the diet become irrelevant and the T3 levels crash as a simple consequence of a lack of energy in the diet (Spaulding. 1976) | Comment on Facebook!

References:

• Loucks, Anne B., and Edward M. Heath. "Induction of low-T~ 3 syndrome in exercising women occurs at a threshold of energy availability." American Journal of Physiology 266 (1994): R817-R817. 
• Spaulding, Stephen W., et al. "Effect of caloric restriction and dietary composition on serum T3 and reverse T3 in man." The Journal of Clinical Endocrinology & Metabolism 42.1 (1976): 197-200.

Overtraining, Undereating & Self-Inflicted Hypothyrodism: Thresholds for Low T3 and High Reverse T3 Levels at 8% & 15% Reduced Energy Intake + Exercise After Only 4 Days!

This is not a "woman thing" only and your T3 levels are not the only thing that's going to "fall flat" if you starve yourself through your workouts! Yep, low libido => low total testosterone => low free testosterone => hypogonadism, that's what we are talking about, guys.

While I did promise to summarize some of the things, I said about creatine kinase, ALT, AST & Co on the last installment of the SuppVersity Science Round-Up on the Super Human Radio Network (I will do that in a future blogpost), today's SuppVersity article will focus on a single and in my experience often misinterpreted and / or overlooked symptom of overtraining that I personally have encountered numerous times in both male and female trainees: Self-induced hypothyrodism, low T3- or the euthyroid sick syndrome are just a couple of names that have been used in the science and laypress to describe this peculiar result of the way trainees deliberately ruin their metabolism by training for hours day in and day out, while following a diet that would hardly nourish a sedentary person, let alone the athlete or fitness model whose physique they are aspiring to achieve.

Pertinent studies are scarce, but they exist

I don't know if the shortage of scientific evidence is a result of the general ignorance of professional athletes, trainers and above all the "average gymrat" that he or she has an organically  healthy thyroid that's just shut off by your body in order not to waste precious muscle and organ weight in a state of constant catabolism.

Despite the scarcity of research, there are two pertinent studies from the Department  of  Biological  Sciences at the College  of  Osteopathic  Medicine of the Ohio  University. Both studies were published in the early 1990s and deal - as you would expect it with female subjects (with no recent history of dieting or weight loss were recruited from the university and surrounding community) who were randomly assigned to a 3x2 experimental design of aerobic exercise and energy availability treatments. The subjects had kept detailed food logs (including weighing and measuring all their foods) before the intervention to have a baseline reading for their energy intake and their heart rates and VO2 max were established during testing seasons before the first workout day.

• 

  Table 1: Detailed information about the participants in the 1993 (Study A) and 1994 (Study B) studies by Loucks et al. (Loucks. 1993 & 1994)

  participants in study A (Loucks. 1993): 51 volunteers 18-29 years of age
• participants in study B (Loucks. 1994): 28 volunteers 18-29 years of age 
• none of the participant was using medication including oral contraceptives, no history of heart, liver, or renal disease, diabetes, menstrual or thyroid disorders, or a history of severe dieting; all had  at least 3 mo of documented menstrual cycles 26-32 days in length and had exercised for only ~60 min per week in the previous 3 months 

Since the basic design of the studies did vary, we are now going to look at the studies separately and in the order in which they've been conducted. This does obviously mean that we'll start with study A the subjects were randomized to groups

• exercising not at all (Z; zero exercise group), 
• expending 1,300kcal/day on low (40% VO2max) intensity exercise (LO)
• expending 1,300kcal/day on high (70% VO2max) intensity exercise (HI)

The exercise was performed under continuous supervision on treadmill and cycle ergometers in 30min and 60min bouts for the high and low intensity groups, respectively.

"So what did happen? Did they drop dead?" Not exactly, no...

Figure 1: Experimental design: dietary energy intake (I), energy expenditure during exercise (E), and net energy availability (A) in the 3 x 2 (exercise X energy availability) experimental design; note: B indicates adequate energy intake, D indicated reduced energy intake (Loucks, 1993)

On the 4 subsequent treatment days the women consumed a liquid clinical dietary product (Ensure, Ross Laboratories, Columbus, OH) was consumed by all subjects as their only food source. The latter contained either

• 30kcal/kg body weight per day (~1,750kcal/day of available energy) in the normal energy group (B) and
• 8kcal/kg body weight per day (~500kcal/day of available energy) in the low energy group (D)

According to the protocol of study A, no effort was made to compensate for the daily energy expenditure and other than the liquid meal replacement Ensure (250 kcal/can, 15% protein, 30% fat, and 55% carbohydrate) the subjects were allowed to consume only plain water.

