The Female(?) Athlete Triad - Part II/III: LH, GH, IGF1, Insulin, Ghrelin, Leptin & Co Form a Self-Perpetuating Vicious Cycle

I usually rant against pizza and beer, but once the athlete triad has struck, they can be an occasional part of the "healing protocol".

In last Sunday's first installment of this series we have taken a look at the prevalence, etiology and fundamental cause of an entity that is, and I am repeating myself here, profoundly mislabeled as the "female athlete triad". In fact, it is, as we have learned in the last installment, neither an exclusively female thing, nor a triad. If anything, it is a quintet or sextet. To make that clear, and give you guys, who make the same mistakes, but usually with less detrimental consequences, I will once more refer to it as "athlete triad" = AT,  in this second part of the Female(?) Athlete Triad Series in which we will take a look at the endocrine underpinnings of the previously described consequences of the temporary and long-term energy deficiency we have identified as the single most important causative factor of the onset of the "triad" last Sunday.

Which endocrine factors are figuring, here?

Instead of overwhelming you with the details right from the start, I decided to compile a list based on a cross-section of the dozens of articles I have read in the course of my eventually futile quest for a single definitive answer to the question, "Which hormonal or metabolic consequence of restrictive eating and excessive training is to blame for the fatigue, the low sex hormones concentration,the  bone resorption, the anemia, the absence of menses / lack of libido, the performance decreases and the whole string of pathological features, we have explored in the last installment?"

"Refeeding is not an option, because you will only become fat!" FALSE! Yet another myth without substantial scientific foundation that probably arises from the disturbed self-perception of those affected by AT and AN. In fact, the fat stores are the last thing that will be restored (Golden. 2004). This is probably also one of the reasons why "refeeding" often does not appear to work, because the basal energy requirements will increase with every pound of lean tissue you add back to your frame, so that athletes suffering from the "triad" will have to continuously increase their energy consumption. Unfortunately, most athletes will fail to do the former (also because exercise & stress can blunt hunger) and instead react with an increase in workout intensity, now that they are finally able to work out, again. This, in turn, will restore or even exacerbate the energy deficit and thus worsen not improve their physiological problems, even if their scale shows that they have already gained 5-10kg. If you take a look at figure 1 you will also realize that, at least in women, a baseline level of total (not relative!) body fat appears to be necessary to maintain regular menses (in men to maintain normal total testosterone & SHBG, but not so much free testosterone levels or reproductive function).

• low luteinizing levels are unquestionably among the elemental features and causally responsible for the occurance of menstrual disorders / lack of libido and the correspondingly low estrogen and testosterone levels in women and men
• TSH levels are not a valid / reliable indicator for the presence of absence of AT, because they can be both slightly increased or normal in the presence of low T4 and low T3 levels, as  - and this is far more often the case - TSH can be low despite low free thyroid hormone levels (usually in the presence of a low T3/rt3 ratio; if anything this would be a good indicator of beginning or full-blown AT)
• the circadian cortisol rhythm is whacked in men and women, alike; characteristic are the absence of an appropriate cortisol spike in the morning as well as the normal decline in cortisol levels  in the course of the day; metaphorically speaking, as the athletes triad progresses, the "mountain range" turns into mesa and eventually into a plane lowland
• the quartet of (mostly) sub-clinical hypogylcemia, low insulin, extreme high / or totally blunted insulin sensitivity, low IGF-1 and high catecholamine levels cannot be seen in isolation, most detrimental are yet probably the first and last of these four glucose-related players in the AT concert, as the former entails the constant risk to run out of "brain fuel" (in the absence of alternative fuel sources) and can - in the absence of adequate corticosteroid expression - become potentially life-threatening and the latter, i.e. low IGF-1 levels and very low IGF-1 to IGF1 binding protein 4 being one of the, if not the central factor involved in the the long-term physical decline of muscle, bone, organ and even brain mass.

As I have repeatedly emphasized in the last installment, the underlying cause, the trigger, maintaining factor and thus most important setscrew of the athlete triad (female or male) is an over-exaggerated and / or  long-lasting (weeks to months, in the worst case years; see Sundgot-Borgen. 2000) discrepancy between energy intake and expenditure, your body will initially try, but eventually fail to compensate by

• tapping into its energy stores in form of body fat, muscle and organ mass, the insulating fat around nerves and organs, etc.,
• continuously decreasing its metabolic activity (esp. thyroid metabolism),
• shutting down non-vital, but energy-intensive (e.g. immune and reproductive system) bodily functions, to prioritize short term survival of the individual over long-term survival and the conservation of the species

Therefore it is an indispensable and in many cases even sufficient prerequisite to restore an adequate supply of nutrients, and abolish temporarily better reverse the discrepancy between "energy in" and  "energy out" (please read the information in the red box next to the list of the previous paragraph, as well).

And what about leptin, ghrelin, adiponectin ... ?

