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. 2013)

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

• Ackerman KE, Slusarz K, Guereca G, Pierce L, Slattery M, Mendes N, Herzog DB, Misra M. Higher ghrelin and lower leptin secretion are associated with lower LH secretion in young amenorrheic athletes compared with eumenorrheic athletes and controls. Am J Physiol Endocrinol Metab. 2013 Apr 1;302(7):E800-6.
• Argente J, Caballo N, Barrios V, Muñoz MT, Pozo J, Chowen JA, Morandé G, Hernández M. Multiple endocrine abnormalities of the growth hormone and insulin-like growth factor axis in patients with anorexia nervosa: effect of short- and long-term weight recuperation. J Clin Endocrinol Metab. 1997 Jul;82(7):2084-92.
• Beals KA, Manore MM. Disorders of the female athlete triad among collegiate athletes. Int J Sport Nutr Exerc Metab. 2002 Sep;12(3):281-93. 
• Boag F, Weerakoon J, Ginsburg J, Havard CW, Dandona P. Diminished creatinine clearance in anorexia nervosa: reversal with weight gain. J Clin Pathol. 1985 Jan;38(1):60-3. 
• Böni-Schnetzler M, Hauri C, Zapf J. Leptin is suppressed during infusion of recombinant human insulin-like growth factor I (rhIGF I) in normal rats. Diabetologia. 1999 Feb;42(2):160-6.
• Caspar-Bauguil S, Montastier E, Galinon F, Frisch-Benarous D, Salvayre R, Ritz P. Anorexia nervosa patients display a deficit in membrane long chain poly-unsaturated fatty acids. Clin Nutr. 2013 Jun;31(3):386-90.
• Davee AM, Rosen CJ, Adler RA. Exercise patterns and trabecular bone density in college women. J Bone Miner Res. 1990 Mar;5(3):245-50.
• Di Carlo C, Palomba S, De Fazio M, Gianturco M, Armellino M, Nappi C. Hypogonadotropic hypogonadism in obese women after biliopancreatic diversion. Fertil Steril. 1999 Nov;72(5):905-9.
• Di Luigi L. Does the high performance athlete need hormone replacement? Endocrine Abstracts. 2013; 29: 35.1 
• Foster-Schubert KE, Overduin J, Prudom CE, Liu J, Callahan HS, Gaylinn BD, Thorner MO, Cummings DE. Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates. J Clin Endocrinol Metab. 2008 May;93(5):1971-9.
• Figueiro MG, Plitnick B, Rea MS. Light Modulates Leptin and Ghrelin in Sleep-Restricted Adults. International Journal of Endocrinology. 2013, Article ID 530726.
• Golden NH, Meyer W. Nutritional rehabilitation of anorexia nervosa. Goals and dangers. Int J Adolesc Med Health. 2004 Apr-Jun;16(2):131-44.
• Hernández M, Argente J, Navarro A, Caballo N, Barrios V, Hervás F, Polanco I. Growth in malnutrition related to gastrointestinal diseases: coeliac disease. Horm Res. 1992;38 Suppl 1:79-84.
• Hobart J, Smucker D. The Female Athlete Triad. Fam Physician 2000; 61:3357-64,3367. 
• Hoppe C, Mølgaard C, Dalum C, Vaag A, Michaelsen KF. Differential effects of casein versus whey on fasting plasma levels of insulin, IGF-1 and IGF-1/IGFBP-3: results from a randomized 7-day supplementation study in prepubertal boys. Eur J Clin Nutr. 2009 Sep;63(9):1076-83.
• Khan KM, Liu-Ambrose T, Sran MM, Ashe MC, Donaldson MG, Wark JD. New criteria for female athlete triad syndrome? As osteoporosis is rare, should osteopenia be among the criteria for defining the female athlete triad syndrome? Br J Sports Med. 2002 Feb;36(1):10-3. 
• Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007 Jan;8(1):21-34.
• Kratz M, von Eckardstein A, Fobker M, Buyken A, Posny N, Schulte H, Assmann G, Wahrburg U. The impact of dietary fat composition on serum leptin concentrations in healthy nonobese men and women. J Clin Endocrinol Metab. 2002 Nov;87(11):5008-14.
• Lagaly DV, Aad PY, Grado-Ahuir JA, Hulsey LB, Spicer LJ. Role of adiponectin in regulating ovarian theca and granulosa cell function. Mol Cell Endocrinol. 2008 Mar 12;284(1-2):38-45.
• Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body weight. N Engl J Med. 1995 Mar 9;332(10):621-8. Erratum in: N Engl J Med 1995 Aug 10;333(6):399.
• Loucks AB, Verdun M, Heath EM. Low energy availability, not stress of exercise, alters LH pulsatility in exercising women. J Appl Physiol. 1998 Jan;84(1):37-46.
• Loucks AB. Energy availability, not body fatness, regulates reproductive function in women. Exerc Sport Sci Rev. 2003 Jul;31(3):144-8.
• Lu M, Tang Q, Olefsky JM, Mellon PL, Webster NJ. Adiponectin activates adenosine monophosphate-activated protein kinase and decreases luteinizing hormone secretion in LbetaT2 gonadotropes. Mol Endocrinol. 2008 Mar;22(3):760-71. Epub 2007 Nov 15.