The blood was sampled for 8 days beginning on the day before the intervention began, in order to track (a) the time course of the development and (b) the persistence of the hormonal changes in the subjects.

Figure 2: Thyroid hormones at the end of the 4-day intervention expressed relative to baseline (Loucks. 1993)

Now, while there were no differences in baseline thyroid status for the participants a brief glance at the data in figure 2 will suffice to see that those were present during and after the intervention. And while the scientists state that ...

"[w]hen dietary energy intake was increased in exact compensation for the energy cost of exercise (LB, HB) [...] even the large volume of exercise performed in this study (similar to running a half marathon each day) had no effect on T3 levels." (Loucks. 1993)

I have my doubts whether "training in the zone" for hours everyday will not shut down the thyroid after 3 weeks and thus 5x the duration of the study. I mean -10% T3 & 5%+ increase in reverse T3 are certainly boding ill (see my comment in figure 2). The data from the two-way ANOVA plotted in figure 3, on the other hand, confirm that the scarcity of energy and thus your bodies' desire to conserve energy is the main factor, here. 

"You're thyroid function is fine - rather high than low!", says the Dr. to the patient

The experiment Loucks et al. conducted does also shows why most patients don't receive adequate counseling (there is no need for treatment) by their doctors and statements like the one above are rather the rule than the exception.

Figure 3: Treatment effects on the changes of total T3 (in nmol/l) in the study particpants of study A (Loucks. 1993)

With normal or low TSH levels (not measured in the study at hand; generally indicating normal or even high thyroid function) and normal or increased T4 levels (this is an exclusive feature of the earlier stages of the overtraining + undereating syndrome) usually being the only additional value you may be able to convince your medical practitioners to measure this appears like an adequate diagnosis. The lowered T3 and even more so the increasing rT3 levels, on the other hand, will go unnoticed by the majority of GPs whose text-book tells them that even a mere TSH test should suffice to determine your thyroid health (in fact that's true, because your thyroid is perfectly healthy).

In a way this is yet better than a Dr. prescribing T4 in these situations. The latter will only be converted to rT3 and can aggrevate the sluggishness and apathy that comes with the low metabolic function due to "low T3 syndrome".

We need more data: Study B (Loucks. 1994)

"How did I let this happen again?", asks Oprah in her own magazine  - the answer is simple, Oprah! Your "diet" programmed the YoYo effect! It happened not after, but right while you were starving... ah, pardon "dieting"! Learn more about the benefits of dieting down slowly.

It goes without saying that the results of study A (Loucks. 1993) of which the scientists themselves point out that it had a "limited purpose" which was to determine (Study B; Loucks. 1994)

1. whether exercise training is capable of altering thyroid metabolism in women, and, if so, 
2. whether this alteration can be wholly explained by the impact of exercise on energy availability, with all other physiological processes occurring during exercise training (i.e., “exercise stress”) having no influence on thyroid metabolism. 

are of low practical relevance, as I would hope that even the most notorious masochists out there won't try to cut on a "8kcal/kg per day" diet... well, I got to qualify this statement, I suppose. In the obese "diets" like that are actually common practice - the "biggest loser" diets often contain 800kcal per day, as does the HCG diet and if you take into account that almost all obese men and a significant amount of obese women weigh more than 100kg, the protocol does no longer seem to be that unrealistic.

