Ask Dr. Andro: The Pharmacokinetics of Creatine (Part II/II) - How Is Creatine Transported into the Muscle?

Illustration 1: There is a bunch of things that could potentially go wrong with creatine uptake: The creatine from dietary sources could be mal-absorbed (1) in the small intestine, (2) not make it into the cell, or (3) be excreted too readily either before or immediately after it was transported into the muscle.

Question from Learner (via comments): Do Creatine Transporters behave the same as glucose transporters? (I.e., serum insulin binds to cellular insulin receptors, which causes Transporters to migrate from inside the cell to the plasma membrane - and the Transporters then pull in the external glucose.)

Answer Dr. Andro: As you may have noticed, I took the freedom to set Learner's question into a broader context. A context I broached in my dissertations on Athletic Edge Nutrition's new creatine product Creatine RT on Tuesday, Aug 16, 2011. Thus, the questions I will be trying to answer (unfortunately, I have to rely on existing studies and do not have my own lab, here ;-) are the following ones:

1. How does creatine get into the blood? (cf. Part I)
   
2. How does creatine get into the muscle?
3. What can influence these processes?
   

Those of you who have already read part I of this installment of "Ask Dr. Andro", will know that, in view of the fact that this is quite an extensive topic, I decided to tackle it in a two part series, where in part 1 (yesterday) I focused on the issue of creatine absorption into the bloodstream, from where I will now go on to explain how the creatine eventually gets stored in the cells of your muscle or cleared by your kidneys (steps 2 and 3 in illustration 1).

How does creatine get into the muscle?

Now that the creatine molecules have successfully passed your digestive tract they are floating largely unbound (binding affinity of creatine to plasma proteins is less than 10%) in your bloodstream. Whatever happens from now on, is called "clearance" in pharmacological terms - this is counterintuitive at first, but it stands in line with what I have already stressed in my blogpost on Creatine RT, Athletic Edge's creatine monohydrate + Russian tarragon formula. You may remember that Jäger et al. assumed that the smaller increase in plasma creatine they observed upon co-administration of Russian tarragon indicated greater "creatine clearance", which would equal greater muscular creatine uptake. Now, it is true that upon supplementation, the main pathway by which your body "disposes" of the increasing level of serum creatinine is skeletal muscle, but firstly, the tarragon extract could have interfered with the absorption of creatine, for example by modifiying gastric pH levels or intestinal permeability (this is not completely unlikely, since this herb has traditionally been used to cure upset stomachs, cf. Tarragon Central), and secondly, muscular creatine uptake is obviously one way the creatine could have been "cleared" from the bloodstream, the kidneys are yet another.

Image 1: Caffeine + Creatine = Increased renal clearance? Yes! Increased renal clearance = lower performance? No!

Did you know that the longstanding myth that caffeine would counter the beneficial effects of creatine on exercise performance and lean mass gains is bunk despite the fact that caffeine does in fact increase urinary creatine clearance? In a recently published paper on the effect of co-adminsistration of caffeine + creatine to rats (Franco. 2011), the scientists observed statistically significant increases in urinary creatine clearance (+38% after the loading phase with 0.43g/kg creatine and +29% in week 6 of the maintenance phase) over creatine alone when the latter (0.143 g/kg creatine) was administered with 15mg/kg caffeine (human equivalent 2.4mg/kg; ~200mg or 2 small cups of coffee for an 80kg human). When it comes to the real-world results you are looking for, this is yet not likely to be significant.

While the increase in urinary loss may increase the time it will take until your muscle creatine stores are saturated, a study by Lee et al. which compared the effects of creatine alone and creatine + caffeine at a much higher dose equivalent to 480mg or 5 cups of coffee found that "caffeine ingestion after creatine supplements augmented intermittent high-intensity sprint performance" (Lee. 2011) - any fears that drinking coffee or even taking stims could completely negate the beneficial effects of creatine are thus unwarranted.

While researchers initially believed that renal creatine clearance would be equivalent to the glomerular filtration rate (GFR) of roughly 7.0L/h, Poortmans et al. found that, under unsupplemented conditions, creatine clearance is 0.3-0.8L/h, which clearly supports a previously forumlated hypothesis that creatine is reabsorbed and thus "recycled" by the kidneys. Evidence from supplementation studies, where the renal clearance rate increased to 9-22L/h supports the idea that (McCall. 2008)

[a]s blood concentrations increase and more creatine is filtered, less reabsorption occurs and a greater percent age of creatine will be lost in the urine [...] as skeletal muscle approaches its capacity to store creatine, the kidney and possibly other tissues are responsible for the removal of creatine from the blood.

If we follow Mc Call's line of thought and assume that renal creatine clearance is essentially determined by the filling level of muscular creatine stores, it becomes obvious that supplementation with agents that increase creatine transport into the cell would be most beneficial in the "loading phase" (max. 7), when there is actually enough "room" for the creatine to be "stored" within the cell.

Creatine storage - how does that work after all?

A pros pos storage, it's actually quite telling that we know much more about what happens to the creatine molecules within the cell, than about how they actually get there. If you are interested in how scientists initially believed that phosphocreatine (PCr) "would represent the long sought-for 'immediate' source of energy for muscle contraction" I suggest you read Chapter one of the aforementioned compendium Creatine and Creatine Kinase in Health and Disease (ed. Salomons. 2008). For our purposes here it is most important to know that the capacity of our organs (skeletal muscle, kidney and possibly other tissues) is limited and creatine clearance (remember, this includes both the uptake by muscle tissue, as well the urinary clearance by the kidneys) decreases when muscular creatine stores increase (cf. figure 1).

Figure 1: Serum creatine levels (in µM) upon administration of identical doses of creatine at the beginning (first dose) and in the course (steady state) of creatine supplementation (based on McCall. 2008)

This is taken into account with the standard dosing regime, which - after an initial loading phase - uses smaller doses over time. McCall and Persky, explain this as follows:

[...] during early doses (i.e., doses within the first one to three days) when clearance is high, doses of 10 to 15 g per day will give blood concentrations greater than the Km [this is the creatine level in the blood, where creatine transport into the cell maxes out] for the creatine transporter. As the muscle becomes saturated and clearance decreases, it may be necessary to ingest 3 to 5 g of creatine a day to maintain similar blood concentrations.

The higher serum creatine levels upon steady state supplementation you can see in the data in figure 1 clearly substantiate this assumption. Together with the previously mentioned inverse relation of serum creatine to urinary creatine loss, it should also be obvious that taking "loading doses" of more than 10g per day for an extended period of time will at best fill the muscular creatine stores of the rats and cockroaches in the sewer (in case they happen live right next to your sewer pipe ;-)

What controls the muscular creatine transporter?

In order to understand the fundamental biochemical underpinnings of this interplay of dietary, serum and intra-muscular creatine, we do yet still have to identify the pathway by which the creatine molecules eventually get into the muscle. According to the most fundamental (and essentially oversimplified) cell model, a cell is a three-dimensional entity that is surrounded by a protective wall - the cell wall. This wall, of which most of you will have heard that it consists of phospholipids (note the word "lipid" indicates that fats! not proteins are the fundamental building blocks of the cell membrane), has the fascinating characteristic of being selectively permeable. Under physiological conditions transporter proteins function as "gate-keepers" and "taxi-drivers". They select and pick up specific molecules from the bloodstream and carry them across the "border" and into the cell (cf. illustration 2).

Illustration 2: A transporter like the creatine transporter is an active gatekeeper within the cell membrane.

