Sunday, September 30, 2012

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!

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