Still, I and I would guess, you, as well, will appreciate that Loucks & Heath conducted a follow up study, in the course of which they wanted to elucidate how important the dietary compensation of the exercise induced energy expenditure is, if you want to keep your thyroid hormone metabolism intact. To this ends the subjects were randomly allocated to four groups (ordered from lowest to highest energy intake):

• 10.8kcal/kg LBM available energy -- this is what's left from a baseline intake of 39.5kcal/kg LBM, after the energy expended during the workouts is subtracted from a diet with a caloric deficit of ~23% below the participants' habitual intake
• 19.0kcal/kg LBM available energy -- this is what's left from a baseline intake of 48.6kcal/kg LBM, after the energy expended during the workouts is subtracted from a diet with a caloric deficit of ~6% below the participants' habitual intake
• 25.0kcal/kg LBM available energy -- this is what's left from a baseline intake of 53.4kcal/kg LBM, after the energy expended during the workouts is subtracted from a diet that had an identical energy content as the participant's habitual diets
• 40.4kcal/kg LBM available energy -- this is what's left from a baseline intake of 68.4kcal/kg LBM, after the energy expended during the workouts is subtracted from a diet with a caloric content that was ~32% above the participants' habitual diets (typo in kcal values corrected)
  

All subjects performed the high intensity protocol of the previous study (70% VO2max) and expended 30 kcal kg LBM of energy in daily exercise for four consecutive days beginning on day 2, 3,4, or 5 of the menstrual cycle (this is important, because the energy expenditure during the workouts was obviously not compensated for in the habitual diet). Just as in the previous study the exercise sessions were performed on treadmill or cycle ergomenter, and in 30 min bouts with 10min breaks in between (obviously until the target calorie expenditure was met).

Figure 4: Effects of training at 70% VO2max aiming for a total energy expenditure of 30kcal/kg LBM at different levels of available energy (intake - expenditure in kcal/LBM) on thyroid hormones; values expressed rel. to baseline (Loucks. 1994)

As the literal "blind man" should see, the combination of what most people would not even necessarily call overtraining (after all it's just 4 days and "only" 70% VO2max) reduces the T3 reserves (total T3) to zero and reduce the purportedly active T3 levels by 28% - a reduction that will have a significant impact on how you feel and how your metabolism will function.

Figure 5: The changes in thyroid hormones come "stepwise" with thresholds at 22.5kcal/LBM body weight for FT3 and  ~14kcal/LBM available energy for FT4 and rT3 (Loucks. 1994)

As the text boxes in figure 5 already tell you, we are dealing with a general 2-step mechanism, here, and it it is fully dependent on the extent of the calorie deficit. For a ~8% reduced total energy intake that corresponds to an available energy level of  ~22kcal/LBM, we see "nothing" but a drop in active thyroid hormones FT3, when the energy deficit increases (and I assume when it persists for longer than 4 days), this reduction is no longer enough to minimize the energy expenditure so that your body resorts to what you may term an STRM, a selective thyroid hormone receptor modulator that goes by the telling name reverse T3. Since rT3 is produced from T4 and the other metabolic pathway, the conversion of T4 to T3 is already shutting down, we see an increase in free T4 levels, which will serve as a substrate for the production of rT3 to further slow down the metabolism (in the days/weeks to come TSH will probably go further down so that you will end up with all levels being suppressed and only rT3 high - if anything).

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As you can see, your body is smarter the average starvation dieter thinks he is. So the bottom line is easily formulated: Don't starve yourself if you don't want do feel and look like miserable, hold water, get fat from whatever you eat and end up as a physiological and psychological wrack.

References:

• Loucks AB, Callister R. Induction and prevention of low-T3 syndrome in exercising women. Am J Physiol. 1993 May;264(5 Pt 2):R924-30.
• Loucks AB, Heath EM. Induction of low-T3 syndrome in exercising women occurs at a threshold of energy availability. Am J Physiol. 1994 Mar;266(3 Pt 2):R817-23.

(Mis-)Managing Hypothyroidism: 7% Reduction in Energy Expenditure & Fat Oxidation in Patients on Levothyroxin (T4) Mono Therapy. Plus: Alternative Dessicated Thyroid?

The thyroid is a real diva. You better treat her with utmost care (learn more)

I guess, ... no, I know that a couple of you have to deal with all sorts of thyroid problems. I know you won't like to hear that, but if you read the SuppVersity Athlete's Triad Series you should know that there is more than just the remote possibility, that food and rest would be everything to "heal" your underactive ductless gland (=thyroid). Good indicators are you train everyday, (1) you eat a high protein, low carb, low to at best medium fat diet with a constant caloric deficit, and (b) your TSH level is low to normal, your free T4 level is low to normal but your free T3 level is sub-par. In consequence you will feel sluggish, look sluggish, train sluggish and won't achieve either your fat loss, performance or muscle building goals.