One of the best-known and most-studied group of these transporters is the solute carrier family 6, which play an important role in neurotransmitter regulation in the brain. In the early and late 1990s the gamma-aminobutryic acid (GABA) and norepinephrine transporters were among the first of these Na+/Cl- dependent neurotransmitter transporters to be discovered. It is due to their dependence on the electrical potential between negative Cl- and positive Na+ molecules that they have also become known as neurotransmitter:sodium symporters (NSS, Saier. 1999). They are functionally identical to the likewise Na+-dependent amino acid carriers for taurine, betaine and creatine.

Image 2: β-Guanidinopropionate
competes with creatine for transpor-
tation across the cell membrane

Contrary to many other carriers, the creatine transporter (CT) is yet highly specific for creatine. Among the few exceptions which compete with creatine transport across the cell membrane is β-Guanidinopropionate. Those of you who follow my advice and scrutinize the nutritional information on the labels of their supplements, may be rubbing their eyes in disbelief, now, because Guanidino Propionic Acid or β-GPA is one of the standard ingredients in many pre-workout products (cf. Supplement Shootout, NO-Xplode). The reason for that probably (I would have to ask the producers, though ;-) is its hypoglycemic effect (Meglasson. 1993), which will probably remind you of Athletic Edge's Russian tarragon (see above) or of a 2009 study Rocic et al. which found remarkably similar effects for creatine, itself (Rocic. 2009).

So after all creatine and β-GPA share the same transporter and artemisia dracunculus (Russian tarragon, RT), creatine and β-GPA share the same beneficial effect on muscular insulin sensitivity. Now, Jäger et al. suggest that by increasing insulin sensitivity their RT extract would increase muscular creatine uptake. While this does seem to make sense, the results of Rocic et al. who found creatine to be equally effective as metformin in reducing blood glucose levels would suggest that creatine administration alone should increase it's own uptake ;-) This formally logical, but not very realistic conclusion is yet undermined by the established effect of guanidino propionic acid, which despite identical effects on insulin sensitivity, decreased creatine uptake by muscle cells by 82% (Willot. 1999) in vitro!

Image 3: Of sugar and salt, the "worst enemies" of many dieting body builders and figure athletes, salt and not sugar (or insulin) turns out to be creatine's most eager supporter on its way across the cell membrane (img. squidoo.com)

In the context of insulin sensitivity, it is interesting to note that Willot also tested the hypothesis that insulin would increase creatine uptake into the cell and found that "insulin had no effect on 14C-labeled creatine uptake at concentrations and under conditions in which effects are seen on glucose uptake glycogen synthesis and glycolysis." This finding does not essentialy contradict previous (Green. 1996), as well as very recent findings (Pittas. 2010), which support the idea of increased creatine retention upon coadministration of insulinogenic nutrients such as carbohydrates and/or protein , because "those may be owing to the expression of the creatine transporter, as opposed to acute effects on the transporter" (Willot. 1999). While it should be mentioned that a previous study by Oodom et al. found a 2x increase in creatine accumulation (again, not uptake! Oodom. 1996) after incubation with 3nM/ml insulin for 48h. The latter lacks real world significance, since even after high-carb meals blood insulin levels do hardly get up to 0.3-0.4pM/ml!.

In view of the fact that a -82% decrease in the Na+ concentration of the incubation medium reduced the creatine uptake by 77%, the addition of sodium to your creatine drink may be of greater importance than the fattening loads of simple carbs, anyway.

A 2003 study by Brault et al. confirms Willot's findings on the effect of guanidino propionic acid on creatine influx and retention into skeletal muscle. In the course of seven weeks on a β-GPA-enriched chow the muscular creatine levels of Brault's laboratory animals dropped by -85% (Brault. 2003). Notwithstanding, the flip side of this apparently undesirable effect of β-GPA are increased insulin sensitivity and, more importantly, at least in this context, profoundly augmented creatine uptake.

Figure 2: Effect of 7 weeks of β-GPA supplementation followed by 3 weeks of creatine supplementation on creatine and β-GPA content of the white gastrocnemius muscle in rats; data expressed relative to maximal concentrations (40µmol/g) of the two molecules (data calculated based on Brault. 2003).

Yet while the β-GPA induced creatine depletion increased creatine uptake in the subsequent supplementation phase (week 7+) by +24% and +33% in the soleus and the red gastrocnemius, respectively, creatine uptake in the glycolytic white muscle fibers of the gastrocnemius stayed constant. On the other hand, the white fibers of the gastrocnemius showed the expected decrease (-45%) in creatine uptake, when creatine was supplemented for 7 weeks at 0.85g/kg/day (~11g for 80kg human being) without prior β-GPA-induced creatine depletion (Brault. 2003a).

Figure 3: Creatine uptake (y-axis, in nmol/h/g) as a function of intramuscular creatine content (x-axis, in µmol/g) as measured by Brault. 2003.

These observation go challenge the previously formulated hypothesis that muscular creatine uptake via creatine transporter would always be linearly dependent on intra-muscular creatine stores. While this seems to be the case for the red, oxidative muscle fibers (violet regression in figure 3), the fast-twitch white glycolytic fibers appear to react assimilate creatine at a constant rate (green regression in figure 3) up to a certain threshold (in Brault's rat study that was ~17µmol/g, which is about +30% more than the maximal creatine content measured in red fibers in the same study), at the creatine uptake suddenly drops (cf. figure 3). What is even more confusing, though is that the insignificant changes in the creatine transporter protein expression measured by the scientists reflect neither the linear decrease nor the constant uptake rates. As Brault et al. point out "it is presently unclear what process may modulate Cr uptake" with high / low intra-muscular creatine levels. Possible mechanisms, according to Brault are...

• with increasing intracellular creatine levels the Na+ gradient, which is necessary to drive the creatine into the cell, could become insufficient (unlikely)
• with more creatine in the cell the release process that takes place once the creatine transporter enters the cell may slow down, as if the "taxi driver" would not find a parking lot 
• the number of creatine transporters in the sarcolemmal membrane could be modulated according to intracellular creatine content in a similar manner as the expression of GLUT-4 is modulated by exercise (Goodyear. 1998)
• high intramuscular creatine levels could lead to posttranslational modification of the creatine transporter, similar to what we see in its "relatives", the GABA/taurine transporters, whose activity
  is modified by protein phosphorylation

In fact, a 2002 study by Wang et al. (Wang. 2002) found an increase in creatine transporter phosphorylation that correlated with a reduction in creatine uptake and Zhao et al. observed a 38% increase in creatine uptake in response to a 30% reduction in serine phosphorylation of the CrT (Zhao. 2002). While it is thus most likely that posttranslational modification, something you probably have encountered in one of my blogpost related to the Akt/mTOR cascade, before is the underlying mechanism that controls how effective our "creatine shuttle" works, the unfortunate truth is that this does not go to tell us how we could possibly influence this process.

Conclusion - little do we know about the actual process of creatine uptake

If you look back at what you may or may not have learned from the second part of this write-up, you may notice that I have artistically evaded a direct response to Learner's question whether "creatine transporters behave the same as glucose transporters". Nevertheless, you should have been able to read between the lines that ...

• despite studies showing increased creatine retention (not celullar uptake or creatine transporter protein expression) upon co-administration of insulinogenic nutrients (carbohydrates in Green. 1996 and carbohydrates + protein in Pittas. 2010), in-vitro studies have shown that insulin has no direct effect on muscular creatine uptake (Willot. 1999) - unless supraphysiological doses are used
• at least in red oxidative muscle fibers, there is an inverse linear relationship between intra-muscular creatine levels and creatine uptake (Brault. 2003)
• increases and decreases in creatine uptake are not mediated by respective increases in creatine transporter protein expression (Brault. 2003)
• the most likely hypothesis explaining how intra-cellular creatine levels control the "effectivity" of the creatine transporter is via posttranslational modification, of which we do not yet know for sure how to influence it (the fact that tarragon and other insulin-sensitizers appear to increase creatine uptake could as well be related to changes in the phosphorylation of the creatine transporter as their insulin-sensitizing effects could be related to dephosphorylation of )

It would yet be unfair to leave you with all those additional gaps in your under understanding of the pharmacokinetics of creatine without a few words on the most important aspect of creatine supplementation, i.e. what works in practice.

