One of the myths surrounding ketogenic diets comes from misunderstanding the role of cortisol — the “stress hormone”.
In a previous post, we addressed one of the arguments behind this myth: the idea that to activate gluconeogenesis (to make glucose out of protein), extra cortisol must be recruited.
That is just factually incorrect, as we showed in the post.
The other argument, which we address here, is more complex.
Like the previous cortisol myth, it involves a faulty chain of reasoning.
Here are the steps:
- Ketogenic diets may raise certain measures of cortisol.
- Chronically elevated cortisol is correlated with metabolic sydrome, and therefore higher cortisol measures may indicate the onset of metabolic syndrome.
- Therefore, ketogenic diets could cause metabolic syndrome.
Metabolic syndrome is a terrible and prevalent problem today.
It is that cluster of symptoms most strongly identified with diabetes — excess abdominal fat, high blood sugar, and a particular cholesterol profile — but also correlated with other life-threatening conditions such as heart disease and cancer.
In this post, we’re going to explain some of the specifics of cortisol metabolism.
We’ll show how this argument is vague, and how clarifying it leads to the opposite conclusion.
The confusion may all stem from misunderstanding one important fact:
different measures of cortisol are not equivalent.
First, though, there is an important reason why the argument doesn’t make sense.
We already know that a ketogenic diet effectively treats metabolic syndrome.
As we will describe below, it turns out that certain cortisol patterns are strongly linked to metabolic syndrome, and might even be a cause of metabolic syndrome.
If the cortisol pattern that develops in response to a ketogenic diet were the kind that was associated with metabolic syndrome, then we would expect people on ketogenic diets to show signs of abdominal fat gain, rising blood sugar, and a worsening cholesterol profile, but we see the opposite.
This by itself makes it highly unlikely that ketogenic diets raise cortisol in a harmful way.
In other words, because cortisol regulation is so deeply connected to metabolic syndrome, the fact that ketogenic diets reverse symptoms of metabolic syndrome is itself strong evidence that they improve cortisol metabolism.
- There are many different measures of cortisol, because researchers have identified many different processes in cortisol metabolism.
- Increases in some of those measurements are consistently linked to metabolic syndrome, and others are not.
- Some researchers believe that cortisol dysregulation is a key underlying factor in metabolic syndrome.
- The cornerstone of this connection may be the activity of an enzyme, 11β-HSD1.
It converts from the inactive form cortisone to the active cortisol.
- In metabolic syndrome, 11β-HSD1 is underactive in liver tissue and overactive in fat tissue.
This results in a high rate of cortisol clearance, and low rate of regeneration.
- These symptoms of cortisol dysregulation associated with metabolic syndrome were found to be reversed by a keto diet in a study that made the necessary measurements.
Does a ketogenic diet raise cortisol?
In a widely-cited study , from the Harvard-affiliated Boston Children’s Hospital, published in the Journal of the American Medical Association,
three different diets were tested: a low-fat diet, a low-carb diet, and a low-glycemic-index diet.
The study showed that the different diets had substantially different metabolic effects, with the low-carbohydrate diet having the best results.
To our surprise, the researchers then recommended the low-glycemic-index diet instead.
As they explained in the accompanying press release:
“The very low-carbohydrate diet produced the greatest improvements in metabolism, but with an important caveat: This diet increased participants’ cortisol levels, which can lead to insulin resistance and cardiovascular disease.”
The Boston Children’s Hospital then went on to produce a graphic advising patients to follow the low-glycemic-index diet,
and giving this as the primary reason not to choose the low-carb diet.
Here is that graphic, which we’ve marked (in black) to show our disagreement. (Click for the full version without our markup.)
The cortisol levels are an understandable concern, because high urinary cortisol has been epidemiologically associated with a greatly increased risk of death from heart attacks .
However, because a ketogenic diet effectively treats metabolic syndrome, we should expect that it also reduces those specific cortisol patterns that are associated with metabolic syndrome (and therefore heart disease).
As we show below, this has, in fact, been found.
How is cortisol associated with metabolic syndrome?
Just as we now understand that measuring an individual’s total cholesterol without looking at its component parts is inadequate for assessing cardiovascular health, there are different ways to measure cortisol, and only specific patterns of measurements are found with metabolic syndrome.
Cortisol can be measured in fluids, such as urine, saliva, or blood.
Within those fluids, the amount of free cortisol can be measured, but so can cortisone, the inactive form, or the metabolites that are the result of enzyme action, and the ratios of any of these to the others can be measured
(see Figure 1).
Moreover, these measurements have a diurnal rhythm, being higher and lower at different times of the day.
The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) can convert back and forth between cortisol and cortisone.
