Thursday, January 9, 2014

True or False - High or Low Protein Intakes Have Profound Influence on Testosterone, SHBG, Estrogen, Cortisol & Co?

We are what we eat! Acknowledged, but does this also go for your hormones and different in protein intakes? Let's have another look at the contemporarily available research to figure that out.
In recent study in the International Journal of Sport Nutrition and Exercise Metabolism a group of researchers from the Faculty of Physical Education and Recreation at the University of Alberta reports: "Supplementing a typical daily food intake consisting of 0.8 g of protein·kg-1·d-1 with a whey protein isolate (an additional 0.8 or 1.6 g·kg-1·d-1) [...] had no effect on glucose, insulin, testosterone, cortisol, or growth hormone following the final meal" (Forbes. 2013).

I know, anything else would have been a real shocker. What it wouldn't be, though, is a total surprise. If you dig through the available literature you can easily find data that would support the scientists' assumption that doing an experiment "to investigate the effects of a controlled typical one day diet supplemented with two different doses of whey protein isolate on blood amino acid profiles and hormonal concentrations following the final meal" (Forbes. 2013) would be a good idea.

True or false? Certainly TRUE!

No, I am not kidding you! We do have plenty of evidence of direct interactions between chronic high vs. low protein intake and the production and metabolism of hormones, like testosterone, cortisol, their corresponding binding proteins, SHGB and CBP, and a whole host of other molecules that act like hormones, although we often don't call them "hormones". Examples? Well, here you go:
  • Low protein = low SHBG (Longcope. 2000) - At least in the 1552 men in their "best age" (40-70 years) who participated in a study by scientsts from the University of Massachusetts Medical School the consumption of a diet that had less than the average 80g/day of protein in it lead to decreases in SHBG and corresponding increases in free (~bioavailable) testosterone. Age, dietary fiber, and smoking, on the other hand were positively correlated with SHBG.
  • Chronically high protein intakes (40% of total energy) lower testosterone / cortisol ratio (Oi. 2001) - The highly significant increase in cortisol and corresponding decrease in the testosterone to cortisol ratio, Oi et al. report in a 2001 paper have luckily (a) been observed in rodents, only, and that's actually the main finding of the study (b) could be countered by the administration of garlic extract.

    Figure 1: In rodents, a high protein intake (40% of total energy from casein) will increase cortisol at stable T-levels and thus decrease the testosterone : cortisol ratio (Oi. 2001)
    I can only speculate whether and to which degree the endocrine effects of high protein diets differ between rats and men (the Anderson study discussed below suggests they don't) - and you know I love facts and hate speculations and unsupported hypothesis. So I stick to an assumption I could support, i.e. the supposition that the improvements in testosterone, the researchers observed, when they fed their rodents garlic was mediated  by its glutathione (GSH) boosting effects. These effects - and you as a regular SuppVersity reader know that are not "garlic exclusive". Whey protein, for example will also increase GSH (Bounous. 1989). Obviously whey doesn't increase your testosterone, but a "protein overload" from a glutathione boosting protein source may not have to be countered by GSH boosters in the first place.
  • A high protein : carb ratio decreases total testosterone levels in man (Anderson. 1987) - Some people live by the principle that things that mustn't be. As a SuppVersity reader you obviously don't belong to this group of people and will thus be willing to accept that Anderson et al. were able to show that...
    "[...] the testosterone concentrations in seven normal men were consistently higher after ten days on a high carbohydrate diet (468 ± 34 ng/dl, mean ± S.E.) than during a high protein diet (371 ± 23 ng/d1, p<0.05) and were accompanied by parallel changes in sex hormone binding globulin (32.5 ± 2.8 nmol/1 vs. 23.4 ± 1.6 nmol/1 respectively, p<0.01)." (Anderson. 1987)
    As a SuppVersity reader you are yet also smart enough to know that this data is irrelevant, without adequately measured free testosterone levels: If we do the math and calculate the latter (obviously not 100% accurately), i.e. free testosterone on normal protein diet: 9.4 ng/dL  =  2.01 % vs. free testosterone on high protein + low carb diet: 9.02 ng/dL  =  2.43 %, the difference does no longer look so bad, anyway - does it?