Image 4: If its not the insulin, then
maybe a steadier influx of creatine
into the blood which can explain the
increased creatine retention upon co-
administration of carbohydrates.

A final note on the issue of carbohydrates: In view of what I have stated in the first installment of this series, i.e. the increase in gastric emptying time due to carbohydrate (and other foodstuff), an alternative explanation for the increase in creatine retention (again, not uptake ;-) upon co-administration of carbohydrates or carbohydrates + protein could be the steadier incline in plasma creatine levels. While the 1996 study by Green lacks the respective data, the figures in Pittas (2010) clearly show that creatine clearance in the creatine-only group increases dramatically after the initial spike in serum creatine levels 30min after the administration of 5g creatine. In view of the negative results of Willot's in-vitro studies on the effects of physiological levels of insulin on creatine uptake and the fact that renal creatine clearance increases with serum creatine levels, while the muscular uptake is maxes out at a relatively low threshold (10-100µM) is surpassed, it is at least possible that it is the steady influx of creatine into the bloodstream and not the insulinogenic effects of carbohydrates that facilitates creatine retention (I hope you remember from the first part of this series that the reduction in creatine influx into the blood due to degradation in the stomach is probably negligible, as long as the dose is large enough to reach blood levels beyond the Km value of 10-100µm)

As I have already hinted at in part I of this installment of "Ask Dr. Andro", for most of us, it does not really matter whether it takes 3, 5 or 10 days until the creatine stores in our muscles are saturated. Moreover, even high quality creatine monohydrate is so "dirt cheap" that you do not really have to care about potential losses (in the 0.3-0.6mg/day range) due to caffeine supplementation or potentially sub-optimal creatine retention in the absence of large boluses of fattening carbohydrates. Personally, I would just stick to what has been working for generations of trainees, now: plain creatine monohydrate taken at a dose of 10-15g/day for 3-5 days followed by a maintenance dose of 3-5g/day.

Ask Dr. Andro: The Pharmacokinetics of Creatine (Part I/II) - How Is Creatine Absorbed into the Bloodstream?

Illustration 1: There is a bunch of things that could potentially go wrong with creatine uptake: The creatine from dietary sources could be mal-absorbed (1) in the small intestine, (2) not make it into the cell, or (3) be excreted too readily either before or immediately after it was transported into the muscle.

Question from Lerner (via comments): Do Creatine Transporters behave the same as glucose transporters? (I.e., serum insulin binds to cellular insulin receptors, which causes Transporters to migrate from inside the cell to the plasma membrane - and the Transporters then pull in the external glucose.)

Answer Dr. Andro: As you may have noticed, I took the freedom to set Learner's question into a broader context. A context I broached in my dissertations on Athletic Edge Nutrition's new creatine product Creatine RT on Tuesday, Aug 16, 2011. Thus, the questions I will be trying to answer (unfortunately, I have to rely on existing studies and do not have my own lab, here ;-) are the following ones:

1. How does creatine get into the blood?
2. How does creatine get into the muscle? (cf. Part II)
3. What can influence these processes?
   

In view of the fact that this is quite an extensive topic, I decided to tackle it in a two part series, where in part 1 (today) I will focus on the issue of creatine absorption into the bloodstream, a putative problem the clever researchers from the supplement industry pretend to have solved, already. Creatine ethyl-ester, Creatine malate, Creatine citrate, Creatine HCL, Creatine whatever, and Krealkalyn(TM)... are the names of the "solutions" to the purported inferiority of creatine monohydrate, the shelves of your local supplement story have to offer.

How does Creatine Get into Your Blood?

In essence all these esters, acids, chlorides and other "creatine + X"-combinations have been designed to mug you... ah, I mean to increase the amount of creatine that makes it into your bloodstream, or in other words, to increase bioavailability. Now, as Wesley Mc Call and Adam Persky state in chapter 13 of Creatine and Creatine Kinase in Health and Disease, there are four potential reasons why creatine bioavailability could be less than 100%, in the first place:

1. Degradation (to creatinine) in the stomach
2. Insufficient dissolution, i.e. passing the intestines "unsolved"
3. Problems with creatine uptake by the epithelial cells
4. Degradation by gut bacteria

1. Creatine could degrade when it reaches your stomach:

We know for certain that creatine degradation is maximal at pH 3 (Cannon. 1927, cf. figure 1). Now, a healthy stomach should have a pH of 1 and for about 84 years everybody (supplement producers included) would have been able to take a look at the data of the 1927 study by Cannon and Shore, who found that after 25 h in a solution with a pH of 1 only ~2% of the creatine would have "degraded" into its dehydration product creatinine and that the often cited "breakdown" of creatine monohydrate in the acidic milieu of your stomach is not really an issue, after all.

Figure 1: Percent creatinine in solution of previously pure creatine after 25, 50, 125 and 1903h at a certain pH (data adapted from Cannon. 1927).

Moreover, the data in figure 1 clearly shows that you would have to have the creatine sit in your stomach for more than 2h before it would make a statistically significant difference (25h: pH1=2%, pH6=2%; 125h ph1=9%, pH6=3%) whether your stomach had a pH 1 or a pH that is greater 6. Now, that certainly sounds ridiculously long, still in conjunction with food (Mc Call. 2008) and outside of the petri dish these effects are, as we are about to see further down, still physiological relevant.

Image 2: You probably expected that it ain't advisable to take your creatine with a Big Mac, but would you have guessed that juices are counter-indicated, as well?

Did you know that the ingestion of a meal will increase the PH of your stomach drastically? Dressman, et al. report an increase to pH ~6 after consuming a hamburger and a glass of milk (Dressman. 1990). After no more than 30 minutes, however, gastric secretion had reduced the pH to 4-3 and after roughly 90 minutes, the stomach of the subjects was the same "acid pit" (pH 1.3) as it was before the ingestion of the meal. This goes to tell you that taking creatine with a meal or even worse right after a meal could be counter-indicated.

Tip: You better wait at least 90 minutes after your last meal, before you flush down your creatine with water, as even the presence of carbohydrates from juices has been shown to "delay the time to peak concentration", which usually is less than 2h and to decrease the maximal concentration at peak concentration (Mc Call. 2008).

What you certainly want to avoid, though, is a pH somewhere between 3-4. However, even in this "worst" case scenario less than 10% of the creatine would undergo the (at higher pH partly reversible!) reaction from creatine to creatinine. So, as Mc Call and Persky point out, the "relatively short time the creatine actually spends in the stomach means that very little of the oral dose of creatine should be lost" (Mc Call. 2008) - at least, if you take it on an empty (and healthy, i.e. highly acidic) stomach.

2. Creatine (Monohydrate) could not dissolve and thus be not absorbed

Illustration 2: Creatine is taken up by enterocytes in the jejunum and the illeum.