11β-HSD1—a subtype of 11β-HSD—converts cortisone to cortisol.
When inactive cortisone is converted to the active cortisol, it is called regeneration.
The other enzymes in the illustration break cortisone or cortisol down into metabolites.
That process is called clearance.
It turns out that measurements of these enzyme are important for evaluating cortisol metabolism.
The cortisol profile that has been associated with metabolic syndrome includes the following characteristics:
- high cortisol production rates .
- high cortisol clearance rates , .
- high 11β-HSD1 expression in fat cells, and low 11β-HSD1 expression in the liver , , which determines when and where cortisol is regenerated.
Similarly to the way total cholesterol measurement is correlated with heart disease, but only because it is roughly correlated with more informative cholesterol measurements, 24-hour urinary cortisol may be a proxy for production or clearance, but a poor one , , .
Cortisol levels are affected by production, but they are also affected by regeneration and clearance.
In other words, if regeneration were increased, or clearance decreased, levels could go up even if production stayed the same or went down.
(We previously discussed a similar situation with blood glucose and faulty inference about glucose production rates.)
This means that levels can look similar, even when cortisol metabolism is very different.
Implication for those following the “adrenal fatigue” hypothesis: if you measure your cortisol, and it is high, you can’t conclude that your adrenal glands are working correspondingly hard. It could be due to increased regeneration and reduced clearance by enzyme activity. Higher cortisol could actually mean the adrenals are working less!
In obesity, it appears that production goes up to compensate for high clearance and impaired regeneration, although sometimes not enough to compensate; blood cortisol is sometimes actually lower in obese subjects .
How does a ketogenic diet affect the relevant cortisol measures?
In , investigators put obese men on either a high-fat/low-carb (fat 66%, carb 4%) or a moderate-fat/moderate-carb (fat 35%, carb 35%) diet ad libitum (eating as much as they wanted).
Note that both diets had the same protein percent, and both were lower carb than a standard American diet, but only the high-fat/low-carb diet was at ketogenically low levels.
For the high-fat/low-carb group, “the metabolic syndrome pattern” was reversed: blood cortisol went up, clearance went down, and regeneration went up.
This was apparently due to an increase of 11β-HSD1 activity in liver tissue.
(Activity of 11β-HSD1 did not go down in fat tissue of those subjects, but the authors point out that the activity in fat tissue tends to go down when more fat is eaten, and the high-fat/low-carb group weren’t actually eating more fat in absolute terms than at baseline, only lower carb.)
This reversal didn’t happen in the moderate-fat/moderate-carb group, even though they lost a similar amount of weight.
So the ketogenic diet actually improved the cortisol profile of the participants, making it less like the cortisol profile seen in metabolic syndrome.
There is some reason to believe that cortisol dysregulation is a key underlying factor in metabolic syndrome , .
The dysregulation has a particular pattern that seems to be caused by a tissue-specific expression of the enzyme 11β-HSD1.
There is a belief among some researchers that ketogenic diets worsen cortisol metabolism (which could lead to metabolic syndrome and heart disease),
but an examination of the specific pattern of cortisol metabolism related to metabolic sydrome shows the opposite.
This is what should have been expected in the first place, since ketogenic diets have already been shown to improve insulin sensitivity (the defining symptom of metabolic syndrome) in repeated randomized controlled trials.
One mechanism by which keto diet improves metabolic syndrome may be its beneficial effect on cortisol metabolism.
For a review of 11β-HSD1, see:
Gathercole LL, Lavery GG, Morgan SA, Cooper MS, Sinclair AJ, Tomlinson JW, Stewart PM.Endocr Rev. 2013 Aug;34(4):525-55. doi: 10.1210/er.2012-1050. Epub 2013 Apr 23.
|||Evidence type: controlled experiment
Ebbeling CB, Swain JF, Feldman HA, Wong WW, Hachey DL, Garcia-Lago E, Ludwig DS.
JAMA. 2012 Jun 27;307(24):2627-34. doi: 10.1001/jama.2012.6607.
Comment: It is ironic that the authors bring up Stimson et al. as an example of a study that corroborates their findings. This is the very study  that, in our opinion, exonerates the VLC diet with respect to cortisol.
|||Evidence type: epidemiological observation
Vogelzangs N, Beekman AT, Milaneschi Y, Bandinelli S, Ferrucci L, Penninx BW.
J Clin Endocrinol Metab. 2010 Nov;95(11):4959-64. doi: 10.1210/jc.2010-0192. Epub 2010 Aug 25.