If that's you, there is need for meditation, not medication, for stress management, not pills. In fact, throwing the "inactive" precursor T4, the textbook treatment for hypothyroidism into the equation, could make things even worse, as your body is going to convert the lion's share of it to the metabolic emergency break rT3, to avoid that increasing levels of the active metabolite T3 start gnawing away on your undernourished muscle and exacerbate the chronic stress you are exposing yourself to.

Is being "euthyroid" really the same as having normal TSH levels?

Data from the The Colorado Thyroid Disease Prevalence Study indicates the risk of suboptimal thyroid function & hypothyroidism is more pronounced in women (Canaris. 2000); associations w/ certain contraception meds, pregnancy & menopause in other studies point towards estrogen / progesteron issues as confounding factors.

Interestingly enough, a recent study from Division of Endocrinology and Metabolic Medicine, Policlinico di Monza and the Department of Biomedical Sciences for Health at the Università degli Studi di Milano, both obviously in Italy, did now reveal that it does note necessarily take overtraining + undereating to end up in a 'metabolically and mentally sluggish euthyroid state'. This became evident, when the Italian researchers compared the body composition and resting energy expenditures of 30 hypothyroid women with an average BMI >25 kg/m² and normal serum TSH levels (<3.5 μU/ml; text-book says: "Your patient has optimal thyroid function, doctor!") who had been on the "gold standard" (*rofl*) replacement therapy with L-T4 (levothyroxin = synthyroid; mean dose: 73±34 μg/d) for at least 2 years to the same parameters in a control group with matched age, BMI, menopausal state and life-style habits (P>0.3 for all).

While neither the average TSH levels, which were 1.92±1.06 µU/ml in the T4 and 1.87±0.89 μU/ml in the control group (P=0.91), nor the body composition (body fat: 41.4±7.4 vs 42.1±8.3%; LBM 58.6±7.4 vs 57.8±8.3%; P>0.7 for all) revealed a statistically significant inter-group difference, the resting energy expenditure of the the hypo- / after medication "euthyroid" women on levothyroxin did:

• 

  Click on the image to learn how to calculate (I should rather say estimate) your resting energy expenditure using different scientifically verified formulas and why it is important not to go below a certain threshold (learn more)

  In absolute terms, the women in the T4 group had a -7% lower REE than the controls (1347±171 vs 1447±154 kcal/d; P<0.05).
• The -7% difference remained the same and had an even higher statistical significance (P<0.02 vs. P<0.05), when the resting energy expenditure was expressed relative to the the subjects lean body mass (28.3±2.6 vs 30.5±3.0 kcal/kg LBM die; P<0.02).
• A smaller yet still significant difference was observed when the actual resting energy expenditure was compared to the "supposed" resting energy expenditure calculated by the means of the Harris-Benedict Equation (91±7 vs 95±7%; P<0.05).

The most significant difference (P<0.01) was yet observed, when the scientists analyzed the respiratory quotient (also respiratory exchange rate, short: RER) of their subjects. The latter is a direct measure of the ratio of glucose to fat your body is using a substrate to fulfill its energy requirements, in particular,...

• 

  Suggested read: Maximal Intra- & Post- Workout Fat Oxidation With Pause or 90min LISS Between 2x40min Incremental Exercise Bouts? (read more)

  higher RER levels indicate a greater contribution of glucose, while
• lower RER levels indicate a greater contribution of fats
• A RER of ~1.0 would be observed in healthy individuals, only, when they are engaging in highly glycolytic + brief exercise bouts like sprinting.
• Many "fat burners" work in part by decreasing the RER. When you are in a caloric deficit (and only then) this is an advantage because you will spare glucose and burn fat. 
• Other supplements like creatine, for example,  gear your metabolism towards an increase in glucose expenditure, which can be beneficial in all sorts of activities that rely heavily on short sprints / brief muscle contraction

In fact, the women on T4 (only) had a 11% higher respiratory exchange ratio (0.92±0.07 vs 0.86±0.06; P<0.01), of which even the scientists have to admit that it's clearly suggesting an "impaired fasting lipid oxidation in hypothyroid women" and would thus support "the view that additional interventions may be necessary to fully revert the entire set of hypothyroidism-related metabolic alterations." (Martucci. 2013)

Aren't there better alternatives? T4+T3 or dessicated thyroid?