Figure 1: In female athletes, only total fat mass, not body fat % or BMI are associated w/ AT (here identified by amenorrhea; top, left); the correspondingly low pulsatile (not baseline, see lower left) of LH correlate negatively with ghrelin and positively with leptin (top, right); while LH and leptin show a lack of pulsality, the ghrelin levels are not simply elevated, they also have a higher pulse size, amplitude and total polsatile secretion compared to control and eumenorrhetic athletes (bottom; LH, ghrelin, leptin expressed relative to non-athletic control; based on Ackerman. 2012)

Similar to the facilitative effects of the "hunger high", the "evolutionary advantage" that's turning its ugly face on everyone, who's willing to dig a deep enough whole (see Part I), the endocrine imbalances, as well as the reduced leptin) or over-pronounced (adiponectin) release of adipokines and the disturbances of the glucose, fatty acid and cholesterol metabolism start to take on a life of their own.

And as if that alone would not already make it difficult enough to separate cause and effect, it does actually appear likely that the order may even be reversed over time - not unlike the chicken that will hatch and eventually lay an egg. 

As discussed in the last installment, the combination of over-exercising and fasting, which may at time-point T0 actually have been the root cause of the problem will often turn into a strategy to stave off the impeding total breakdown. It becomes sort of a conditioned response to the constant starvation, which  will then no longer manifest itself in the form of hunger, but as anxiety and an almost compulsive urge to exercise (this is particularly well-established for anorexics; Teufel. 2008). And while the latter can be motivated by the desire to increase athletic performance and/or lose even more body fat, it does have a very real, often under-appreciated, physiological underpinning.

If you like, you could argue that the urge of the starved athlete to exercise is yet another "evolutionary conserved" automatism that mirrors the well-known food-seeking behavior rodents display  in periods of food deprivation and in response to the stimulatory effects of ghrelin on the orexin neurons in the brain (Yamanaka. 2003).

From ghrelin to growth hormone to IGF-1 and back

At the same time, the combination of exercise, low triglyceride, low free fatty acid and exuberant levels of the "hunger hormone" ghrelin leads to an overexpression of growth hormone (Scacci. 2003), subsequent increases in adiponectin (Wölfing. 2008), which will in turn decrease progesterone and androstenedione production and LH receptor expression in ovarian cells (Lagaly. 2008) and GnRH and LH release in the pituitary (Rodriguez-Pacheco. 2007; Lu. 2008). The surprisingly high adiponectin levels (surprisingly in view of the often dangerously low levels of adipokine producing body fat) will further increase the borderline pathological insulin sensitivity and thus lower the already rock bottom blood glucose and basal, as well as (post-)prandial insulin levels even further.

Figure 2: Illustration of the self-perpetuating vicious cycle of the athlete's triad (AT)

With their suppressive effect on leptin (Böni-Schnetzler. 1999), the high growth hormone levels and low body fat reserves are probably the most important contributers to the pathologically low, in fact quasi non-existent basal leptin secretion (see figure 1). And the low insulin levels don't just compromise the normal food-induced prandial suppression of ghrelin (Murdolo. 2003), they also hamper the production of IGF-1 (especially in the liver), so that athletes who suffer from the "triad" cannot derive any anabolic benefits from their high growth hormone levels, since the latter are largely mediated by the stimulatory effect of growth hormone on the production of IGF-1... what you are seeing here is thus a self-perpetuating vicious circle, you can extricate yourself from only by a multi-faceted approach the pillars of which are an..

* in view of the insulinogenic effects of whey and the pro-IGF-1 effects of casein (Hoppe. 2009), and the anti-catabolic effects of CLA & omega-3 you should - if by any means possible - incorporate dairy products from preferably grass fed dairy (butter, milk, cheese, yoghurt, quark / curd cheese, fermented dairy and if you want protein powders) in your diet regularly, better daily.

1. adequate and continuous energy supply to control ghrelin levels and help stabilize blood sugar (and thus glucocorticoid) levels and restore normal leptin and adiponectin expression,
2. increased low GI (to avoid reactive hypoglycemia) carbohydrate and protein intakes to normalize glucose levels, suppress ghrelin, increase insulin and IGF-1 levels* (Foster-Schubert. 2008; suggested read: "Carbohydrate Shortage in Paleo Land"),
3. balanced intakes of all types of natural fats, with an emphasis on long-chain PUFAs from food including a reasonable amount of "bad" omega-6 fatty acids and w/out fish oil or other omega-3 supplements, which would further blunt the already compromised glucocorticoid response and the leptin secretion (Kratz. 2002; suggested read "Omega-3 and Low Cortisol"), and
4. profound reductions in training volume to lower GH, cortisol, catecholamin and energy requirements and a (temporary) reorientation towards low volume strength training that will help increase bone density and IGF-1 expression (Davee. 1990)

Now, this may sound hilarious, but for the time being, laziness, pizza and beer - in moderation - are actually your friends. In that, I am not suggesting that you have to copy the patient, Chris Kresser mentioned several times on the old "Healthy Skeptic" podcasts (now RHR) about a client, who "cured" his longstanding physiological, and as I suspect psychological problems with pizza and beer, but the third pillar of this guy's regimen is actually a must: Go out with friends and start to enjoy your life again! Without thinking about food and exercise and sticking to whatever form of restrictive "diet" all the time.