The issue of undissolved creatine monohydrate crystals, has been discussed on bulletin-boards and in the ads of several supplement companies ever since the first "advanced" creatine products hit the market. Yet, while it is beyond debate that the enterocytes of your small intestines (in rats creatine has been found to be absorbed in the ileum (Peral. 2005) and the jejenum (Tosco. 2004), cf. image 2) cannot absorb bulky creatine crystals, the solubility of creatine monohydrate in water at 20°C is 14 g/L at a neutral pH of 7. Now, with lower pHs and higher temperatures (as mentioned before your stomach should have a pH of about 1-2 and your body temperature obviously is ~37°C) it is absolutely unlikely that the creatine would not dissolve. Using creatine citrate, which, due to its lower pH (solution has pH 3.5), has a 1.5x higher solubility, or other highly soluble forms of creatine is thus not necessary, if your stomach is the warm acid pit it is supposed to be.

Interestingly, a study by Harris et al. suggests that the creatine from meat such as the paddies of the burger in image 2 (I am assuming here that there is still some meat in McDonalds burgers / here in Germany they have recently begun advertising their meat quality ;-) is more readily absorbed (this refers to absolute amounts, not to the time-course) than either creatine suspended (=more creatine in water than can be solved) in water or creatine tablets / lozenges (Harris. 2002). A probable explanation for this phenomenon could be that the creatine is safely contained in the meat, until the latter is broken down by enzymes that are activated as  the pH of the stomach is decreasing. Thus only very limited amounts of free creatine will be exposed to pH levels in the detrimental3-4 range.

3. Creatine could simply not be taken up by the enterocytes in the small intestine

Obviously, any general digestive problem related to nutrient transport across the epithelial barrier in the intestines could compromise creatine uptake, as well. As mentioned earlier the presence of large (180g) amounts of carbohydrates have been shown to slow gastric emptying and consequently creatine absorption, considerably (Vist. 1995). In addition several other meal-constituents could also increase the pH temporarily and thus initially decrease solubility (when pH is still very high) and consequently increase creatine to creatinine breakdown (when the pH passes the critical 3-4 range, see above).

4. Creatine could be degraded by bacteria in the gut

Image 2: Biridobacterium tongum is a probiotic and a natural enemy of putrefective bacteria, who "suffocate" from the lactic acid, acetic acid and bacteriocins (image from dophilus.com)

Even if the creatine survives passage through the stomach, is dissolved and the enerocytes are ready to absorb it, it could still be taken up by putrefective bacteria (bacteria that break down organic material) of which William C. Rose in a paper in the Annual Review of Biochem. writes that they transform creatine  into methylhydantoin, which previously had been shown to yield sarcosine under the influence of micro-organisms" (Rose. 1933) Unless you want Patrick Arnolds sarcosine as an adjunct to d-aspartic acid (as in TestForce 2), I would say this is another good reason to keep your gut clean and tidy ;-)

Conclusion: Absorption should not be an issue

If your gut is healthy, acidic and free of pathogenic amounts of putrefective bacteria there is absolutely no reason you could have problems absorbing creatine - especially if you stick to my recommendations and

• do not escalate single dosages beyond 5g, 
• take your creatine on an empty stomach (or at least 90 min after your last meal)*
  (taking creatine with carbs + protein will increase breakdown to creatinine, and decrease the maximal serum levels, but, on the other hand, it will increase muscular creatine retention, cf. Part II)
• do not take creatine with a meal or protein or large amounts of carbohydrates**
  (read more on the carb issue in the 2nd part of this installment of "Ask Dr. Andro", tomorrow)

A tweak to this general guideline resolves around the "mysterious" issue of alkaline creatine. The results from the Cannon study show that you have the choice:

• increase your stomach pH beyond 6, or 
• decrease your stomach pH below 2 

 if you want to avoid the breakdown of creatine to creatinine.

Figure 2: Relative increase in creatine in dry muscle mass of horses, after supplementation with creatine monohydrate, kre-alkalyn or Gastner's patented creatine + sodium carbonate +sodium hydrogen carbonate formula (Gastner. 2010)

Timing creatine away from meals would be option #2, option #1, on the other hand, would entail supplementing with some strong alkalizing agent such as sodium or potassium bicarbonate, and in fact, this is exactly what KreAlkalyn, the purported "super-creatine" is - a ph-buffered creatine-monohydrate product. Thomas Gastner holds the patent to a formula of which had a higher stability than KreAlkalyn and consists of nothing else but 2.98g creatine monohydrate + 150mg sodium carbonate + 118mg sodium hydrogen carbonate. According to self-conducted animal experiments (horses= the increased stability entailed a statistically significant improvement in muscular creatine retention after 4 weeks on creatine enriched feed pellets (+7% over creatine monohydrate and +10% over KreAlkalyn).

Image 3: Kre-Alkalyn - expensive, but probably
useless - at least when taken with food.

The results of Gastner's experiment should obviously be taken with some skepticism. Nevertheless, the picture we are seeing here is conclusive, because either you rely on the acidity of your stomach (using plain creatine monohydrate) or you put enough alkaline buffers into your product so that the acidity of the stomach remains greater than pH 6 for a long enough amount of time. With Kre-Alkalyn (and horse stomachs) it appears that Jeffrey Gollini who holds the patent for KreAlkalyn managed to hit exactly that most unfavorable pH range, where the overall pH of the food + KreAlkalyn solution in the (horse-)stomach falls back into the 3-4 range very quickly and the creatine uptake is reduced due to the increased breakdown of  creatine to creatinine.

In summary, this is a clear points win for creatine monohydrate taken on an empty stomach (or, alternatively with a significant amount of buffers + food). Fidgeting with citrates, malates, and esters which will eventually be cleaved (if you are unlucky at the very same moment your gastric pH has returned to the "danger zone" of 3-4), may be promotional, but either is not likely to be superior (citrate, malate & co) or has been shown (creatine ethyl ester, cf. Spillane. 2009) to be inferior to the undefeated 'top dog' creatine monohydrate.

Click here to read Part II: How Does Creatine Get into the Muscle

Ask Dr. Andro: Are Colostrum and Milk Products in General Healthy Muscle Builders, a Waste of Money or Toxic Waste?

Image 1: Colostrum and other milk products
Milky muscle builders or murky allergens?
(image from SportRevue 6/2010)

Question from Peter Art (via Facebook): Do you still have a plan to release a write up about colostrum or it may be delayed? I am just asking.

Answer Dr. Andro: In fact it got delayed, the delay got delayed again and now there is so much delay that I felt like further delaying the write-up would border pathological procrastination... Instead of citing the three existing studies on colostrum, however, I decided to do a more comprehensive "Ask Dr. Andro" segment on the powers and perils of the milky mammalian life-elixir that has been used and later abused (I am referring to the modern way of food processing here) by generations of human beings and is still considered as an "evolutionary inappropriate" foodstuff by some.

"Muscle building magic happens, when you put the right stack together", says Carl Lenore in a spot for IronMagLabs prohormones - Well, guess what milk may be the original "stack"

Image 2: If you are interested in the way
the US government treats non-compliant
raw dairy producing listen to Carl Lenore's
rant against the "Rawsome Raid"

It is not by accident that milk (and colostrum) have always had the reputation of being powerful muscle and strength builders. Few modern bodybuilders would go without their whey protein and at least among the non-carbophobic body builders there are still a few who swear by the consumption of gallons of the "white gold" - at least in the off-season. In fact, nature invented the milky liquid not as "a", but as "the" source of essential amino acids and more. And, as we will see, part of this "more" is what either fascinates or scares people about milk.

Depending on which expert you are asking you will either be told about the life-threatening dangers or the almost magical benefits of the biologically active proteins, peptides, lipids and sugars in milk and related dairy products. In that, it stands out of question that these peptides display antimicrobial, opioid, mineral-binding , antihypertensive, antithrombotic, and immunomodulating properties. 