In a way it is funny - or should I say tragic(?) - that this is the first study in years that bothers with the metabolic and often psychological downsides of T4 only regimen in a way that goes beyond the analysis of TSH levels. After all, the Internet and the waiting rooms of medical practitioners all over the world are full of (mostly female) patients complaining about the non-existent benefits and / or side effects of levothyroxin, only, therapies.

It should be obvious that some of those patients may belong to the initially referred to group of people who suffer from self-induced hypothyrodism in response to undereating and/or overtraining, while others may have confounding, often undetected pathologies that are responsible for their compromised metabolism, their inability to lose weight, their sluggishness, brain fog etc.

Suggested read: "Dietary Thyroid Treatment: Beef, Green Vegetables, Full-Fat Milk & Butter Normalize TSH in Subclinical Hypothyroidism " (read more)

If you do however put the results of the study at hand in perspective with previous studies comparing "T4 only" vs. "T4+T3" treatments and the overall patient-preference of the latter, and combine that with the results of a very recent comparison of levothyroxin vs. natural dissicated thyroid treatment, in the course of which researchers from the Department of Endocrinology at the Walter Reed National Military Medical Center and the University of Health Sciences in Bethesda observed significant weight (I highly suspect fat) loss in the 70 18–65 year-old patients with primary hypothyroidism who had been on a stable dose of T4 for 6 months, when the subjects were given desiccated thyroid extract (DTE) instead of levothyroxin (1 mg DTE ~ 1.667 g L-T4; cf. Hoang. 2013).

Interestingly, the patients had significantly lower rT3 levels, higher total T3 levels, lower otal and free T4 levels and that in the presence of higher, but normal TSH levels (inter-group difference p=0.032) during the DTR part of the 2x16 week cross-over trial. A health hazard, as it is often argued that it would be the result of depressed TSH levels is thus a weak argument against using an alternative treatment strategy, of which I would highly suspect that it could resolve part of the metabolic dysadvantages arising in the context of T4 monotherapy and which was preffered by 34 of the patients in the Hoang study.

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Bottom line: Whether using T4 + T3 or natural dessicated thyroid as the treatment method of choice is necessary or the best strategy for everyone is something that remains to be seen. Something that stands out of question, though, is that the stubborn adherence to the textbook standards, the blind reliance on TSH tests and the ignorance doctors display towards the complaints of their patients is not going to solve an increasingly prevalent problem (+3% increase in congenital hypothyrodism per year in the US, esp. in white and hispanic newborns; cf. Hintnon. 2010)

References

• Canaris GJ, Manowitz NR, Mayor G, Ridgway E. The Colorado Thyroid Disease Prevalence Study. Arch Intern Med. 2000;160(4):526-534.
• Hinton CF, Harris KB, Borgfeld L, Drummond-Borg M, Eaton R, Lorey F, Therrell BL, Wallace J, Pass KA. Trends in incidence rates of congenital hypothyroidism related to select demographic factors: data from the United States, California, Massachusetts, New York, and Texas. Pediatrics. 2010 May;125 Suppl 2:S37-47.
• Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MK. Desiccated Thyroid Extract Compared With Levothyroxine in the Treatment of Hypothyroidism: A Randomized, Double-Blind, Crossover Study. J Clin Endocrinol Metab. 2013 Mar 28.
• Martucci F, Manzoni G, Lattuada G, Perseghin G. Overweight/obese women with primary acquired hypothyroidism in appropriate levothyroxine replacement therapy are characterized by impaired whole body energy metabolism. Endocrine Abstracts (2013) 32 P1004 | DOI:10.1530/endoabs.32.P1004 Share on facebook Share on twitter Share on digg Share on stumbleupon Share on delicious Share on linkedin | Share on email Share on print

Science Round-Up Seconds: Vitamin E Succinate, How It's Extracted from Barley Leaves, Kills Cancer, Ramps up Growth Hormone & Spikes Prolactin. Plus: Testostosterone & Thyroid Hormone Decline Due To Plyometrics & HIIT

Regardless of all the hypocritical hoopla around his persona, Lance Armstrong has always been able to push himself like no one else. No wonder that intense plyometrics were part of his regimen.