• Manore MM. Dietary recommendations and athletic menstrual dysfunction. Sports Med. 2002;32(14):887-901. 
• Mikos AE, McDowell BD, Moser DJ, Bayless JD, Bowers WA, Andersen AE, Paulsen JS. Stability of neuropsychological performance in anorexia nervosa. Ann Clin Psychiatry. 2008 Jan-Mar;20(1):9-13.
• Miller SM, Kukuljan S, Turner AI, van der Pligt P, Ducher G. Energy deficiency, menstrual disturbances, and low bone mass: what do exercising Australian women know about the female athlete triad? Int J Sport Nutr Exerc Metab. 2013 Apr;22(2):131-8.  
• Modan-Moses D, Stein D, Pariente C, Yaroslavsky A, Ram A, Faigin M, Loewenthal R, Yissachar E, Hemi R, Kanety H. Modulation of adiponectin and leptin during refeeding of female anorexia nervosa patients. J Clin Endocrinol Metab. 2007 May;92(5):1843-7. Epub 2007 Feb 27.
• Mont L, Castro J, Herreros B, Paré C, Azqueta M, Magriña J, Puig J, Toro J, Brugada J. Reversibility of cardiac abnormalities in adolescents with anorexia nervosa after weight recovery. J Am Acad Child Adolesc Psychiatry. 2003 Jul;42(7):808-13.
• Murdolo G, Lucidi P, Di Loreto C, Parlanti N, De Cicco A, Fatone C, Fanelli CG, Bolli GB, Santeusanio F, De Feo P. Insulin is required for prandial ghrelin suppression in humans. Diabetes. 2003 Dec;52(12):2923-7.
• NCAA® Sports Sponsorship and Participation Rates Report • 1981-82 – 2010-11.  
• Orlandi E, Boselli P, Covezzi R, Bonaccorsi G, Guaraldi GP. Reversal of bone marrow hypoplasia in anorexia nervosa: case report. Int J Eat Disord. 2000 May;27(4):480-2.
• Ott V, Fasshauer M, Dalski A, Meier B, Perwitz N, Klein HH, Tschöp M, Klein J. Direct peripheral effects of ghrelin include suppression of adiponectin expression. Horm Metab Res. 2002 Nov-Dec;34(11-12):640-5.
• Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, Heiman ML, Lehnert P, Fichter M, Tschöp M. Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol. 2001 Nov;145(5):669-73.
• Rguibi M, Belahsen R. Body size preferences and sociocultural influences on attitudes towards obesity among Moroccan Sahraoui women. Body Image. 2006 Dec;3(4):395-400. Epub 2006 Sep 7.
• Rodriguez-Pacheco F, Martinez-Fuentes AJ, Tovar S, Pinilla L, Tena-Sempere M, Dieguez C, Castaño JP, Malagon MM. Regulation of pituitary cell function by adiponectin. Endocrinology. 2007 Jan;148(1):401-10.
• Scacchi M, Ida Pincelli A, Cavagnini F. Nutritional status in the neuroendocrine control of growth hormone secretion: the model of anorexia nervosa. Front Neuroendocrinol. 2003 Jul;24(3):200-24.
• Scheid JL, De Souza MJ. Menstrual irregularities and energy deficiency in physically active women: the role of ghrelin, PYY and adipocytokines. Med Sport Sci. 2010;55:82-102.
• Schtscherbyna A, Barreto T, de Oliveira FP; Luiz RR, de Abreu Soares RR, Gonçalves Ribeiro B. Age of onset training but not body composition is crucial in menstrual dysfunction in adolescent competitive swimmers. Rev Bras Med Esport. May/June 2013; 18(3).
• Steinberg SE, Nasraway S, Peterson L. Reversal of severe serous atrophy of the bone marrow in anorexia nervosa. JPEN J Parenter Enteral Nutr. 1987 Jul-Aug;11(4):422-3.
• Skarda ST, Burge MR. Prospective evaluation of risk factors for exercise-induced hypogonadism in male runners. West J Med. 1998 Jul;169(1):9-12.
• Sundgot-Borgen J. [Physical activity and reproductive health]. Tidsskr Nor Laegeforen. 2000 Nov 20;120(28):3447-51.
• Teufel M, Zipfel S, Herpertz S, Zwaan M. (ed.). Handbuch Essstörungen und Adipositas. Springer Berlin Heidelberg. 2008. 
• Williams NI, Helmreich DL, Parfitt DB, Caston-Balderrama A, Cameron JL. Evidence for a causal role of low energy availability in the induction of menstrual cycle disturbances during strenuous exercise training. J Clin Endocrinol Metab. 2001 Nov;86(11):5184-93.
• Wölfing B, Neumeier M, Buechler C, Aslanidis C, Schölmerich J, Schäffler A. Interfering effects of insulin, growth hormone and glucose on adipokine secretion. Exp Clin Endocrinol Diabetes. 2008 Jan;116(1):47-52.
• Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, Tominaga M, Yagami K, Sugiyama F, Goto K, Yanagisawa M, Sakurai T. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron. 2003 Jun 5;38(5):701-13.