Figure 3: Development of BMI (blue), leptin (red), adiponectin (green) levels in 8 female adolescent malnourished AN patients (based on Modan-Moses. 2007)

Apropos, third pillar. I have already had my short intense workout for the day, I have eaten well, but I have not hung out with friends. In other words, I will postpone the in-depth discussion of the energy and nutrient requirements, useful and detrimental supplements and medications, as well as necessary and facilitative tweaks to your workout routine to the next week, add another Roman "I" to the second "II" in "Part II/II" in the preliminary headline of this post and leave you (hopefully not too frustrated) with the graphical illustration of the effects re-feeding, alone, and a normalization of the body weight from a BMI of 16kg/m² to ~19kg/m² can have on the skewed basal leptin and adiponectin in figure 3.

In view of the fact that other studies have shown that this increase in weight, which must not be confused with a mere increase in adiposity, i.e. body fat percentage (go back to figure 1 if you already forgot that the absolute not the relative fat mass counts and please remember that the latter includes the fat in the myelin sheaths of your nerves, the protective fat around the organs, the fat in your brain etc.), does help with the normalization of both insulin and ghrelin (Otto. 2001), growth hormone and IGF-1 (Argente. 1997) and is in some cases even sufficient to restore most of the endocrine abnormalities (Scheid. 2010), many of the lessons we will learn in the next (and according to my current plans last ;-) installment can also be applied to a lean bulk - and that goes irrespective of your gender and your whether or not you have already fallen victim to the athlete triad!

References

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Intermittent Thoughts on Intermittent Fasting - The Fast #1: Metabolic and Endocrine Response(s) During the Fast.

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Hypothyroid, Cold, Tired & Depressed? Try Replacing 50µg of T4 With 12.5µg of T3 - Study Shows, 65% of Patients Would not Want to Go Back to Synthyroid (T4), Only!

Image 1: Are you taking copious amounts of synthyroid (levothyroxin, T4), already, and feel as if your hypothyroidism became rather worse than better? Does Your Dr tell you that your TSH is fine and you should just exercise more and eat less to stop gaining weight like mad? Than this post is for you!

The issue of optimal thyroid medication resurfaced as of late on the SuppVersity facebook wall, when I posted the link to a recently conducted retrospect study in patients who had undergone total thyroidectomy and were now receiving postoperative levothyroxin only hormone therapy by Ito et al. Not to my personal, but obviously to the researchers surprise, the textbook prescription of the "metabolically inactive"  T4 (essentially that is as almost 90% of "general knowledge about thyroid hormone metabolism incorrect as T4 can very well interact with thyroid receptors, it is though TR-alpha specific and has little metabolically activating effects, cf.  Koury. 2009) did not suffice to restore the circulating levels of the active thyroid hormone T3 to the preoperative levels (Ito. 2012). Only when so much T4 was administered that the thyroid stimulating hormone (TSH, also known as thyrotropin) were "suppressed" (as per textbook definition) the circulating T3 levels got back within the physiological normal range.

"Nurse, send the patient home and show me his lab report!"

The real-life consequences of treating lab values instead of patients and going by textbook prescriptions instead of the often debilitating symptoms of hypothyroidism which range from

• physical problems such as weight gain, constipation, constant cold, feeling of cold, blurred vision, nausea, sleepiness, low blood pressure, high cholesterol and blood glucose levels, etc. to
• psychological issues such as general cognitive decline, inability to concentrate, mental fatigue, anger, confusion and depression

and often become rather worse than better, when patients who still have their thyroid gland are going on "partial replacement" or start taking a "supportive" dose of synthyroid (levothyroxin, T4) to help a sluggish thyroid along.

Image 2: Ladies, you are lucky you got all that subcutaneous fat to absorb those lubricants and PCB laden cosmetics you are using and stash it away ... a pity it's all going to haunt you, when you want to get rid of those fatty, unaesthetic dumping grounds.

Weight loss and thyroid function: Beyond overdieting and undereating While those two, i.e. training like mad and eating like too little or only protein are unquestionably the main culprits, when it comes to diet-induced thyroid malfunction (in this cases thyroid medication is by the way counter-indicated; T4 would not work, T3 would simply burn away even more muscle mass), there is another interesting phenomenon you maybe have not heard about: Self-intoxication! Well, at least this is how I would call the sudden drop of thyroid function that is only one of the nasty effects the release of organochlorines, which have accumulated in the fat tissue of the dieters over years and are now liberated within months, in morbidly obese patients on "zero calorie" diets often weeks, has on the whole endocrine system of formerly big losers (Pelletier. 2002; Tremblay. 2004; Hue. 2006). Pelletier et al. for example found statistically significant negative correlations between the circulating levels of active thyroid hormone T3 and the amount of ...

• hexachlorobenzene (HCB), which was used as a pesticide until 1965 and was also used in the production of rubber, aluminum, and dyes and in wood preservation and is currently formed as a byproduct during the manufacture of other chemicals, mainly solvents and pesticides, and 
• PCB 156, one of the members of the olychlorinated biphenyl (PCB) family of chemicals that has now been banned from industrial insulators and lubricants, because of substantial evidence of its carcinogenic and neurotoxic effects.

... And you bet that this is only the tip of an iceberg. After all, fat is not just a storage site for useful energy, it is also the dumping ground for everything fat soluble you better lock away so that it cannot harm important organs; now, when you think about that, it stands to reason why the fat of animals that have been fed corn or whatever else that's been exposed to one or another of these compounds probably actually is, as common "wisdom" says, associated with an increased cancer risk and all sorts of other ailments.