If the SuppVersity Science Round Up was a meal, I guess you could say that Carl Lanore and I were sort of gluttonous, yesterday (click here to download the podcast, if you have not already done so). We almost raced from one topic to another and therefore all the good stuff from the list is gone already and I am a bit pressed on time to get some "private life" in, so that I am not psyched about the idea of writing about auxiliary stuff.

Against that background and in view of the fact that I felt that the pace of yesterday's show did not really leave enough room for some important details, I will stick to rehashing and expanding on the stories about Vitamin E succcinate and the detrimental effects of beating the crap out of yourself doing plyometrics or crazy HIIT workouts (too regularly), in today's installment of the SuppVersity Science Round-Up Seconds.

Let's see. Why don't we start at the end of yesterday's show?

• Vitamin E succinate the most potent anti-cancer tocopherol known to man. As you have heard on the show, vitamin E succinate attaches directly to a protein that's preferentially expressed in carcinogenic or pre-carcinogenic cells. It goes by the name α-Tocopherol-associated protein (TAP) and was found to be one of the major α-tocopherol binding proteins in serum, liver, brain and prostate. What has as of yet not been so clear, though, is that the expression of this protein increases with the malignancy of (breast) cancer (Tam. 2012). 
  
  

  

  Figure 1: Effects of alpha tocoperyl succinate alone (TOS), doxorubicin alone (DOX) or both (DOX + TOS) on cell viability in human MB231 breast cancer cells (my edits, original from Tam. 2012) - note: The effect was less pronounced in other cancer cells, so that it is reasonable to assume that the efficacy of the therapy will depend on the exact genotype of the cancer (for those tested in the study it was MB231 > SKBR3 > MCF 10A)

  When alpha tocopherol succinate binds to the protein on the cancer cells, this will either alone, or in combination with chemotherapy trigger apoptosis and cell death. It is as of yet not fully elucidated why vitamin E succinate is highly cancer-specific and leaves the healthy cells intact, but this could be related to the high metabolic rate and exuberant ROS production of cancer cells. There is however some research that would suggest that the cancer cells literally suffocate in their own radical oxygen specimen (ROS), which can no longer be cleared from the cell, due to the alpha-tocopheryl succinate induced displacement of ubiquinone from CII and the subsequent blockade of succinate dehydrogenase (SDH) activity (Dong. 2012).  If this hypothesis holds true it would therefore appear that long-term chronic supplementation with vitamin E succinate cannot be recommended until future studies on its general safety have been undertaken. As an adjuvant to chemotherapy, on the other hand, it could drastically reduce the dosage requirements during chemotherapy in specific types of cancer (see figure 1) and thus minimize side effects.
  
  You see, there is more to it than you can say in two minutes on the radio and this is why I will make sure we don't rush through the items that fast, in the next show. Ah,... of course the dietary source. I had almost forgotten about that one. As mentioned on the show, alpha tocopheryl succinate was originally extracted from Barley leaves. An while this may not be the first paper dealing with this "natural vitamin E analog", the one by Badamchian et al. is probably the one you will be most interested in.
  
  Published in the Journal of Nutritional Biochemistry the paper does not only describe the isolation of vitamin E succinate from green barley leaf extract (BLE)...
  

  "BLE [barley leaf extract] powder (50 mg/mL) was suspended in water and stirred for 1 hr at room temperature. The mixture was then centrifuged at 3000g for 30 minutes using a bench-top centrifuge. The pellet was discarded and the supernatant was pre-filtered through a Millipore DEPTH filter. The filtrate was then filtered through 0.45 I.tM mem- brane and stored at -20 ° C for HPLC or biological assays." (Badamchian. 1999)

  ... it does also shine another spotlight on its potential biological effects, as far as it's ability to increase growth hormone, but (unfortunately?) also prolactin in isolated anterior pituitary cells from female rodents:
  

  

  Figure 2: Prolactin and growth hormone release in anterior pituitary cells of female rodents after incubation with different amounts of green barley extract in which vitamin E succinate had been deterimed as the main ingredient before (based on Badamchian. 1999)