194 Bananas in 3 Weeks, Same Liver Fat & Lower Body Fat 6 Months After; Nigella Sativa Boosts Testosterone & Fertility; Sugar Dampens Caffeine Rush + Thyroid & Body Comp.

Three weeks of +1,000 kcal carb overfeeding (approx. 194 bananas!): Does it supersize your liver fat? This and more in today's installment of On Short Notice

As promised in yesterday's first part of the weekly written news-round up aka On Short Notice, we won't waste any time on lengthy introductions (the "short" items themselves are already long enough ;-) and get right down to business! For today this means that we are going to take a peak at the latest studies on

• the reality of thyroid hormone metabolism
• the dampening effects of sugar on high dose caffeine
• the sugary truth about the reversibility of early NAFLD
• the pro-testosterone, pro-fertility effect of black cumin

as well as the latest data on US drug sales and an upcoming blogpost discussing "training for anabolism" - enjoy!

Just in case you feel that's not enough, I suggest you listen to this week's installment of the SuppVersity Science News Roundup (click here to download) on Super Human Radio, as well!

• 

  Figure 1: The more energy reserves a metabolically healthy and euthyroid person has and the more he or she eats (though this was not quantified we can probably assume that the heavier participant also consumed more energy on a daily basis), the less energy efficient is his metabolism going to be - the margin is yet not unlimited, eat 40% more and get fat regardless of what type of food those calories come from (generated based on Roef. 2013)

  Levels of thyroid hormone associated with greater body weight and body fatness I know this sounds surprising, but int he end the latest results from the Department of Endocrinology at the Ghent University Hospital in Belgium only confirm what I keep preaching here at the SuppVersity over and over again: The main reason that the calories in vs. calories out calculations don't work is that the "calories out" part of the equation depends on both the "calories in" and the "calories stored", as well as the "accessibility of the calories stored" parameters, and [...].
  Put differently, the reason that the 941 generally healthy and euthyroid (=normal thyroid function) male siblings (25-45 yrs, median BMI 24.6) with the highest body weights and the greatest body fat mass also had the highest levels of leptin, free and total T3 & T4, as well as thyroid binding globulin is simple: In the presence of ample energy supply their bodies will treat their resources more wasteful, than those of the skinny or wanna-be-skinny, ah... I mean "ripped" guys who undereat and overtrain.
  The opposite is the case for the more muscular study participants, whose greater lean mass and muscle cross-sectional area were associated with lower (F)T3, (F)T4 and TBG levels (p ≤0.0003). They simply cannot afford (you could also say that they don't need) to ramp up their already higher fatty acid oxidation and overall energy expenditure, even further. Lastly, there was a clear-cut association with higher free T3 levels and lower insulin sensitivity, and - I had almost forgotten to mention that - "[n]o associations between TSH and body composition or metabolic parameters were seen."
  I suggest you print the finding about TSH levels and ask your doctor if he judges the speed of his car by looking at the gaspedal (TSH is more or less the gas-pedal that will tell your thyroid how hard it's got to work, but won't tell you how much of active thyroid hormone it is capable of producing) rather than the speedometer, when he is too cheap to order a full thyroid panel the next time you ask him to do so ;-)

• 

  Figure 2: While the initial caffeine spike is blunted by the ingestion of a sugar-laden breakfast, the area under the curve (bottom, right) a similar, yet less pronounced effect and both, the reduction of the initial spike in serum caffeine, as well as difference of the total influx over time are dose dependent (Skinner. 2013)

  Sugary breakfast reduces early rise in serum caffeine levels by up to 90% That's at least the result of a recent study by Tina Skinner and her colleagues from the University of Queensland in Down-Under. The high carbohydrate meal, in this case a toast with jam, cordial, and an energy bar ("Vanilla Crisp" PowerBar Performance Bar), the scientists served their 14 healthy active male participants (age 24.8 ± 3.7 yrs, body mass 74.6 ± 8.5 kg, height 184.0 ± 8.5 cm; mean ± SD) who had reported fasted, well hydrated and 48h after they had consumed their last caffeinated beverage at the lab (Skinner. 2013). It does not really take a rocket scientist to see that the absence of the initial onslaught of caffeine as a result of the pre-ingestion of the sugary "breakfast" will probably diminish, if not totally blunt the stimulating effects of coffee.
  In view of the fact that this effect was particularly pronounced during the "high dose" (=9mg/kg body weight; ~540-900mg; equiv. to 3-4.5 large cups of strong coffee), it is yet probably of greater importance for stim junkies and athletes looking for the pre-workout edge before they hit the gym, than for the average white color worker who needs to get his daily buzz, if he does not want to miss his bus (or train ;-)
• Liver-fattening effects of carbohydrate overfeeding are genetically dispositioned, but the recently published data from a study that was conducted by scientists from the Minerva Foundation Institute for Medical Research, the University of Helsinki and other Finnish research facilities shows that an appropriate diet can reduce increased liver and body fat levels, reduce body fat levels and improve lipid and glucose metabolism, regardless of the genotype (PNPLA3-148II = disadvantaged vs. PNPLA3-148MM) of the subjects.
  But let's take on thing after the other. After some standard baseline tests, the 16 subjects (mean age 54 year; BMI at baseline 30.6kg/m²; 5 men, 11 women) were "overfed" with a high carbohydrate diet from the "every low-carbers worst nightmare" category:
  

  

  Figure 3: Change in body composition from due to 3-week overfeeding (blue), 6 months dieting (compared to post overfeeding - red; Sevastianova. 2013)

  "The subjects were instructed to continue their normal diet and in addition to consume an extra 1000 kcal/d with 98% of energy from carbohydrates. The extra diet consisted of candy (Oy Karl Fazer Ab), pineapple juice (Tuko Logistics Oy), sugar-sweetened soft drinks (Oy Hartwall Ab), and/or carbohydrate-loading drink (Squeezy Sports Nutrition GmbH) and was provided free of charge from the research unit to the study participants." (Sevastianova. 2013)

  As you will probably have expected the highly insulinogenic, additional 21,000kcal from glucose and fructose (~5250g or 194 bananas, medium size to be precise ;-) did leave "their marks" on the waist and hips of the subjects, but probably not to the extend you may have anticipated (see figure 1). Even more suprisingly, the short term overfeeding did not deteriorate any of the blood glucose parameters (all changes had p-values way beyond what would be statistcally significant, the glucose clearance over 2h did even improve! - statistically likewise non-significant, though).
  Most importantly, however, the body composition, triglyceride levels (-6%), HDL (+11%) and all the important body composition measures (see figure 3) improved and the liver fat returned to baseline in the course of the 6-months "diet period", which consisted of - mark my words - nothing but making a switch to a diet with more vegetables, less simple sugars, white flour, and alcoholic drinks and dietary counseling wrt to food types and appropriate (=moderate) portion sizes. No extreme low carbing, no drastic calorie reductions, just healthy whole foods - regardless of "your bad genes"!
• Nigella sativa, aka black cumin, jacks up testosterone and makes tired sperm get a move on Being well aware that you cannot go without a weekly post about at least one natural testbooster,  you will probably be relieved to hear that Rahmatollah Parandin, Namdar Yousofvand and Rostam Ghorbani have published a paper in the latest issue of the Iranian Journal of Reproductive Medicine in which they describe the fertility and testosterone boosting effects of 200 and 400mg/kg of an alcoholic extract from Nigella sativa seeds (Parandin. 2013).
  *Reminder: Regardless of whether we are dealing with rodents or humans, a "testosterone booster" that works in sick animals or humans does not necessarily work in healthy ones, as well. It is much more likely, that the effects on testosterone are secondary to the effect of the effect the herb or whatever else has on the overall health of the lab animals / participants, so that someone who is not sick in the first place won't see any (or at best minimal) improvements.
  The seed extract that was administered to healthy*  male Wistar rats 60 days contained a mix of various active ingredients
  