Physiological Effect / Classification	Compound(s)
Opioid agonists (decrease gastric mobility, increase electrolyte and amino acid uptake)	α- ,β-caseins, α-lactalbumin, β-lactoglobulin, serum albumin
ACE inhibitors (increase blood flow to intestinal epithelium)	α- ,β-caseins
Mineral binding (increase absorption)	α- ,β-caseins
Immunomodulators (increase immune response and phagocytic activity)	α- ,β-caseins, gG, IgA, lactoferrin, glycolipids, oligosaccharides, prolactin, cytokines
Antimicrobial	αs1 and s2-casein, lactoferrin, oligosaccharides, prolactin
Antithrombotic	κ-casein
Probiotic	κ-casein, lactoferrin, oligosaccharides
Opioid antagonist	κ-casein, lactoferrin
Organ development and function	IGF-1, TGF-α, EGF, TGF-β
Increase calcium metabolism and uptake	Parathromone - P
Table 1: Milk as a "functional food". Physiological effects and their respective triggers. (adapted from Schanbacher. 1998; Meisel. 1998 and Clare. 2000)

The overview in Table 1 makes it quite clear, milk derived peptides are hardly inferior to pharmacological agents. Whey proteins and peptides derived from the enzymatic proteolysis of casein and whey, for example, modulate a variety of processes such as lymphocyte activation and proliferation, cytokine secretion, antibody production, phagocytic activity, and granulocyte and natural killer (NK) cell activity (Gauthier. 2006).

Illustration 1: Bioactive components in milk and their respective beneficial effects on health markers.
(adapted from Corhonen. 2009; in Park, ed. 2009, ISBN 978-0-8138-1982-2)

Whether we want to exploit or rather avoid these effects (cf. illustration 1) is yet still a matter of constant debate and the increasing financial interests of the "functional food" industry is beginning to compromise the objectivity, or, to be fair, I should say the "balance" of scientific research.

Did you know that a 2007 forecast estimated the sales in functional foods for the US to 3,478 million US$? I suppose now you will begin to understand why companies are willing to spend millions of dollars into respective research and nobody really cares about potential negative side effects of what I would like to call "functional food gone disfunctional"... its a pity!

The Immunoglobulin / Allergy Side of the Coin

In view of the current scare of gluten-, soy and whatever anti-bodies to food your body is able to produce, it must be said that mammalian immunoglobolins (IGs) are essential to the humoral part of the immune defense of the neonate. Milk, and colostrum in particular, one could say, are specifically "designed" by nature to provide the newborn with antibodies until its own immune system learns to handle the constant assault on its own.

Figure 1: Bioactive substances in colostrum and milk - note the particular differences in immunoglobolin, lactoferrin, serumalbumin and growthfactors (data adapted from Corhonen. 2009; in Park, ed. 2009, ISBN 978-0-8138-1982-2)

From the perspective of the opponents of milk / colostrum consumption, a keyword in this context is "immune maturity". "Why?", they will be asking the proponents of milk consumtion (or even deliberate enrichment of dairy products with immunoglobulins), "Why would a grown up mammal want to consume foreign anti-bodies, if he/she is well able to produce all the necessary immunoglobulins on his/her own?"

Image 3: It is a reasonable, yet not
scientifically studied question, if
milk per se, or rather the industrialized
variety you buy at the grocery store
is the cause of all sorts of autoimmune
reactions (image from CCRecycling)

If you just have a look at the sheer amount of studies PubMed returns for the keywords "milk AND immunoglobulins AND allergy" (1639 hits!) the answer appears to be a clear "No reasonable mammal would want that!" (This does yet raise the question if humans can be regarded as "reasonable mammals"... well, you decide ;-) Already at the ninth position, right after a comprehensive review on the "Epidemiology of food allergies" there is a study reporting beneficial effects of fermented milk products grass allergies (Wassenberg. 2011) and a random klick on review #5, "Food allergy therapy: is cure within reach?" by Nowak-Wegrzyn and Muraro (2011) is surprisingly not about curing milk allergies, but about curing allergies with milk products.

These random examples are not meant to negate the well-established prevalence of autoimmune reactions (often in its immediate form, which most of us associate with the term "allergy) to milk products. According to Cattan et al. (2011) 2%-3% of young children display are affected by cow's milk allergy. I do yet wand to submit that even this unfortunate statistic does not answer the question whether it is the "living nutrient" milk or rather its dead, highly contaminated industrial incarnation that affects the children.

Figure 2: Concentration of immunoglobulins in bovine and human milk and colostrum; mind the logarithmic scale!
(data adapted from Stelwagen. 2009 according to Butler. 1973)

Although the immonoglobulin-composition of bovine milk is obviously different from the one of human milk (cf. data in figure 2), the increasing number of studies which show beneficial immunological effects related to the consumption of colostrum or respective concentrates, as well as epidemiological and controlled studies on the consumption of "real", i.e. raw milk from pastured cows, seem to suggest that individual genetic factors aside, the "contamination" of commercial milk products could well be one of the underlying factors of its allergy-triggering effects in certain populations. After all, milk is meant to nourish an infant, so that it becomes a carbon-copy of its parent, which, as it survived evolutionary selection pressure and successfully reproduced, should be healthy and not unviable and drugged to the eyeballs as the average dairy cow, today.

Is there any "Raw Truth" to the Stories About Unpasteurized Milk?

The remarks on the industrialized dairy production at the end of the previous paragraph bring up the question whether milk from the opposite site of the spectrum, i.e. raw milk from happy pasteur-fed cows, would really be a better or even generally healthy alternative to the white potage in your fridge. A first clue that this may in fact be the case can be found in a 2006 paper (with no declared conflict of interests) by the British scientists Michael R. Perkin and David P. Strachnan on the inverse association between farming lifestyle and childhood allergy (Perkin. 2006), in which they state that

current unpasteurized milk consumption was associated with significantly less current eczema symptoms (adjusted OR, 0.59; 95% CI, 0.40-0.87; P 5 .008) and a greater reduction in atopy (adjusted OR, 0.24; 95% CI, 0.10-0.53; P 5 .001) [... and] was associated with a 59% reduction in total IgE levels and higher production of whole blood stimulated IFN-g (P = .02)

The most interesting finding, however, was that "the effect was seen in all children, independent of farming status".

Figure 3: Percentage of pathogen infected samples of different foodstuffs; missing bars indicate no sample available
(data adapted from a presentation by Baars. 2010)

Now, you may say that all this sounds fine, but everyone knows that raw milk contains pathogens that are a potential thread to your life... well, the actual data on the issue of microbial risks and foodborne illnesses by pathogens like campylobacter, salmonella, staph. aureus, EHEC, etc. in raw milk, presented by Prof. Dr. Ton Baars from Department of Biodynamic Agriculture at the University of Kassel (Germany) at the 2nd Annual International Raw Milk Symposium in Madison (WI) on April 2010 speaks a very different language. Obviously, people who are afraid of raw milk would never even remotely consider eating raw chicken (the worst offender on the list), but some of them may have been to one of the hip sushi restaurants, lately, and would thus have had a 7.4x higher chance of infecting themselves with listeria, an infection of which 20 to 30 percent of the clinical infections result in death, than raw milk drinkers... But hey, I am losing track, here. The raw vs. pasteurized, conventional vs. grass-fed and medically treated vs. medication-free debate would be a topic for an individual installment of the "Ask Dr. Andro Series" and thus I will try to get back to the question at hand.