What most doctors either don't know or simply ignore is the fact that the thyroid produces T3 and T4 at a very specific natural ratio of about 100/6 (I deliberately did not cancel the fraction, and wrote 50/3, instead, because 100/6 is the thyroid's daily production of T4/T3 in mcg, the rest of the approximately 20mcg of T3 come from local deiodinase processes at in other organs). Now, if we simply add say 50µg of T4, the corresponding decline in TSH will reduce the overall thyroid hormone output from the gland; and though the exact degree of "suppression" will depend on absorption kinetics, inter-individual differences, the presence / absence of inflammation and the specific activity of deiodinase enzymes which convert T4 to either T3 or reverse T3 (rT3) in the peripheral organs (esp. the liver and the kidneys), we will at this point simply assume that corresponding to the daily T4 output of 100µg the 50µg dose will suppress the total (T4+T3) output of thyroid hormones by ~50%:

Figure 1: Illustrative "calculation" of the effects of partial thyroid hormone replacement with 50mcg T4 only.

As my example calculation in figure 1 shows, this would equal a reduction of roughly -10% in terms of thyroid hormone activity and that despite the fact that the textbook will tell you that it would not make a difference. That I write "roughly" and not "definitively" is yet quite important, here, as there are too many confounding factors, such as the...

• possible increase in conversion of T4 to rT3 and thus "anti-thyroid" activity; the latter is especially prominent in insulin resistant individuals (Ruhla. 2011) and those receiving high doses of T4 (Clur. 1986)
  Note: this renders the recommendation to simply up the doses of T4 to levels with partially suppressed TSH levels Ito et al. make in the initially cited study pretty much nonsensical
• lack of enzymatic conversion at the level of the target tissue and consequently even lower thyroid activity; something that is often seen in patients who have a "sluggish thyroid metabolism" anyways and receive only a partial substitution

... which will eventually determine both, the hormone production, as well as its metabolic effects to make any clearcut statement. Unfortunately, the same is true, but rarely appreciated for the success of the standard (T4 only) treatment for hypothyroidism, the efficiacy of which will likewise vary from person to person and is even highly susceptible to fluctuations and changes in body weight, inflammation, macro- and micronutrient content of the diet etc.

Against this background, it stands to reason that the argument "but it works for most of my clients" you will often hear from your Dr. is of little significance for you as an individual and even a statement like "but didn't you feel better, when we initiated the treatment 2 months ago" could not just be missing the boat, altogether, but brings another commonly overlooked problem to mind: If you have been suffering from symptoms of hypothyroidism for a couple of years, you would probably feel "major improvements" if you went from a "1" as in "very bad" to a "3" as in "bad", without knowing that you may, just as the majority of the subjects in a study that's been published in The New England Journal of Medicine in 1999, feel even better if you received 12.5mcg of T3 instead of 50mcg of the T4 your Dr. has prescribed.

T4 + T3 therapy makes subjects feel better, 20/32 don't want to go back on monotherapy

The 31 hypothyroid patients who took part in the 10-week study during which the participants received in random order either their regular "T4 only" thyroid medication (e.g. 200mcg of T4) or an identically looking combination preparation in which 50mcg of the original T4 dosage had been replaced with 12.5mcg of T3 (e.g. 150mcg T4 + 12.5mcg T3). The patients, 31 women and 2 men with a mean age of 46 years and either autoimmune thyroiditis or thyroid cancer that was treated with baseline doses of 75±53 µg T4 per day  (range 100-300 µg), were closely monitored during the both of the 5-week interventions and biochemical, physiologic, and psychological tests were performed at the end of each treatment period.

Figure 2: Cognitive performance and psychological well-being of the 32 subjects of the Bunevicius study assessed by standardized tests on either regular T4 only or T4 and T3 combination protocols (based on Bunevicius. 1999)

A cursory glance at the subjects' "objectively" measured cognitive performance (figure 2, left) and pyschological well-being (figure 2, right) does already reveal that there were statistically improvements in a host of parameters that are of unquestionably greater importance to your daily life than an "optimal" level of thyroid stimulating hormone.

Figure 3: Mood and physical symptoms in the 32 subjects of the Bunevicius study assessed by straight forward questionnaires with visual analogue scales - this is the "how do yo actually feel" data (based on Bunevicius. 1999)

If you combine that with the information the patients provided on a visual analogue scale questionnaire on their perceived psychological and physiological well-being, where every single test result spoke in favor of the combination therapy(!), it is thus not very surprising that

[w]hen asked at the end of the study whether they preferred the first or second treatment, 20 patients preferred thyroxine plus triiodothyronine, 11 had no preference, and 2 preferred thyroxine alone (P=0.001).

These results were unrelated to the order of treatment and the two patients who preferred the T4 only treatment had probably ended up slightly hyperthyroid as they were complaining of feeling "slightly nervous during combined treatment" (Bunevicius. 1999). The others however emphasized that they "noticed that they were more energetic, had better concentration, and simply felt better" (ibid.) than on T4 alone.

The Bunevicius study in nuce

Protocol Reduce T4 intake by 4mcg per 1mcg of T3 you introduce; optimally reduce T4 intake by 50mcg and att 12.5mcg of T3 in.

Results Thyroid hormone levels staid in range (see table above), the +3beat/min increase in pulse rate is harmless and the non-significant drop of 6 and 2pts in systolic and diastolic blood pressure is nothing to speak of.