  • 30-48% Thymoquinone,
  • 7-15% P-cymene, 
  • 6-12% Carvacrol, 
  • 2-7% 4-terpineol, 
  • 1-4% T-anethole, and 
  • 1-8% Sesquiterpene,
  of which Prandin et al. state that Thymogquinone is currently considered to be be the pharmacologically active constituent of N. sativa (cf. Padhye. 2008) - keep that in mind, when you cannot resist giving this stuff a try ;-)
  Now, the ~23% increase in testosterone is certainly nothing like the "140% increase in testosterone" certain supplement companies state one of the testers had (without any peer-reviewed data whatsoever, by the way), but as mediocre as it may seem, it was achieved from a healthy baseline level and it went hand in hand with improvements in all sperm parameters, of which I picked the sperm count and plotted it together with the latest human data from the University Department of Growth and Reproduction at the Rigshospitalet of the University of Copenhagen in Denmark in the second graph in figure 3 (Jørgensen. 2013).

  

  Figure 4: Yeah, Nigella boosts testosterone by 20% (left), but there are other things in life... what about it's effect on sperm count (right) for example? The increase the rodents in the high-dose group experients would catapult the infertile Danish men almost into the normal zone (based on Jørgensen. 2013 & Parandin. 2013)

  Now this is certainly by no means scientific evidence and I am not suggesting that it will help solve potential fertility problems (not just because sperm count is only one out of a dozen parameters, but also because we don't know whether what works in healthy rodents will work in sick people; see red box above for the other side of the coin). What I found quite important though, is to give you an idea of what those abstract numbers could eventually mean. Contrary to the 20% increase in testosterone which will hardly help you to build significantly more muscle mass, a similar bump in sperm count (and other fertility parameters) could very well make the difference between fertile and infertile!
  So, at whichever Internet source you may be able to dig up a respective extract and regardless of whether you want it for fertility or futility, ah... I mean "testosterone boosting" issues, make sure that it has a high Thymoquinone content and that you have enough of it to hit the human dose equivalent (click here to learn how to calculate HEDs) of 65mg/kg or 4-5g per day!
  

Figure 6: US Drug sales 2010 & 2011 as posted on the SuppVersity Facebook wall earlier today (based on Lindsay. 2013).

The End - for today, at least. I guess I won't take too much away, if I tell you that there was actually another item scheduled for today... a post about "High or Low, Long or Short, Heavy or Light what are the Best Set Numbers and Rest Times,Weights and Rep Schemes, When You're Training for Anabolism" - and while this is "anabolism" in the old and actually sort of outdated sense of more testosterone and less cortisol, I'm pretty confident that the muscle-heads among you would have liked it, if it did not get longer and longer, so that I decided to polish it up a little and put you on the rack for another two days or so ;-)

So, in case that's driving you crazy, you may want to consider asking your Dr. for a script for an antipsychotic, currently the #5 on the 2011 (=the latest) US drug sale ranking (see figure 6; remember the data is $-based not script-based), I posted along with a handful of other interesting news-items earlier today on the SuppVersity Facebook wall.

References:

• Jørgensen N, Joensen UN, Jensen TK, Jensen MB, Almstrup K, Olesen IA, Juul A, Andersson AM, Carlsen E, Petersen JH, Toppari J, Skakkebæk NE. Human semen quality in the new millennium: a prospective cross-sectional population-based study of 4867 men. BMJ Open. 2013 Jul 2;2(4).
• Lindsley CW. The top prescription drugs of 2011 in the United States: antipsychotics and antidepressants once again lead CNS therapeutics. ACS Chem Neurosci. 2013 Aug 15;3(8):630-1.
• Roef G, Lapauw BM, Goemaere S, Zmierczak HG, Toye K, Kaufman JM, Taes Y. Body composition and metabolic parameters are associated with variation in thyroid hormone levels among euthyroid young men. Eur J Endocrinol. 2013 Sep 6.
• Padhye S, Banerjee S, Ahmad A. Mohammad R. Sarkar FH. From here to eternity- the secret of Pharaohs: Therapeutic potential of black cumin seeds and beyond. Cancer Ther 2008; 6: 495-510
• Parandin R, Yousofvand N, Ghorbani R. The enhancing effects of alcoholic extract of Nigella sativa seed on fertility potential, plasma gonadotropins and testosterone in male rats. Iran J Reprod Med. July 2013; 10(4): 355-362.
• Sevastianova K, Santos A, Kotronen A, Hakkarainen A, Makkonen J, Silander K, Peltonen M, Romeo S, Lundbom J, Lundbom N, Olkkonen VM, Gylling H, Fielding BA, Rissanen A, Yki-Järvinen H. Effect of short-term carbohydrate overfeeding and long-term weight loss on liver fat in overweight humans. Am J Clin Nutr. 2013 Sep 5.
• Skinner TL, Jenkins DG, Folling J, Leveritt MD, Coombes JS, Taaffe DR. Influence of carbohydrate on serum caffeine concentrations following caffeine ingestion. J Sci Med Sport. 2013 Sep 7.

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. 2013). 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. 2013 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.

On Short Notice: Testosterone - 12% Drop /W 75g Glucose? Fat Loss - Adzuki, Leucine + B6 or HiMaize? Thyroid - T3↓ + rT3↑, Is Blood Sugar to Blame and Can TUDCA Help? +More!