Colostrum, Milk and the Athlete

Image 4: Over years, milk has
been marketed by athletes in
Germany (image (c) CMA)

German soccer star Miroslav Klose (image 4) says "Milch ist meine Stärke!" (loosely translated "Milk is the reason for my success!") in an advertisement of the German CMA which mentions the usual suspects, calcium, lactose and protein, as the cornerstones of what a world-class striker needs. And in fact, an "expert" discussion on the benefits of whey vs. casein as part of the ideal post-workout supplement in an old thread of the Mind and Muscle Forum yielded a result with a nutrient composition that looked surprisingly familiar: some fast digesting whey + some casein for a sustained protein supply, a few carbs, some minerals and vitamins = the ideal post-workout supplement, or put more simply, MILK! And in fact, science seems to confirm what the brainy trainees on a bulletin-board have thought out.

As an avid reader of the science news on the SuppVersity you will probably be familiar with the fact that, time and again, plain chocolate milk, with its mixture of fast and slow digesting carbs and proteins, has either stuck with or even outperformed expensive post-workout formulas (cf. table 2)

Author(s)	Result(s)
Ferguson-Stegall. 2011b	"CM [chocolate milk] postexercise improves aerobic power and body composition more effectively than CHO [carbohydrate] alone"
Ferguson-Stegall. 2011a	"CM supplementation can improve subsequent exercise performance and provide a greater intracellular signaling stimulus for PRO synthesis compared to CHO and placebo"
Gilson. 2010	"CM provided similar muscle recovery responses to an isocaloric CHO beverage during four-days of ITD [increased training duration]. Future studies should investigate if the attenuated CK [creatine kinase = marker of muscle damage] levels observed with CM have functional significance during more demanding periods of training"
Pritchett. 2009	"These findings indicate no difference between CHOC and this commercial beverage as potential recovery aids for cyclists between intense workouts."
Thomas. 2009	"Participants cycled 51% and 43% longer after ingesting CM (32 +/- 11 min) than after ingesting [commercially available] CR [carbohydrate drink] (21 +/- 8 min) or FR [fluid replacement drink] (23 +/- 8 min)"
Carp. 2006	"[...] chocolate milk is an effective recovery aid between two exhausting exercise bouts"
Table 2: A selection of recent studies on the ergogenic effects of (chocolate-)milk

On the other hand, most of these beneficial effects on regeneration, protein synthesis etc. could be attributed to the nutrient content of (chocolate) milk alone. A question that would be of much greater interest to the majority of athletes and fitness enthusiasts would though be, whether or not they could benefit from the various growth factors scientists have found in milk and dairy products since the initial discovery of growth-promoting or -inhibitory peptides in colostrum in the 1980s.

Colostrum: A Miracelous, White "Growth Factors" Elexir!?

Now, as the data in figure 1 indicates, colostrum is by far the best source of these growth-regulators, as I would like to call them. BTC (beta cellulin), EGF (epidermal growth factor), FGF1 and FGF2 (fibroblast growth factor), IGF-I and IGF-II (insulin-like growth factor), TGF-β1 and TGF-β2 (trans- forming growth factor) and PDGF (platelet  - derived growth factor) - for all of them applies that their concentration, both in human, as well as in bovine colostrum is highest during the first hours after childbirth / calving (cf. figures 3 and 4).

Figure 4: Reduction in immunoglobulins in colostrum after two and three days relative to immunoglobulin content of colostrum on day one post-partum (data calculated based on Kelly. 2003)

The question we would have to answer to understand whether and to which extend athletes could benefit from the presence of this 53 to 425 amino residue polypeptides in colostrum (and in much lower concentrations in milk) is threefold:

1. Which of these growth factors could improve athletic performance?
2. Is the dose of the respective growth factors in milk / colostrum sufficient to illicit physiological effects? And most importantly...
3. Can these oral growth factors nature intended as a supplement for the newborn calf do their magic in adult human beings, as well?

The latter question obviously implies that the large majority of athletes won't be able to obtain human colostrum and would thus have to rely on the bovine variety, which is readily available at local farms and, as a powdered supplement, at various bulk supplement vendors on the Internet.

Figure 4: Reduction in cytokines in colostrum after two and three days relative to cytokine content of colostrum on day one post-partum (data calculated based on Kelly. 2003)

With regard to the powdered supplements, but also in view of the potential benefits of "regular", i.e. pasteurized milk, it should be noted that the growth factors present in milk seem to withstand pasteurization and even ultrahigh temperature (UHT) heat treatment of milk relatively well (Gauthier. 2006). While EGF and BTC, as stimulators of epidermal, epithelial and embryonic cells, are relatively uninteresting for healthy athletes, their ability to promote wound healing and bone resorption could be particularly interesting for injured athletes. The same is true for the two forms of TGF-β, both of which stimulate the proliferation of connective tissue cells.

The two forms of IGF, on the other hand, stimulate the proliferation (cell growth) of various tissues, and regulate metabolic functions such as glucose uptake and the synthesis of glycogen. It stands to reason that their highly marketable presence in colostrum is the main reason for athletes and fitness enthusiasts to invest a non-negligible share of their hard-earned money into respective supplements. The question yet remains, are they wasting their money?

Will the Growth Factors Be Absorbed, At All?

It has been established by animal studies that EGF, TGF and also both IGF isoforms "provoke various local effects on the gastrointestinal tract and can be absorbed intact or partially from intestine into blood circulation" (Korhonen. 2009; in Park, ed. 2009, ISBN 978-0-8138-1982-2). As you may have read in my dissertations related to the IGF1-spray, rodent studies show that naturally occuring proteins (e.g. casein) and protease inhibitors in milk protect these peptides against gastric and intestinal breakdown. The number of human studies on the subject is yet not very extensive, to say the least. The most comprehensive research has probably been done by Antti Mero and his group at the Department of Biology of Physical Activity at the University of Jyväskylä in Jyväskylä, Finland. Their results show that in the absence of performance increases in vertical jump performance, 8 days of supplementation with a commercially available colostrum product (Bionervie) dose-dependently increased serum IGF-1 levels (Mero. 1997).

Figure 5: Changes in IGF serum concentration [in nmol/L] between pre- and posttraining in 9 male sprinters and jumpers; note: a follow up study showed that the increase in IGF was not a result of immediate oral absorption, but a downstream effect of colostrum supplementation (data adapted from Mero. 1997)

These observations are not only noteworthy because they suggest that IGF1 from bovine colostrum survives gastrointestinal passage and would (read the rest of this post!) be readily absorbed into the blood stream by the gut lining in human beings, but also because the effects of 25ml and 125ml also compensated the training induced decrease in IGF1 measured in the placebo group (cf. figure 3).

Image 5: Creatine Monohydrate increases
IGF1 by 24% over placebo (Burke. 2008).

Did you know that plain creatine monohydrate, taken at a dose of 0.25 g/kg lean-tissue mass for 7 days (loading phase) and 0.06 g/kg lean-tissue mass for 49 days (maintenance phase) increased intramuscular IGF1 levels in 12 men and women, who did nothing but 30 minutes of very light aerobic activity per day, by a whopping +24% over placebo? Regardless of whether or not you believe that colostrum works. Creatine certainly does! And I stand to what I said before: Creatine monohydrate is still the king of all dietary supplements.

Within the scientific community the results of Mero's study were highly disputed, claims were made that the increase in IGF concentrations was "spurious, caused by inaccurate measuring techniques" etc. In an experimentally more sophisticated (gel electrophoresis techniques) follow up study, Moreno et al. were however able to replicate the results from the previous study with another colostrum product (Dynamic). Much to the scientists surprise, however, the measured increase in serum insulin like growth factor was not a result of direct oral absorption of the growth factors from the colostrum, but the result of an increased endogenous IGF production that was triggered by the intake of the supplement (Mero. 2002):

Absorption data show that ingested 123I-rhIGF-I [that is the previously radiolabelled IGF1 in the colostrum] is fragmented in circulation and that no radioactive IGF-I is eluted at the positions of free, or the IGF, binding proteins, giving no support to the absorption of IGF-I from bovine colostrum.