	T4	T4+T3
TSH (µU/ml)	0.8	0.5
TSH = 0*	7	5
T4 (µg/dl)	15.2	11.3
T3 (ng/dl)	87	117

Table 1: Serum levels of selected hormones and *# of patients with serum TSH <0.05µU/ml

Side Effects Two subjects felt slightly agitated on T4 + T3, no other side effect were reported

Useful for people who are taking high (>>50mcg) doses of T4 (only under supervision of your Dr!)

Not useful for people who don't need thyroid medication and simply suffer from low thyroid hormone due to overtraining, undereating or both (see links below).

Suggested reads

• (Over-)Motivational Orthorexia,
• Overtraining, Inflammation,
• Dietary Thyroid Treatment
• more on overtraining
• more on thyroid

Implications: Especially the usually overlooked effects on mood, cognitive function and "subjective" well-being, or rather the negative effects T4 only treatment has on these parameters, do speak in favor of putting the unwarranted prejudice against the "myotoxic" (=heart damaging) T3 overboard. We are, after all, not talking about the induction of full-blown hyperthyroidism, the detrimental effects of which on the hearts of rodents are essentially what brought the myth of the "dangerous T3" to live; we are just talking about doing our best to emulate the natural balance, which is not adequately and reliably measurable by taking the thyroid stimulating hormone (TSH) levels in the blood of a patient as your only reference.

Moreover, the notion of "just throwing in T4 and waiting for the target tissue to produce as much T3 from it as needed" is intrinsically flawed as it negates the established exogenous T3 requirements of the mammalian brain (~20% of the T3; cf. Silva. 1984), as well as the local downregulation of the T4 => T3 conversion in the brain upon exposure to elevated serum thyroxine (T4) levels (Silva. 1985), as they will occur whenever you simply "up the dosage" of levothyroxine in the false belief that this would help you to get rid of persistent symptoms of hypothyroidism. Against that background it appears to be rather the exception than the norm that you would be optimally functioning on T4 only and not end up

1. still systemically hypothyroid with even lower serum T3 levels (or T3-to-rT3 ratios), than before, or
2. now centrally (in the brain) hypothyroid despite "normal" or even suppressed TSH levels and adequate or high circulating thyroid hormone levels

Against that background, the researchers conclusion that the "ideal replacement regimen [especially] when thyroid-gland function is absent or nearly absent might consist of 10 µg of triiodothyronine daily in sustained-release form (because the hormone is rapidly absorbed and metabolized), along with enough thyroxine to ensure euthyroidism" (Bunevicius. 1999) does appear reasonable, although the necessity and value of "sustained" release formulas is certainly debatable, esp. for lower doses of T3.

References:

• Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999 Feb 11;340(6):424-9.
• Clur A. Reverse tri-iodothyronine as part of alpha 2 adrenergic receptors. Med Hypotheses. 1986 Nov;21(3):281-92.
• Hue O, Marcotte J, Berrigan F, Simoneau M, Doré J, Marceau P, Marceau S, Tremblay A, Teasdale N. Increased plasma levels of toxic pollutants accompanying weight loss induced by hypocaloric diet or by bariatric surgery. Obes Surg. 2006 Sep;16(9):1145-54. 
• Ito M, Miyauchi A, Morita S, Kudo T, Nishihara E, Kihara M, Takamura Y, Ito Y, Kobayashi K, Miya A, Kubota S, Amino N. TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy. Eur J Endocrinol. 2012 Jun 18.
• Koury EJ, Pawlyk AC, Berrodin TJ, Smolenski CL, Nagpal S, Deecher DC. Characterization of ligands for thyroid receptor subtypes and their interactions with co-regulators. Steroids. 2009 Feb;74(2):270-6. 
• Ruhla S, Arafat AM, Weickert MO, Osterhoff M, Isken F, Spranger J, Schöfl C, Pfeiffer AF, Möhlig M. T3/rT3-ratio is associated with insulin resistance independent of TSH. Horm Metab Res. 2011 Feb;43(2):130-4. 
• Silva JE, Matthews PS. Production rates and turnover of triiodothyronine in rat-developing cerebral cortex and cerebellum: responses to hypothyroidism. J Clin Invest 1984;74:1035-49.
• Silva JE, Leonard JL. Regulation of rat cerebrocortical and adenohypophyseal type II 5'-deiodinase by thyroxine, triiodothyronine, and reverse triiodothyronine. Endocrinology 1985;116:1627-35.
• Tremblay A, Pelletier C, Doucet E, Imbeault P. Thermogenesis and weight loss in obese individuals: a primary association with organochlorine pollution. Int J Obes Relat Metab Disord. 2004 Jul;28(7):936-9.

Thyrotoxins: Soy, Hormonal Contraceptives, Gut Bacteria or Simply Inflammation - Ladies (and Gents), You've Got the Choice, Hypothyroidism Lies Just Beyond the Corner.

Image 1: Thyroid for energy para-
thyroid for bone metabolism.