Image 1: It's quite funny, I am piling up so many of these interesting mini-news that I actually had to drop a few or postpone them to next week to keep the size of this post manageable without a direct brain transmission device like the one you see in this picture ;-)

"On short notice" is the name of the new 'saturdaily' SuppVersity column and therefore I will try to make it short: After all, you've got a hell lot to learn today and unless you have just crawled out from beneath your sheets, your testestorone levels and with it your cognitive abilities will aready have declined - that's not you? Well I guess you have the hubris of a boxer, then, or you did simply sleep so little that even your increased energy consumption could not make up for the memory dysfuction that's been brought about by the sleep deficit. Let's just hope that your cell mass is at least so high that your basal energy expenditure is sufficient to burn those serotonergic carb binges off, because I am pretty sure that the leucine + B6 combo from NuSirt Science won't do that for you... what? You don't understand a word? Don't worry, you will, once you are done with today's installment of "On Short Notice"...

Adzuki bean extract - just another fat binder or more?

Image 2: Those Adzuki beans look pretty much like kidney beans, don't they? Ah, btw. you did know that kidney beans contain a "carb blocker" (a molecule that hampers carbohydrate digestion; cf. Mosa. 2008) - did you?

I am really no a fan of those "anti-fat absorption agents", as most of them will have immediate or long-term consequences on your supply of fat soluble nutrients which could in fact be worse for your overall health than the few additional lbs of body fat you may be carrying around. That being said, you may still be interested in the latest results from Tomoko Kitano-Okada and his colleagues from the Department of Food Science, Obihiro University of Agriculture and Veterinary Medicine in Inadacho, Obihiro, Hokkaido, Japan. In a combined in-vivo (rodent) and in-vitro study, the researchers found that control and high fat diets with 1% adzuki bean extract, despite having only non-significant effects on the high fat diet (HFF) induced weight gain, did not just ameliorate the HFD induced deteriorations in serum low-density lipoprotein (LDL) and triglyceride (TRIG) levels, but lead to marked improvements in LDL and TRIG in the rodents on the standard diet (55% cornstarch + 10% succrose, 20% casein, 5% soybean oil), as well.

Figure 1: Absolute total cholesterol and triglyceride levels, as well relative (expressed in percent of respective values for animals on control diet) liver and faecal matter weight and lipid content in male Fischer rats after 4 weeks on control (high carb) or high fat diets (data based on Kitano-Okada. 2013)

This is interesting as it appears to confirm the hypothesis that the Adzuki beans do not work their anti-hyperlipidemic (=cholesterol and triglyceride lowering) effects solely via their ability to increase the fat content of the excrements, but also via other mechanisms of which Kitano-Okada et al. identified the reduction of inflammatory cytokines (e.g. 24–51% IL-6 reduction following treatment with Adzuki bean extract containing polymerised polyphenols) and the likewise dose-dependent profound reduction in glycerol-3-phosphate dehydrogenase, an enzyme that is necessary to generate glycerol (fatty acids) from carbohydrates, in in-vitro cell studies with human adipocytes by up to -50%!

Implications: Just in case you are now interested in popping some of those beans you should be aware that the product that was used in the study contained 16% polyphenols (including 470 mg anthocyanidins, 20.7 mg catechins, 2.33 mg caffeic acid, 2.62 mg ferulic acid, 44.5 mg quercetin, and 102 mg protocatechuic acid), that the human dose equivalent would ~5-6g /day and that you should try to get an extract with polymerized (=interconnected) phenols, as those were roughly 2x more active in the in-vitro essays (although it is questionably if this translates into better real world results).

Marathon running is for the metabolically efficient!

Image 3: Marathoners have nothing to lose!

Just in case you have ever wondered what makes a good marathon runner a very good marathon runner, the results of a study that was published in the latest issue of Sport Sciences for Health could hold the answer: Marathon champions have a surprisingly high metabolic efficiency (Andreoli. 2013), or put more simply, they are carrying little to no (for their goals!) useless ballast like profane fast-twitch muscle fibers and only so much fat as it takes to optimally protect their organs (in percentages this is yet still way more than the guys with the "profane" fast-twitch fibers are carrying around)

As the data in figure 2 goes to show, their body cell mass (BCM), a more accurate measure of the amount of metabolically active tissue in their body than "lean mass" (Moore. 1963), is about equal to the one of division 1 football players (data compiled from Andreoli. 2003 and Andreoli. 2013), but their lean mass is much lower (as mentioned before they have no use for heavy type I and type IIX muscle fibers).

Figure 2: Body composition data (fat free  mass, body cell mass, body fat percentage) in different athletes and control (left), as well as correlation between BCMI (BCM / height) with marathon running time (right; data compiled from Andreoli. 2003 and Andreoli. 2013)

In conjunction with higher metabolic rates, of which Andreoli et al. found that they are the 2nd best predictor of marathon times (correlation r = -0.69 vs. BCMI = BCM / height with r = -0.73), a high amount of "oxygen-exchanging, potassium-rich, glucose-oxidizing, work-performing cells" (=what the BCM measures ;-) and correspondingly high resting energy expenditures (r = 0.77) do thus make the difference between victory and defeat.

Sounds strange, when you come to think about it - right? "People with higher energy expenditures make good marathon runners?" Well, I guess you better think of it differently: Bigger engines need more fuel and as we have seen yesterday, a very welcome side effect of "mitochondrial biogenesis that's induced by Chitooligosaccharide supplementaton" was an increase in endurance - that those big engines have to be fueled adequately, by the way, does also explain why people like Michael Phelps do in fact have to eat like a horse - that he really needs 12,000-15,000 calories per day is yet probably just another of those urban legends.