    Figure 2: Total (TT in ng/dL) and free testosterone (FT in ng/dL), SHBG (µg/L) and testosterone : cotisol ratio after one months on high protein + low carb vs. control (Anderson. 1987)
    This would not change the fact that you'd suffered a -42% decrease of the testosterone : cortisol ratio from 60.5 to 35 which occurred in the Anderson study, when the participants were put on a meat, fish, poultry, egg white, and protein supplement based 44% protein, 35% carbohydrates, 21% fat diet.
  • A high protein very low calorie diet can increase testosterone levels, but it will do so only if it is used to produce significant weight loss in obese adolescents, whose abundant body fat stores are gnawing away their androgens. In a corresponding study by Brown et al., the eight 11-15-year-old boys and girls where put on liquid (starvation) diets with a protein / carb / fat ratio of 67% / 28% / 5% that containing a total of 492-709 kcal per day.
    Figure 3: Total testosterone levels (ng/dl; left axis) and insulin levels (in µU/ml) in 14 (subj. 3 & 7) and 18 year-old male adolescents before and after 5 weeks on low calorie high protein liquid diets (Brown. 1983)
    As you can see in Figure 3 the significant reduction in body weight (13.5 kg total, 70-75% fat) went hand in hand with improvements in insulin sensitivity and the previously mentioned increase in total testosterone levels in the 14 year-old subjects 3 & 7 and the 18 year-old male adolescents (subject 6) - the only subjects for whom a complete testosterone panel was available.
  • High protein diets are driving forces of GH induced skeletal muscle IGF-1 expression (Sanchez-Gomez. 1999) - With IGF-1 being equally important to men and women, it does not matter that the "subjects" in the study at hand were female growing rats that received either a high- or a low-protein diet with crude protein contents of 222 and 83 g/kg respectively.

    After 14 days on which the rodents were concamittantly injected with saline control, or growth hormone (rhGH) or recombinant human IGF-I (rhIGF-I) at dosages of 350 and 500µg/day, respectively, Sanchez-Gomes et al. observed that
    • Learn more about IGF-1.
      ...the low-protein diet alone reduced IGF-I concentrations in serum and in tissue taken from the gastrocnemius muscle as well as IGF-I mRNA from the same muscle, significantly.
    • ...the high protein diet amplified the retention of injected rhIGF-I in the muscle tissues and was associated with significant improvements of the nitrogen balance
    Based on these results, Myriam Sanchez-Gomez conclude that "the level of dietary protein ingested regulates not only the effect of IGF-I on whole-body N economy but also the regulation of IGF-I gene expression in muscles" (Myriam Sanchez-Gomez. 1999). 
  • Increased f 2-hydroxylation of endogenous estrogen with high protein diets could have cancer protective effects (Anderson. 1984) - Certainly far fetched but not impossible is the connection between the increased 2-hydroxylation of endogenous estrogen in response to high protein diets Anderson et al. observed in a 1984 study in male study participants and the significant association between lower ratios an the risk of breast cancer (Liehr. 1996).

    Table 1: Cox regression of energy-adjusted dietary predictors of breast cancer recurrence and death (Saxe. 1999)
    It goes without saying that this is nothing but a hypothesis - a hypothesis that would yet be supported by a 1999 paper on "dietary predictors of breast cancer recurrence and death" by Saxe et al. which is based on one of the few papers that did not control for "meat" intake (you know that Pizza Salami qualifies as "meat", right?) in which each 5% increase in protein intake was associated with risk reductions of 18% for breast cancer recurrence and 44% for death in premenopausal women (Saxe 1999).