I don't know about you, but sometimes I get the feeling I am not doing enough for the female readers of this blog. And, while even this blogpost is not exclusively addressed to the ladies, the majority of hypothyroid patients are women. Part of the explanation for this phenomenon can be found in the title of this blogpost, already. Both, soy, as well as hormonal contraceptives are "ladylike", these days. Accordingly, overcolonization of Bifidobacterium and Lactobacillus, or inflammation is all that remains for "real men" (who obviously do not take synthetic gestagens and probably refrain from consuming soy products) to catch up on their female fellow sufferers. But before I totally confuse you, let's take a look at the most recent scientific results.

Still ahead of print is a paper by Claudia Lorenz and colleagues (Lorenz. 2011) in which the scientists report on the effects the synthetic gestagen levonorgestrel (LNG), which is "a widely used component of several hormonal contraceptives, such as the birth control pill, progestogen only pill or the emergency contraceptive pill" has on thyroid function of tadpoles (X. laevis). While this obviously is no adequate model for the human endocrine system, their finding that despite lack of histopathological changes in the thyroid glands, the aquatic organisms developed full blown hypothyroidism, which was presumably mediated via a large increases in prolactin and consequent interference with the thyroid system, would warrant further investigations in mammals and humans to exclude the possibly hitherto overlooked, histopathologically nondescript side effects of widely prescribed hormonal contraceptives, which is something the scientists from the German Institute of Freshwater Ecology and Inland Fisheries were obviously less interested in.

Figure 1: Isoflavone content in mg per 100g of various commercially available soy foods
(data calculated on the basis of soyfoods.com)

Much sturdier are the results a research group from India present in a paper published in the June issue of the Indian Journal of Medical Research (Mittal. 2011). The scientists  conducted a  randomized, double blind, placebo-controlled trial on 43 oophorectomised women [women who had their ovaries removed] to evaluate the effect of soy isoflavones (75 mg/day for 12 wk) on serum thyroid profile (free T3, free T4, TSH, TBG and anti–TPO antibody titres) at baseline, 6 and 12 wk after randomization.

Notice: You get the same overall amount of isoflavones that was administered to the women in this study from roughly 40g of mature soybeans, uncooked roasted soybeans or soy flour. Alternatively you can also drink 850ml soy "milk" or have a protein shake with 40g soy isolate (cf. figure 1).

The desired decrease in menopausal symptoms aside [induced by the estrogenic activity of the isoflavones], Mittal et al. found a 7% decrease in serum free T3 levels from 4.0 to 3.76pmol/l after 12 weeks and a 75% increase in TSH [thyroid stimulating hormone] the scientists obviously preferred to VERSCHWEIGEN in their abstract, in order to draw the ridiculously skewed conclusion that the

modest reduction in serum free T3 levels in the isoflavone group in the absence of any effect on other thyroid parameters might be considered clinically unimportant

If the data in table III of the studies (cf. figure 2) is not simply false, the above statement is at least premature. What's more is that the huge standard deviations (+/-3.01uIU/ml) of the TSH values after 12 weeks of treatment suggest that thyroid function may actually have compromised in some subjects, but in these cases even more severely. Allegedly, the "normal range of TSH is 0.5-5.5 micro IU/ml" and TSH increased in control, as well (cf. figure 2), but both the onset of the effect and the small dosage of isoflavones that has been used in this study would warrant further investigations into the effects of longer duration and/or higher dosages of isoflavone supplementation.

Figure 2: Serum value of Free T4, free T3 and TSH in control and soy treated women after 12 weeks.
(data adapted from Mittal. 2011)

In view of the positive reputation of soy products as being "cholesterol free", "low in fat" and "especially healthy for women", it cannot be excluded that a group of presumable female customers eats several of the products from figure 1 everyday and would thus potentially be exposed more than twice the amount of isoflavones used in the study for years. A continuous decline in the responsiveness of the thyroid to thyroid stimulating hormone (TSH), of which the decline in T3 despite rising TSH values is indicative, could easily make thyroid patients out of health-conscious costumers.

Contraceptives and soy, are yet by far not the most reliable tools to mess up your thyroid. Data from a  recent paper by Kiseleva et al. (Kiseleva. 2011)

are arguments in favour of the assumption of the possible role of PM [probiotic microorganisms] of the genera Bifidobacterium and Lactobacillus in triggering ATD [autoimmune thyroid disease] by the mechanism of molecular mimicry.

Or in other words, because the anti-bodies that attach to those two microorganisms are structurally almost identical to thyroid anti-bodies, it is possible, if not likely, that what was meant by our body as a means to ward off intestinal bacteria ends up attacking our thyroid, because the anti-bodies cannot distinguish one from another. The scientists do yet emphasize that

The data obtained in silico and in vitro should be proven by use of animal models and clinical studies for extrapolations to the whole body. Possible antigenic properties of components/proteins of bifidobacteria and lactobacilli, selectively binding anti-TPO and anti-Tg should be taken into consideration.

They also point out that current diagnostics using ELISA may even mistake "normal" bacterial antibodies for thyroid antibodies due to cross reactions which "can lead to unspecific false positive results and, hence, to an incorrect diagnosis."