Yet even if colostrum does not do its magic by delivering IGF and other growth factors into the bloodstream, it appears to "work" and thus the question that remains to be answered is whether plain milk, or rather a whey protein supplement, which currently is the gold-standard for the majority of athletes and fitness enthusiasts, would not be as effective as the more expensive colostrum supplements.

Illustration 2: According to Buckley. 2003 there may be a 500% difference in price, the effect on serum IGF1 and exercise performance of 60g colostrum and 60g whey per day, are yet 100% identical.

The answer to this question comes from a 2003 study by Buckley et al. who compared the effect of 60g of bovine colostrum to the effects of the same amount of a standard whey protein supplement and found similar performance increases in both groups and no effect on IGF levels in any of the 51 men (Buckley. 2003). Moreover, Burke and Deakin remark in their review of the literature in Chapter 16 of the third edition of Clinical Sports Nutrition that studies using trained subjects were less likely to show any effect of colostrum supplementation at all (Burke. 2006).

Author(s)	Result(s)
Shing. 2006	"[10g/day] bovine CPC [colostrum concentrate] supplementation elicited improvements in TT40 [40 km time trial] performance during an HIT period and maintained ventilatory threshold following five consecutive days of HIT"
Buckley. 2003	same increase in peak power for 60g colostrum as with whey protein; no increase in IGF1
Brinkworth. 2004a	"[cross sectional area of biceps increased more in trainees supplemented with 60g bovine colostrum than in whey control, but that was] due principally to a greater increase in skin and subcutaneous fat (SSF) CSA"
Buckley. 2003	same increase in peak power for 60g colostrum as with whey protein; no increase in IGF1
Buckley. 2002b	"[...] latively few scientifically controlled studies have been conducted. The limited evidence that is currently available suggests that BC supplementation can increase lean body mass and improve exercise performance and recovery for a number of athletic activities, but an understanding of the mechanism by which this supplement exerts these effects remains elusive"
Buckley. 2002a	"[...] supplementation with intact powder did not increase plasma IGF-I concentrations or improve performance during an initial bout of incremental running to exhaustion in our sample. However, performance during a second bout of exercise may be improved by as much as 5.2% in the average subject after 8 weeks of supplementation, possibly due to an enhancement of recovery"
Coombes. 2002	"Oral bovine colostrum supplementation at 20 g or 60 g/d provided a small but significant improvement in time trial performance in cyclists after a 2-h ride at 65% VO2max." [improvements were 20g colostrum+40g whey  60g+ colostrum 60g+ whey]
Antonio. 2001	"[...]supplementation with bovine colostrum (20 g/d) in combination with exercise training for 8 wk may increase bone-free lean body mass [+1.5 kg, while whey-placebo group increased overall BM by +2 kg] in active men and women."
Mero. 1997	"appears that a bovine colostrum supplement (Bioenervi) may increase serum IGF-I concentration in athletes during strength and speed training" (cf. discussion in the text)
Table 2: A selection of studies on the ergogenic effects of colostrum

Personally, I would trace these subject-specific differences back to an already optimized nutrient supply, where the addition of the beneficial amino acids, minerals and vitamins from colostrum (or milk) does not make much of a difference. Otherwise, I would allign myself with the following statements Burke and Deakin make in view of the expedience of colostrum supplementation

[t]he only consistent findings from the present studies of colostrum supplementation are that there are no apparent benefits to the outcomes of resistance training (Antonio et al. 2001; Buckley et al. 2003; Brinkworth et  al. 2004), and that when benefits are detected, they are apparent only after more than 4 weeks of treatment (Buckley et al. 2002, 2003).

[...] The lack of a plausible hypothesis to explain how colostrum might enhance the response to exercise is also an important absence.

[...] Whether all colostrum supplements are of equal quality or efficacy is also a concern.

In view of the exorbitant costs of a colostrum supplements (cf. illustration 2) and the absence of any reliable quality standards (you never know if "your" colostrum has even remotely the same nutrient / growth factor composition as the one used in one of the studies) I thus strongly advise against spending the roughly 270$ a month supply of bulk colostrum powder (of questionable quality) would cost you, if you wanted to mimic the 60g/day dose that was used in the majority of studies with beneficial outcome.

Figure 6: 1st-day Colostrum is a particularly
rich source of antibody against all
sorts of pathogens (adapted from
Stephan. 1990 and Rump. 1992)

Colostrum, Pathogens and Infections

I've broached the issue of possible infections from (raw) milk in a previous paragraph, already. As it turned out, chicken, meat and most notably fish, one of the only foods even the "hip", health-conscious Men's Health or Shape readers are scarfing down raw, are the major offenders, when it comes to pathogen infections. Now, what's even more interesting is that to protect the growing calf from harm, colostrum comes with a whole host of antibodies against all your favorite pathogens:

• Helicobacter plyori
• E. coli (remember the recent death-toll in Europe?)
• Rotavirus
• Salmonella 
• Staphylococcus
• Candida albicans
• and many more

And these are only the best-known of the antibodies that have hitherto been identified in 1st-day colostrum (cf. titer=antibody count values in figure 1).

In view of the sheer amount of highly bioactive compounds in colostrum, it is no wonder that the "early milk" has also been implicated as a viable treatment for several gut pathologies. Its ability to eradicate gut parasites such as candida or helicobacter plyori aside, its effect on intestinal permeability may be of greatest value for athletes, who experience significant (sometimes more than 2.5x, which is similar to what is seen upon the administration of particularly nasty NSAIDs such as indomethacin) increases in gut permeability as a consequence of streneous exercise.

Image 6: Could Glutamine be
the cheap colostrum?

Did you know that the cheap supplement l-glutamine has also been shown to protect athletes from exercise induced increases in gut permeability and the consequent influx of toxins and pathogens into their blood stream? No? Well I guess than you have missed the Amino Acids for Super Humans Series, a joint project of the SuppVersity and Carl Lenore's Super Human Radio and a "must read / listen", if you are interested in the ergogenic of these nitrogen containing molecules which are much more than just building blocks of protein and muscle.

Click here to read all about l-glutamine

A very recent study by Marchbank et al. shows that the administration of 20g/day of colostrum in the 14 days prior to a standardized exercise test blunted 80% of the detrimental effects on intestinal permeability and thus protected the subjects from the influx of luminal toxins in the post-exercise period (Marchbank. 2011).

Staving off the Common Cold (and Other Ailments) with Supplemental Colostrum!?

Compared to the information on its effect on gut health, the scientific data on the immune-strengthening effects many people associate with, or even expect from the consumption of colostrum is less unequivocal. While long term studies (10 and 12 weeks of 25g/day supplemental colostrum) showed improved immunity and reductions in upper-respiratory tract infections in distance runners (Crooks. 2006) and swimmers (Crooks. 2010), respectively, a 2011 study by Carol et al. showed no improvement in the immune reaction to a 90-minute glycogen-depletion trial over skim-milk, when the subjects had consumed a similar colostrum supplement as it was used in the Crooks studies in the ten days prior to the experiment (Carol. 2011).

Image 7: Long distance endurance athletes
such as swimmers and marathon runners
probably benefitmost from colostrum.