“Context: The stress hormone cortisol has been linked with unfavorable cardiovascular risk factors, but longitudinal studies examining whether high levels of cortisol predict cardiovascular mortality are largely absent.
|||Evidence type: experiment
Enhanced cortisol production rates, free cortisol, and 11β-HSD-1 expression correlate with visceral fat and insulin resistance in men: effect of weight loss
Jonathan Q. Purnell, Steven E. Kahn, Mary H. Samuels, David Brandon, D. Lynn Loriaux, and John D. Brunzell
Am J Physiol Endocrinol Metab. 2009 February; 296(2): E351–E357.
“Controversy exists as to whether endogenous cortisol production is associated with visceral obesity and insulin resistance in humans. We therefore quantified cortisol production and clearance rates, abdominal fat depots, insulin sensitivity, and adipocyte gene expression in a cohort of 24 men. To test whether the relationships found are a consequence rather than a cause of obesity, eight men from this larger group were studied before and after weight loss. Daily cortisol production rates (CPR), free cortisol levels (FC), and metabolic clearance rates (MCR) were measured by stable isotope methodology and 24-h sampling; intra-abdominal fat (IAF) and subcutaneous fat (SQF) by computed tomography; insulin sensitivity (SI) by frequently sampled intravenous glucose tolerance test; and adipocyte 11β-hydroxysteroid dehydrogenase-1 (11β-HSD-1) gene expression by quantitative RT-PCR from subcutaneous biopsies. Increased CPR and FC correlated with increased IAF, but not SQF, and with decreased SI. Increased 11β-HSD-1 gene expression correlated with both IAF and SQF and with decreased SI. With weight loss, CPR, FC, and MCR did not change compared with baseline; however, with greater loss in body fat than lean mass during weight loss, both CPR and FC increased proportionally to final fat mass and IAF and 11β-HSD-1 decreased compared with baseline. These data support a model in which increased hypothalamic-pituitary-adrenal activity in men promotes selective visceral fat accumulation and insulin resistance and may promote weight regain after diet-induced weight loss, whereas 11β-HSD-1 gene expression in SQF is a consequence rather than cause of adiposity.
|||Evidence type: observational
Cortisol clearance and associations with insulin sensitivity, body fat and fatty liver in middle-aged men
Holt HB, Wild SH, Postle AD, Zhang J, Koster G, Umpleby M, Shojaee-Moradie F, Dewbury K, Wood PJ, Phillips DI, Byrne CD.
Diabetologia. 2007 May;50(5):1024-32. Epub 2007 Mar 17.
|||Evidence type: experiment
Association of 24-hour cortisol production rates, cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult men and women.
Purnell JQ, Brandon DD, Isabelle LM, Loriaux DL, Samuels MH.
J Clin Endocrinol Metab. 2004 Jan;89(1):281-7.
|||Evidence type: review of human and non-human animal experiments
Adipose tissue expression of 11beta-hydroxysteroid dehydrogenase type 1 in Cushing’s syndrome and in obesity.
Espíndola-Antunes D, Kater CE.
Arq Bras Endocrinol Metabol. 2007 Nov;51(8):1397-403.
|||Evidence type: observational
Local and systemic impact of transcriptional up-regulation of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity.
Wake DJ, Rask E, Livingstone DE, Söderberg S, Olsson T, Walker BR.
J Clin Endocrinol Metab. 2003 Aug;88(8):3983-8.
|||Evidence type: review
Extra-adrenal regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1: physiological regulator and pharmacological target for energy partitioning
Brian R. Walker
Proceedings of the Nutrition Society / Volume 66 / Issue 01 / February 2007, pp 1-8
|||Evidence type: randomised controlled trial
Dietary macronutrient content alters cortisol metabolism independently of body weight changes in obese men.
Stimson RH, Johnstone AM, Homer NZ, Wake DJ, Morton NM, Andrew R, Lobley GE, Walker BR.
J Clin Endocrinol Metab. 2007 Nov;92(11):4480-4. Epub 2007 Sep 4.
|||Evidence type: authority (review article)
11β-Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus.
Pereira CD, Azevedo I, Monteiro R, Martins MJ.
Diabetes Obes Metab. 2012 Oct;14(10):869-81. doi: 10.1111/j.1463-1326.2012.01582.x. Epub 2012 Mar 8.
|||Evidence type: non-human animal experiment
Chronic inhibition of 11 β -hydroxysteroid dehydrogenase type 1 activity decreases hypertension, insulin resistance, and hypertriglyceridemia in metabolic syndrome.
Schnackenberg CG, Costell MH, Krosky DJ, Cui J, Wu CW, Hong VS, Harpel MR, Willette RN, Yue TL.
Biomed Res Int. 2013;2013:427640. doi: 10.1155/2013/427640. Epub 2013 Mar 18.