Figure 1:  Drugs influencing thyroid economy
towards hyper (left) and hypothyroidism (right)
(adapted from Economidou. 2011)

The last thyroid related paper (Economidou. 2011) for today comes from Foteini Economidou, MD, PhD at the Department of Intensive Care Medicine of the University of Athens and his colleagues, whose review on Thyroid Function During Critical Illness may be of greater importance to many "hypothyroid" patients out there, than you would think. Reduced thyroid function is a protective mechanism the human body employs, when it is severely energy restricted or inflamed. Reduced TSH levels despite normal to low T4 and often low levels of T3, which are accompanied by increases in the purportedly unactive thyroid metabolite rT3, are clear signs of what is also called the euthyroid sick syndrome [euthyroid = healthy thyroid], where decreases in thyroid functions are only secondary to other health conditions (i.e. hypothyrodism is a symptom not a cause of your ailments) including constant dieting and (hidden) inflammation. You should keep that in mind, when even high doses of levothyroxin (T4) tablets won't solve your "pseudo-hypothyrodism". Chances are, the whole package would not produce any noticeable effects, because your body regulated the deiodinase enzymes, so that the inactive T4 will never be broken down to T3 or - if it is - the latter will immediately be "deactivated" into rT3. As Economidou et al. point out:

Only a few studies have examined the use of supplemental thyroid hormone therapy in critically ill [if you are chronically starved or inflamed you may consider yourself critically ill] general medical patients. Brent and Hershman examined the effect of thyroid hormone therapy in medical intensive care unit patients. The patients included in the study had serum T4 levels <5 µg/122 with no evidence of intrinsic thyroid dysfunction and were given either T4 or placebo intravenously [notice due to the low absorption of oral T3, the doses were obviously much lower than those you or your hypothyroid friend are taking] on a daily basis. There was no significant difference in mortality [take that as "no difference in how you will feel" in case of the euthyroid sick syndrome] between the two groups and the T4 replacement was detrimental to the restoration of normal pituitary-thyroid regulation.

This leads the scientists to conclude that ...

"levothyroxine therapy applied for the management of the euthyroid sick syndrome is not expected to have any effect because of the pronounced inhibition of conversion of T4 to T3 in these patients" (Economidou. 2011)

Bottom line, don't fix the symptoms (low thyroid) by popping T4 like candy (you know it doesn't help you), but try to find the original cause of disease, which -contraceptives, soy, gut bacteria and inflammation and overdieting aside (by the way, is it just me or do you also feel like you knew a young lady where all these come together) - could also be one of the drugs I listed in figure 3.

Iodine Induced Reduction in Hepatic Deiodinase Activity Leads to Hypothyrodism and the Accumulation of Liver Fat That May Eventually Pave the Way to Diabesity

While us Westerners think of goitre mostly as a result of iodine deficiency, the Chinese have learned by hard that the opposite is about as likely - goitre in response to iodine in the drinking water is a huge health problem in certain parts of the country (Zheng. 2000)

As colorful as the web may have become, it is still full of paradigmatic black-and-white thinking: The world is either black or white and if you browse the blogosphere, it would appear that iodine would certainly belong to the white part of our world. That in exactly those people who are often referred to as an example of the multitude of beneficial health effects, namely the Japanese, a high intake of iodine has repeatedly been shown to be associated with low thyroid function and even full-blown hypothyroidism, on the other hand, is something you will probably not learn from the tons of unreferenced stuff you'll find on the Internet about how good, if not essential it was for your health to take copious amounts of iodine everyday (about the same amount you would take if the nuclear powerplant next to you exploded to saturate and shut down your thyroid and prevent it from taking up the radioactive iodine).

The Ying and Yang of high and low iodine intake

A recently published rodent study from the Huazhong University of Science and Technology, the Binzhou Medical University and the Shen Zhen Center for Chronic Disease Control, in China (Xia. 2013) does now shed some light onto the underlying mechanisms of the well-known thyroid disrupting effects of the structural backbone of all mammalian thyroid hormones, iodine. While the whole spectrum of disorders of iodine excess includes hypothyroidism, hyperthyroidism, autoimmune thyroiditis,embryo toxicity, and depression of brain development (Guo. 2006; Rose. 2001; Roti. 2001; Yang. 2006) Yun Xia et al. are probably the first to investigate its hazardous effects of iodine excess on the liver.

To this end, the Chinese researchers supplemented rats on a standard diet containing a baseline level of 365μg/kg iodine with different doses of iodine in the form of potassium iodate (KIO3) in the drinking water for 3 months:

"In 2000, the Chinese Nutrition Society stated that the recommended nutrient intake (RNI) of iodine of adults is 150μg/day and the tolerable upper intake level (UL) is 1,000μg/day.
Conversely, intake of iodine at about sixfold of its RNI may induce injury. In addition, many excess iodine animal experimental data indicate that ten times the normal iodine intake in mice for about 3 months can cause damage. Moreover,the results of our previous experiment show that drinking 1.2 mg I/L iodine water for 1 month had no significant effect on serum lipid metabolism, while prolonged exposure for 3 months induced an increase of serum cholesterol." (Xia. 2013)

According to these results, the mice in the study were randomized to receiver either 0, 0.3, 0.6, 1.2, 2.4, and 4.8 mg I/L iodine, corresponding to 0-, 1-, 2-, 4-, 8-, and 16-fold of the adequate/normal iodine intake for 3 months to explore the dose-dependent effect of iodine on hepatic steatosis. In the course of the trial, dood consumption, water consumption of each group, were recorded meticulously and the weight gain of each mouse was recorded daily.