Implications: Interestingly enough, the necessity of having a "big engine" (=huge metabolically active cell mass) does also implicate that the formerly obese, who appear to flock around marathon or at least endurance running, with their slabs of metabolically unactive tissue and suppressed metabolic rates due to months or years of undereating and overtraining have little to no chance of ever winning a marathon race, which  - and this may be the most surprising finding of the study - is not the prerogative of the person who "burns the less fuel"  - at least not as long as nobody takes away their 30 bananas a day and the highly concentrated energy gels marathoners use on their 42-km run, I guess ;-)

Can 75g of Glucose Reduce Testosterone by 10% Within Minutes?

In a recently conducted trial, Lisa M. Caronia and her colleagues from the Massachusetts General Hospital in Boston observed an astonishing -12% drop in total testosterone within 30 min of the ingestion of an 75g of glucose - the same amount you would ingest in every regular oral glucose tolerance test (OGTT) and even less than some hilarious "expert suggestions" will tell you would need to optimally replenishing your allegedly depleted glycogen stores after an intense workout.

Figure 3: Glucose, insulin, SHBG, lepin, LH and testosterone levels in response to the oral ingestion of 75g glucose in 74 young men; data expressed relative to baseline (data adapted from Caroni. 2013)

If you take a closer look at the exact data in figure 3 you will probably be as startled with respect to the underlying mechanism behind this reduction as the researchers were. Aside from the drop in testosterone, the only statistically significant changes (indicated by * in figure 3) the scientists observed, were a profound drop in leptin and the explosive increase in glucose and insulin - both of which, the decrease in leptin and the increase in insulin, have yet been shown to augment testosterone production in previous studies (Adashi. 1982; Giovambattista. 2003). At least with respect to the drop in leptin, Caronia et al. do yet point out, that it could be a mere conseqence of "circadian fluctuations in leptin that are unrelated to glucose administration" (Caronia. 2013; those fluctuations, by the way, have been observed by e.g. Panarotto. 1999)

Symptoms of low Testosterone

• Lean muscle loss, agitation/motor dyskinesia, decreased appetite
• Depression, guilt, low-self esteem, anhedonia, decreased cognitive capacity
• Increased stress, general fatigue, sleep disturbances
• Decreased libido, decreased spontaneous erections, decreased ejaculate, erection dysfunction, decreased sexual fantasies, anorgasmia

Furthermore, neither cortisol (not shown in figure 3), a potential suppressor of testicular testosterone production, nor luteinizing hormone (LH), which stimulates testicular testosterone production and should actually increase in response to the drop in testosterone, did budge in the course of the 120 min after the 74 men (age range: 19-74 years, mean: 51.4 ± 1.4) who reported to the lab after a 12-hour overnight fast had ingested the 75g of glucose.

As Caronia et al. point out, the non-existent response of the luteinizing hormone (LH) levels to the reduced testosterone levels, is probably the only clue we have as far as the underlying mechanism of allegedly glucose-induced reduction in testosterone levels is concerned, because "one would anticipate that the decreased negative feedback of T would lead to increased LH levels" (Caronia. 2013). And though Caronia et al. are certainly right that this and the fact that this was not the case and that the effect occured in healthy, in insulin resistant and in diabetic subjects (where it was slightly more pronounced, though; data not shown), clearly "suggests an additional central component", the latter should actually, as it was observed by  Iranmanesh et al. only recently involve a drop in luteinizing hormone (Iranmanesh. 2013).

After thinking about that for a couple of minutes I was just about to write in the implications that this would be another good reason not to go overboard on fast carbs, when I remembered my previous research on all things testosterone for the "Intermittent Thoughts on Building Muscle" Series and what the scientists themselves had said about the declining leptin levels - well, let's take a look at what the testosterone levels of both young and old men do between 8:00am and 12:00pm, i.e. during the exact time the subjects in the Caronia study ingested their allegedly anti-androgenic bolus of 75g of glucose:

Figure 4: An analysis of the natural diurnal testosterone rhythm in young men (dotted line in graph in the background; Diver. 2003) reveals that the "drop" in testosterone in response to the OGT is likely only a consequence of the pronounced diurnal rhythmicity of the total testosterone levels - in older men we see the exact same phenomenon, but the effect is about 50% less pronounced.

The data from the Diver study in figure 4 does not leave a slight doubt that the OGTT, or rather the 75g of glucose the subject had to consume probably had no independent effect on the level of testosterone and that the decline Caronia et al. observed is simple a result of the natural diurnal rhythm. This does not exclude that the latter is per se connected to food intake as the availability / influx of energy is, beside light, probably, the most important setscrew for our clock-genes.

Image 4: Conclusions are rarely 100% conclusive.

Implications: There are actually two important take home messages from this study and "carbs are so bad for you" is not one of them:

1. draw your own conclusions, and don't trust those of others blindly regardless of their "credentials"
2. make sure that you don't ignore the diurnal rhythmicity of testosterone, and are thus fooled to believe that short term changes in the +/- 50% range would make you build or lose muscle, let alone your virility

The second take home message is also of great importance when you test your own testosterone levels and/or read about the testosterne boosting magic of the latest supplement scam (aka "natural testosterone booster"). As you can see, you can easily achieve a  70-80% increase or decrease in testosterone by simply measuring at different points in the day.

On Very Short Notice

• 

  Figure 5: Changes in fatty acid metabolism (top) and inflammatory markers (bottom) in response to 4 weeks of thrice daily NuFit (250mg leucine + 30mg vitamin B6) supplementation to 20 obese men and women (based on Zemel. 2013)