Regarding the results of the 2006 Crooks study, it is important to note that a 2010 study by Peters et al. (Peters. 2010) found that their markers of immune status, i.e. the number and composition of immunoglobulins, did not correlate with incidences of upper-respiratory tract infections in marathon runners. It is thus questionable how significant the increases in salivary immunoglobulins they observed in their 35 distance runners actually is, as far as its real-world outcomes are concerned.

Whether the differences we see in the results of these studies are related to milking time (remember the immunoglobulin content is highest in day 1 colostrum) and thus the product quality, the type of exercise (repeated long-distance endurance exercises such as running and swimming are notorious for wreaking havoc on your immune system) or simply the duration of supplementation is hard to say. If you nailed me down to a single answer, I would say chronic stress, as in long-distance running, requires chronic supplementation of a stress-reducing supplement. Thusly, I would blend the last two of my suggested explanations into a single more comprehensive one.... Nevertheless, even if you are a marathon runner or Ironman competitor you should ponder, whether these inconclusive results really warrant an investment of more than 112$ for a month supply of colostrum (this is what it would cost you if you used the 25g/dose that worked for the swimmers in Crooks. 2010).

Hormones and Other 'Fun' Compounds in Milk and Colostrum

Figure 7: Androgen and estrogen content in
milk from French supermarkets collected in 2006
and 2007 (data adapted from Courant. 2008)

Last but not least, and as we will see probably less related to athletic performance than to unwanted side-effects, is the often cited endless list of

• gonadal hormones (estrogens, progesterone, androgens), 
• adrenal (glucocorticoids), pituitary (prolactin, growth hormone), and hypothalamic hormones (gonadotropin - releasing hormone, luteinizing - hormone – releasing hormone, thyrotropin - releasing hormone), and 
• peptides and hormone-like substances like somatostatin, bombesin, calcitonin, insulin, melatonin, and parathyroid hormon, and
• pesticides and other toxins, beta-agonists, non-steriodal-antiinflammatory drugs, etc.
• melamine (the stuff the Chinese add as a protein substitute that then kills their babies)

that have been found in colostrum or milk of bovine origin.

I've already broached the issue of peptides, will leave aside the toxins, pesticides and co, simply because these are exogenous contaminants you may or may not find in your milk products (not to mention that this blogpost is already epic enough ;-) and conclude this epic "Ask Dr. Andro" segment with a brief discussion of the potential dangers or benefits of naturally occuring hormones in milk. 

By now, the presence of all sorts of hormones in "white gold" actually should not surprise you anymore. I've already mentioned in one of the previous paragraphs that the milk of a mammal is just as much a mirror of its metabolic and endocrine status, as is its blood. This obviously entails that if you inject your cows with growth hormone (as it is obviously still allowed in the US) or other hormones to increase milk production or whatever other wicked intention you may be harboring, you will obviously find "traces" of these exogenous hormones in the milk and, even more so the, colostrum of your cow.

Figure 8: Naturally occuring androgen and
estrogen content in different forms of colostrum
(data adapted from Farke. 2011)

Other factors that will influence the type and amount of hormones you will find in your milk, i.e. the milk you buy at your grocery store, farmers market or friendly dairy farmer, are related to

• what the animals were fed
• which medications the animals received
• when, i.e. in which hormonal phase (note: the melatonin content even varies with the time of the day), the cows are milked
• what "happened" to the milk on its way from the cow / farmer into your fridge

These are, quite obviously, too many factors for me to consider, but if you look at the little publicized data, there is, you will find that some information that applies to pretty much all (uncontaminated) milk and colostrum products, regardless of whether you bought them from your local farmer or the grocery store (cf. figures 8 and 9):

1. colostrum (skimmed) contains roughly 19x more androgens and 213x more estrogens than whole milk
2. for milk and colostrum the full fat variety tends to have generally higher levels of both androgens and estrogens - for colostrum, for example the fat fraction contains 10x androgens and 10x more estrogens than the skimmed variety, which is also used as a base for most powdered colostrum supplements
3. in the case of milk, the ratio of androgens to estrogens (AE-ratio) drops by -34% during the skimming process; in fact, skimmed milk contains more estradiol (per liter) than whole milk.

Now to put these general observations as well as the data in figures 7 and 8 into a "health perspective" we got to have a look at the respective "acceptable daily intake" (ADI) established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the maximum secure daily intake established by the FDA:

• 17beta-testosterone - 2µg/kg (ADI), 320ng/kg (FDA)*
• 17beta-estradiol - 50 ng/kg, 65ng/kg (FDA)
  
  * Isn't it strange how the FDA allows roughly 160x the amount of testosterone to be present in foodstuff than the WHO considers an "acceptable daily intake"? How come steroids are illegal in the US, then ;-)?

Now how much of our milk products would an 80kg human or his/her 1 year old toddler have to consume in order to surpass these levels?

Figure 9: Number of 0.3l cups of milk or colostrum an 80kg adult human being or a 1 year old 10kg toddler would be "allowed" to consume according to the JECFA acceptable daily intake (ADI) and the maximum secure intake as established by the FDA (FDA); data has been calculated on the basis of figures 8 and 9, i.e. based on naturally occuring levels of the respective hormones

As my calculations in figure 9 clearly show, the general public is not really in danger of hormonal "intoxication" by colostrum, let alone milk consumption - at least as long as the dairy does not come from cows who have been treated with hormones. Even if we assume that all the hormones would pass right through the endothelial layer of your intestines and into your blood stream it would still take 4 full 0.3l cups of the fat fraction of colostrum for a toddler to surpass at least the WHO's very rigid acceptable daily intake recommendation for testosterone.

Image 7: If you want the anabolic effect
from milk or colostrum you better buy
yourself this 45,000$ milk truck!

Just a short note on possible performance enhancements. Let's say the average bobybuilder does not even start to see significant results below a weekly dose of 500mg of testosterone. Now (we are again assuming that he would in fact assimilate all the hormonal content of milk and colostrum), this would mean that the poor guy would have the choice between 388 milk trucks with whole milk, 18 milk trucks full of skimmed milk or just two 5000 gallon trucks that are filled to the seams with the fat fraction from 1st day colostrum per day(!) to get his weekly dose of anabolics - Cheers!

An Overdue Preliminary Conclusion

Image 8: Even colostrum won't
make you unbreakable... it is
yet about as unlikely that it
will kill you, as some anti-dairy
activists would have it.

Will milk and/or colostrum kill you? No. Will milk and/or colostrum make you look like Jay Cutler and unbreakable like Bruce Willis aka David Dunn in the Y2K thriller Unbreakable within days? Certainly not. 

Well, I guess these are the two polar extremes of the preliminary conclusion to this "Ask Dr. Andro" segment and, as it is so often the case, the truth lies somewhere in between. I cannot tell you your exact position on the death to ultimate health continuum as far as your personal reaction to dairy consumption is concerned, I can only tell you that even if your genetic polymorphisms allow you to consume dairy, the chance that replacing your whey protein by a 6x more expensive colostrum powder will make a beneficial difference in how you look, feel and perform are minimal. I am not so sure however, if you would not see some, if only psychological (placebo) benefits if you mixed that whey into some real, i.e. whole, liquid and not powdered, 1st day colostrum you bought the very same day from your local farmer ;o)

That being said, I could certainly go on forever on milk, organic milk, milk from happy and milk from pasteur fed cows, the effects of soy on the milk you consume, raw milk, 1st day and 4th day colostrum, and so on and so forth, but I suppose that Peter, who posed the original question (just in case you forgot due to the informational overkill of this not even half-done write-up), and the rest of you have enough to think about for the coming week. Ah... and in case you can't get enough of milk (I mean metaphorically) just pose another, hopefully more concrete "Ask Dr. Andro" question in the comment area or on the SuppVersity's facebook page  ;-)