    And what's more, the fact that the associations were less pronounced in the post-menopausal study participants (the "low estrogen counterpart", if you will; see Table 1) only support the notion that the protective effects of protein may (at least in part) be mediated by its effects on estrogen metabolism.
Bottom line - Back to the Forbes study: In view of the conclusive evidence that the changes in total testosterone and cortisol are mediated by (a) changes in the amount of steroid binding proteins in the blood (albumin, SHBG, CBG), (b) weight loss / general health improvements and (c) the scarcity of dietary glucose on high protein diets, it's not surprising that the glucose, insulin, testosterone, cortisol, and growth hormone levels of Forbes' nine male volunteers (age: 29.6 ± 6.3 yrs), who participated in ...
  • "Protein Requirements of Dieting Strength Athletes: More is Better Only in the Presence of Adequate Carb & Fat Intake. Optimal Muscle Retention With 2-3g/kg Lean Body Mass " | more
    a control (C) condition of a typical mixed diet containing ~10% protein (0.8 g·kg-1), 65% carbohydrate and 25% fat; 
  • a placebo (P) condition calorically matched with carbohydrate to the whey protein conditions; 
  • a low dose condition of 0.8 g /kg body weight whey protein isolate (W1) per day in addition to the typical mixed diet; or 
  • a high dose condition with 1.6 g/kg bw. whey protein isolate (W2) in addition to the typical mixed diet,
in random order, didn't change within a day of being fed high vs. normal protein diets - and that irrespective of whether the diets were supplemented with a whey protein or not.
  • Anderson, K. E., Kappas, A., Conney, A. H., Bradlow, H. L., & Fishman, J. (1984). The influence of dietary protein and carbohydrate on the principal oxidative biotransformations of estradiol in normal subjects. Journal of Clinical Endocrinology & Metabolism, 59(1), 103-107.
  • Anderson, K. E., Rosner, W., Khan, M. S., New, M. I., Pang, S., Wissel, P. S., & Kappas, A. (1987). Diet-hormone interactions: protein/carbohydrate ratio alters reciprocally the plasma levels of testosterone and cortisol and their respective binding globulins in man. Life Sciences, 40(18), 1761-1768.
  • Bounous, G., Gervais, F., Amer, V., Batist, G., & Gold, P. (1989). The influence of dietary whey protein on tissue glutathione and the diseases of aging. Clin Invest Med, 12(6), 343-9. 
  • Brown, M. R., Klish, W. J., Hollander, J., Campbell, M. A., & Forbes, G. B. (1983). A high protein, low calorie liquid diet in the treatment of very obese adolescents: long-term effect on lean body mass. The American Journal of Clinical Nutrition, 38(1), 20-31. 
  • Forbes, S. C., McCargar, L., Jelen, P., & Bell, G. J. (2013). Dose Response of Whey Protein Isolate in Addition to a Typical Mixed Meal on Blood Amino Acids and Hormonal Concentrations. International journal of sport nutrition and exercise metabolism. 
  • Liehr, J. G., & Ricci, M. J. (1996). 4-Hydroxylation of estrogens as marker of human mammary tumors. Proceedings of the National Academy of Sciences, 93(8), 3294-3296.
  • Longcope, C., Feldman, H. A., McKinlay, J. B., & Araujo, A. B. (2000). Diet and sex hormone-binding globulin. Journal of Clinical Endocrinology & Metabolism, 85(1), 293-296. 
  • Sanchez-Gomez, M., Malmlöf, K., Mejia, W., Bermudez, A., Ochoa, M. T., Carrasco-Rodriguez, S., & Skottner, A. (1999). Insulin-like growth factor-I, but not growth hormone, is dependent on a high protein intake to increase nitrogen balance in the rat. British Journal of Nutrition, 81(02), 145-152.
  • Saxe, G. A., Rock, C. L., Wicha, M. S., & Schottenfeld, D. (1999). Diet and risk for breast cancer recurrence and survival. Breast cancer research and treatment, 53(3), 241-253.