  Astonishing improvements in RQ & fatty acid oxidation from 2g of leucine and 30mg vitamin B6 - Although you need to be somewhat cautious with a study that was financed by NuSirt Sciences the producer of the 750mg leucine + 10mg pyridoxin supplement under scrutiny (Zemel. 2013), the effect the ingestion of those caps had on the fatty acid metabolism and moreover the expression of inflammatory markers in 20 overweight or obese subjects was literally marvelous (I leave the interpreation of this term up to you ;-). A decrease in respiratory quotient (=greater fatty acid, lower glucose oxidation), an increase in total fatty oxidation per day and more importantly and probably causally the decreases in TNF-alpha and CRP are changes I would not have expected to see within 4 weeks on 2.25g of leucine and 30mg of vitamin B6. After all,  you should see similar effects with almost every cheap (or expensive) BCAA supplement on the market - aside from even greater amounts of leucine most of them contain at least 10mg of additional B6.
• Fat burning machines can't have orange juice for breakfast - The additional 210kcal the subjects of a 2013 trial by scientists from the Children’s Hospital Oakland Research Institute consumed in form of "healthy" orange juice were not just more or less empty calories, they also reduced the postprandial fatty acid oxidation by whopping 25%. This lead Stookey et al. conclude that "independent of a state of energy excess, [drinking] a caloric beverage instead of drinking water with a meal [will decrease] the amount of fat consumed in the meal before their next meal." (Stookey, 2013) If you want to become / stay a fat burning machine (and in my humble opinion even if you just want to stay lean and healthy) you better eat your fruit and never drink it (let alone other caloric beverages, see "Fat content per Energy Drink 0g, Fat Gain Per Energy Drink 16g").

• 

  Image 5: The first hit on google says HiMaize will cost 8$/340mg; mimicking the dosage used in the study would thus be ~1$ per day; relatively cheap if you consider that it is not necessary a supplement, but can also be used for baking & co

  Resistant starch could stop and reverse developing diabetes - scientists from the University of Surrey and the venerable Imperial College in London were able to show that their 12 overweight (BMI 28.2±0.4 kg/m2) prodiabetic subjects' first-phase insulin secretion, which is the one that determines whether you do or don't go hyperglycemic right after the ingestion of a meal, by improved by ~35% after only 4 weeks of consuming a mildly resistant (60% resistant / 40% digestible) maize starch. Probably as a direct result of this early pro-insulinogenic effect, the HiMaize260 RS2 starch produced a -10% reduction in fasting blood glucose, compared to a regular tapioca starch of which the subjects in the control group consumed only 27g to assure that they would ingest equal amounts of glucose (Bodinham. 2013).
  Despite the fact that WM HDP is an artificial restistant starch, of which even less will be digested and absorbed as glucose in the small intestine, these results do confirm what we have already seen in the WM HDP studies and what some of the latest blogposts bordering on dietary fiber have hinted at, as well (e.g."Weightloss Threesome"): The effects of these not, or only partially digestible fibers and carbohydrates go way beyond simply filling you up or being non-insulinogenic (=not causing an insulin spike as even the low GI starches do). There is however, as Carolin L. Bodinham and her colleagues rightly point out, need for "further studies [...] to confirm these findings and to elucidate the mechanisms" and, as I would add, to identify whether or not this could work for people who have already developed type II diabetes, as well.
• Counter-intuitive effects of high glucose-dependent insulinotropic polypeptide (GIP) levels in form of increased insulin and reduced obesity: While the hitherto published studies on WM HDP (see previous bullet point) clearly suggest that part of its fatburning effect is mediated by a reduced, even almost non-existant GIP (and subsequently insulin response), a recent study from Canada clearly suggest that whenever you do consume regular starch a more pronounced incretin response will not just avoid hyperglycemia (due to the more pronounced release of insulin from the pancreas), but also improve / prevent adipose tissue inflammation, hepatic steatosis (non-alcoholic fatty liver disease) and even weight gain - remember: we are talking about higher insulin responses, here (Kim. 2013)! Unfortunately, the anti-obesity effect Su-Jin Kim and his colleagues observed in their experiments with GIP-overexpressing rodents, were mostly a direct consequence of reduced energy intakes and that those hardly ever translate into the real world is something I believe I don't have to tell you, right?

• 

  Figure 6: If your body does not convert T4 into T3 adequately taking levothyroxin (T4) may even worsen many of the symptoms of hypothyroidism due to increased conversion to r-T3 and an even more sluggish metabolism that certainly won't help to get blood glucose back under control (see also "Natural Thyroid Treatment with food")

  Low T3 syndrome (pseudo-hypothyroidism) or diabetes? This is an "oldie, but goldie", i.e. a study I happen on while doing research on this and that... in this case I do not even really know how this study appeared on my radar, but according to Kabadi et al. high blood sugar in type II diabetes does reduce the conversion of the "inactive" form of thyroid hormone, T4, to its active cousin, T3 and increases the conversion of T4 to rT3 (reverse T3). The latter is believed to act similar to a receptor blocker, which hinders T3 do to its metabollically activating job. The statistically highly significant (p < 0.0001) correlation (r = 0.611) the scientists observed between rT3 and fasting blood glucose would suggest that improper blood glucose management could be the root course of the heavily lamented high rT3 levels of thousands of posters on various bulletin boards all across the Internet (Kabadi. 1982). Now, the good news is that the researcher found that by controlling blood glucose levels you can return your rT3 and T3 levels back into the normal zone. 
• Tauroursodeoxycholic (TUDCA) and 4-phenylbutyric (4-PBA) increase T3 to T4 conversion - The chemical chaperones TUDCA and 4-PBA, of which the former has as of late been hailed as the new "milk thistle", i.e. the go-to-supplement for liver health among athletes who use oral anabolic steroids, could turn out to be a valuable tool not just to escape from the aforementioned vicious circle of low T3 and high rT3 levels, but also as a means to kickstart your metabolism. Although this hypothesis is based on data from a combined in-vitro + in-vivo rodent study (da-Silva. 2011), the shift away from glucose and towards fatty acid oxidation, as well as the doubled activity of the fat burning brown fat and the profound improvements in glucose tolerance, da-Silva et al. observed in their high-fat fed rodents certainly won't harm your physique.