  It's really hard to estimate whether or not one of these effects would translate from a rodent cell in the petri dish to you or me popping a cap with vitamin E succinate everyday. That's particularly true in view of the fact that the underlying mechanism of the increase in GH and the imho more concerning increase in prolactin is neither mediated by increases in intracellular C-AMP, as it would be the case for GRF (old acronym for growth hormone releasing hormone), nor is it induced by the hydrolysis of polyhoshpoinositide, which is the underlying mechanism of the stimulative effect of TRH (thyrotropin releasing hormone). So basically we neither know how it works, nor do we know, whether the oral ingestion of vitamin E-succinate would be sufficient to produce serum concentrations in the pituitary that would be high enough concentrations to make any difference at all (note: the scientists excluded the influence of other components of the extract by testing alpha tocopherol succinate on its own in a separate trial)
  
  Bottom line: Based on roughly one dozen of in-vitro studies there is simply still to little evidence to decide who, outside of people with a history of cancer or someone who is just undergoing chemotherapy would benefit. Therefore, I suggest you wait before you add vitamin E succinate to your list of 'must have' supplements. Is it promising? Sure! Is it exciting, yeah! Is it save for a healthy being to be taken chronically??? I can't tell.
• The detrimental hormonal effects of pushing yourself beyond the tolerable threshold - Hardcore plyometrics and heavy HIIT and their impact on testosterone, cortisol, thyroid hormone and co: I guess you did already get the main message when you listened to the show, but just to give you an idea about the actual quantities, I thought it would be nice to provide you with two graphs as a reference.
  

  

  Figure 3: Comparison of the hormonal responses measured in the plyometrics (left) and the HIIT vs. LISS (right) study (based on Ozen. 2012 and Hackney. 2012)

  If you focus mainly on the differential cortisol responses in the two studies, it would appear likely that we are dealing with two very different forms of 'overtraining' here. While the HIIT protocol (90s at 100-110%, 90s active recovery at 40% matched for workload with steady state jogging at 60-65% of the VO2 max) probably wouldn't be a problem, if the athletes would get adequate rest and nutrition in the days after the session, the 6-weeks of plyometrics (15 session, increasing density, 90-195 reps per session) were enough to send the participants right into the vicious circle of the Athlete's Triad (if you have not done so already, I suggest you read up on that in the eponymous SuppVersity series).
  
  And you know what? Despite, or I should probably rather say due to their compromised hormone levels the guys in the plyometrics study did not lose a single gram of body weight. Good for their muscle, bad for the fat which was likewise preserved by the hormonal shut down, which affected both cortisol and testosterone in a similar way. So is that good or bad news? Well, let me say it this way:. Usually I see people training for a purpose and while the outcome often is stagnation and chronic fatigue, I would suspect that only few of you will have that on their mind, when they are hitting the gym, right?

Apropos viscous circle, and overtraining in order to avoid "overblogging" I will call it a day for today. Come back tomorrow for a couple of wholly new studies from the realms of exercise and nutrition sciences and in case you are planning to drink this evening, I highly suggest you check out the SuppVersity Facebook newspost on the effects of green tea extract on the uptake of alcohol. It may well be that those old fatburner caps of yours can be put to a way better use ;-)

References:

• Badamchian M, Spangelo BL, Bao Y et al. Isolation of a vitamin E analog from green barley leaf extract that stimulates the release of prolactin and growth hormone from rat anterior pituitary cells in vitro. Journal of Nutritional Biochemestry. 1994; 5: 145-150.
• Dong LF, Low P, Dyason JC, Wang XF, Prochazka L, Witting PK, Freeman R, Swettenham E, Valis K, Liu J, Zobalova R, Turanek J, Spitz DR, Domann FE, Scheffler IE, Ralph SJ, Neuzil J. Alpha-tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II. Oncogene. 2008 Jul 17;27(31):4324-35. Epub 2008 Mar 31.
• Hackney AC, Kallman A, Hosick KP, Rubin DA, Battaglini CL. Thyroid hormonal responses to intensive interval versus steady-state endurance exercise sessions. Hormones (Athens). 2012 Jan-Mar;11(1):54-60.
• Ozen, SV. Reproductive hormones and cortisol responses to plyometric training in males. Biol Sport.2012; 29 (3).
• Tam KW, Ho CT, Lee WJ, Tu SH, Huang CS, Chen CS, Lee CH, Wu CH, Ho YS. Alteration of α-tocopherol-associated protein (TAP) expression in human breast epithelial cells during breast cancer development. Food Chemistry. 2012 [ahead of print]