Additionally, another 60 weaning female Balb/c mice were randomly assigned to six groups and given iodine at different levels (0, 0.3, 0.6, 1.2, 2.4, and 4.8 mg I/ml) for 1 month just for
measuring the oxidative stress parameters in serum and liver.

Figure 1: Triglyceride content in liver and serum, as well as SREBP-1c and fatty acid syntethase (FAS) activity after 3 months on diets with additional iodine (Xia. 2013)

While neither food intake, nor water consumption or weight gain differed significantly between the groups (data not shown), a brief glance at the data in figure 1 should suffice to see that there was a dose-dependent increase in hepatic triglyceride levels (=fatty liver disease) that was accompanied by corresponding increases in serum triglyceride, when the liver was clogged up to the max - as it appears to be the case with 8x or 16x higher than normal levels in the diet (for humans that would thus be ~1.6g or 3.2g of potassium iodiate).

Figure 2: Total antioxidant capacity, glutathione peroxidase, SOD, and lipid peroxidation (MDA) after 1 and 3 months expressed relative to untreated control (Xia. 2013)

The fatty acid accumulation in the liver was accompanied by profound changes in total antioxidant and SOD and glutathione status, as well as significant increases in lipid oxidation (as indicated by the +61% and +85% increase in MDA in the groups with the highest intake of supplemental iodine). Contrary to the commonly propagated myth that tons of supplemental iodine would increase the thyroid function these changes were accompanied by profound decreases in D1 deiodinase activity and correspondingly decreased conversion of T4 to T3 (see figure 3).

Figure 3: Changes in thyroid hormone and deiodinase levels; expressed. rel. to control (Xia. 2013)

It should thus not surprise you, that the levels of TSH and T4 in the rodents increased, while those of T3 decreased (no conversion = hypothyroism, no matter how much T4 you got floating around).

Low D1 => Low T3 => fatty liver disease

In fact, the reduced local conversion of T4 to T3, is also behind the accumulation of triglycerides in the liver and blood of the animals, as the

"[r]educed plasma T3 level resulted in the upregulation of SREBP-1c mRNA and FAS mRNA that ultimately led to the accumulation of triglycerides in the liver. [...] Evident hepatic steatosis was observed in mice challenged with 2.4 and 4.8 mg I/L iodine in drinking water. " (Xia. 2013)

As a SuppVersity student you know about the downstream effects, but I guess it makes sense to reiterate them for the newbies: Since the liver plays a, if not the pivotal role in systemic lipid homeostasis the reduced oxidation of triglycerides and the increased storage will sooner or later lead to an increased secretion of triglyceride-rich lipoprotein (VLDL) as a compensatory response by which the liver will desperately try to spread the lipid burdon to other organs and tissues. Overwhelmed with the sudden onslaught of triglyceride laden VLDL particles which are easily oxidized during their voyage through your blood stream, this opens the door to a narrowing of the arteries, cardiovascular disease and stroke.

---

For the majority of you, overtraining and undereating is probably a much greater threat, when it comes to hypothyrodism (learn more about "self-inflicted hypothyrodism"). However, contrary to excess iodine intake that will not clog up your liver and arteries and eventually cause heart disease and stroke.

Bottom line: If we assume based on the available epidemiological data that the general mechanism was identical in human beings, the ingestion of large amounts of iodine which are often touted as a remedy to all sorts of metabolic syndroms may in fact exert the exact opposite effects.

Yet, although I would be cautious about extrapolating the exact cut-off levels, it appears that dietary intakes in the 800µg range and thus 4-6x more than the RDA can still be considered relatively save. So if you are neither taking high dose supplements or living on tons of seaweed, this is probably not much of a concern for most of you. In addition it would warrant investigation if / to which extent the addition of extra selenium would ameliorate these effects. After all, the latter has been shown to have protective effects against iodine intoxication in the very same rodent model in a 2006 study by Xu et al. (Xu. 2006).

References:

• Guo H, Yang X et al. Effect of selenium on thyroid hormone metabolism in filial cerebrum of mice with excessive iodine exposure. Biol Trace Elem Res. 2006; 113:281–295. 
• Rose NR, Bonita R et al. Iodine: an environmental trigger of thyroiditis. Autoimmun Rev. 2002;  1:97–103.
• Roti E, Uberti ED. Iodine excess and hyperthyroidism. Thyroid. 2001;11:493–500.
• Xia Y, Qu W, Zhao LN, Han H, Yang XF, Sun XF, Hao LP, Xu J. Iodine Excess Induces Hepatic Steatosis Through Disturbance of Thyroid Hormone Metabolism Involving Oxidative Stress in BaLB/c Mice. Biol Trace Elem Res. 2013 May 28. 
• Xu, J, Yang, XF., Guo, HL, Hou, XH Liu, LG, & Sun, XF. Selenium supplement alleviated the toxic effects of excessive iodine in mice. Biological trace element research; 2006 111(1-3), 229-238. 
• Yang XF, Xu J et al. Developmental toxic effects of chronic exposure to high doses of iodine in the mouse. Reprod Toxicol. 2006: 22:725–730. 
• Zhao J, Wang P, Shang L, Sullivan KM, van der Haar F, Maberly G. Endemic goiter associated with high iodine intake. Am J Public Health. 2000 Oct;90(10):1633-5.