• 

  Figure 7: Narcicistic personality traits of kickboxers, freestyle and  Greek Roman wrestlers, Boxers and Weightlifters (based on Tazegül . 2013)

  Weight lifters and boxer are the most narcissistic athletes - At least among the five groups the Turkish scientist Ünsal Tazegül analyzed for his recently published paper, the 17-19-year old male boxers and weight lifters had the most pronounced narcissistic character traits. While the boxers were the most exhibitionists and pretentious, the weight lifters were the most rebellious, inadaptable, spiteful, disrespecting (subsumed under exploitation) and ambitious, power-thirsty and spiteful among the subjects who participated in this study. Interestingly enough, the freestyle wrestlers appeared to be the guys with whom you would probably get along best. So what does that tell you? Nothing... and that's why this study is only on very short notice ;-)
• If you don't sleep yourself smart, you got to binge yourself half-smart: Just in case you have already forgotten what you read a few paragraphs above, the reason could be sleep deprivation. And while cognitive deficits due to sleep deprivation is nothing essentially new, another thing, namely the effectivity of increased daytime energy intake to recover your mental capacity, is something a recent study by Nina Herzog et al. has investigated for the first time (Herzog. 2013). Unfortunately, binging rescues only the procedural part of your memory (where you store how to brush your teeth before you go to bed ;-), it will not compensate for the detrimental effects a lack of adequate sleep will have on your declarative memory. If you also  take into account that it is going to make you fat and sick, I would thus suggest you go to bed now, after all you havale already done the single most important thing of the day - you've gotten your daily dose of SuppVersity news! And let's be honest, you don't want to forget any of these valuable lessons, do you ;-)

References:

1. Adashi EY, Fabics C, Hsueh AJ. Insulin augmentation of testosterone production in a primary culture of rat testicular cells. Biol Reprod. 1982 Mar;26(2):270-80.
2. Andreoli A, Melchiorri G, Brozzi M, Di Marco A, Volpe SL, Garofano P, Di Daniele N, De Lorenzo A. Effect of different sports on body cell mass in highly trained athletes. Acta Diabetol. 2003 Oct;40 Suppl 1:S122-5.
3. Andreoli A, Marfe G, Manzi V, Sinibaldi-Salimei P. Is body cell mass a predictive index of performance in male recreational long-distance runners? Sport Sci Health. 2013; 8:47–50
4. Bodinham CL, Smith L, Wright J, Frost GS, Robertson MD (2013) Dietary Fibre Improves First-phase Insulin Secretion in Overweight Individuals. PLoS ONE 7(7): e40834.
5. Diver MJ, Imtiaz KE, Ahmad AM, Vora JP, Fraser WD. Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men. Clin Endocrinol (Oxf). 2003 Jun;58(6):710-7.
6. Giovambattista A, Suescun MO, Nessralla CC, França LR, Spinedi E, Calandra RS. Modulatory effects of leptin on leydig cell function of normal and hyperleptinemic rats. Neuroendocrinology. 2003 Nov;78(5):270-9.
7. Herzog N, Friedrich A, Fujita N, Gais S, Jauch-Chara K, et al. (2013) Effects of Daytime Food Intake on Memory Consolidation during Sleep or Sleep Deprivation. PLoS ONE 7(6): e40298.
8. Iranmanesh A, Lawson D, Veldhuis JD. Glucose ingestion acutely lowers pulsatile LH and basal testosterone secretion in men. Am J Physiol Endocrinol Metab. 2013 Mar;302(6):E724-30.
9. Kabadi UM, Premachandra BN, Maayan M. Low serum 3, 5, 3'-triiodothyronine (T3) and raised 3, 3', 5'-triidothyronine (reverse T3 or RT3) in diabetes mellitus: normalization on improvement in hyperglycemia. Acta Diabetol Lat. 1982 Jul-Sep;19(3):233-42.
10. Kim S-J, Nian C, Karunakaran S, Clee SM, Isales CM, et al. (2013) GIP-Overexpressing Mice Demonstrate Reduced Diet-Induced Obesity and Steatosis, and Improved Glucose Homeostasis. PLoS ONE 7(7): e40156.
11. Kitano-Okada T, Ito A, Koide A, Nakamura Y, Han KH, Shimada K, Sasaki K, Ohba K, Sibayama S, Fukushima M. Anti-obesity role of adzuki bean extract containing polyphenols: in vivo and in vitro effects. J Sci Food Agric. 2013 Apr 11.
12. Moore FD, Olesen KH, McMurray JD. The body cell mass and its supporting environment. WB Saunders, Philadelphia, 1963.
13. Mosca M, Boniglia C, Carratù B, Giammarioli S, Nera V, Sanzini E. Determination of alpha-amylase inhibitor activity of phaseolamin from kidney bean (Phaseolus vulgaris) in dietary supplements by HPAEC-PAD. Anal Chim Acta. 2008 Jun 9;617(1-2):192-5. Epub 2008 Feb 1. 
14. Panarotto D, Maheux P. Reduction of plasma leptin during a short-term fast, an oral glucose tolerance or a meal test can be a misleading bias in clinical studies. Diabetologia. 1999 May;42(5):634.
15. da-Silva WS, Ribich S, Arrojo e Drigo R, Castillo M, Patti ME, Bianco AC. The chemical chaperones tauroursodeoxycholic and 4-phenylbutyric acid accelerate thyroid hormone activation and energy expenditure. FEBS Lett. 2011 Feb 4;585(3):539-44.
16. Stookey JD, Hamer J, Espinoza G, Higa A, Ng Vivian, Tinjero-Deck L, Havel PJ, King JC. Supplement: 2nd Forum on Child Obesity Interventions: Orange Juice Limits Postprandial Fat Oxidation after Breakfast in Normal-Weight Adolescents and Adults Adv Nutr July 2013.
17. Tazegül, Ü. Comparison of narcissims in some branches of athletes. International Journal of Sport Studies 2011, 1 (4), 168-179.
18. Zemel, M.B.; Bruckbauer, A. Effects of a Leucine and Pyridoxine-Containing Nutraceutical on Fat Oxidation, and Oxidative and Inflammatory Stress in Overweight and Obese Subjects. Nutrients 2013, 4, 529-541.