The (Fake) Existence of Adrenal Fatigue

July 02, 2021

Fatigue: don’t blame it on the adrenals


The existence of a disease called “adrenal fatigue” has been claimed by several doctors and healthcare providers, who claim that the adrenal glands are exposed to severe stress for long periods of time, which will eventually lead to an ‘underfuncioning’ of the glands. To demonstrate this, direct stimulation tests of the adrenal glands would be the gold-standard method, since a subnormal response could indicate a relative adrenal insufficiency. We aimed to investigate the correlations between fatigue and cortisol levels. However, the We went beyond. We considered all articles that tried through any sort of methods, regardless of being validated or not, in order to avoid claims that the systematic review did not cover all publications out there.

At the same time, we differentiated between association and demonstration of causality. Of 3,470 articles that we analyzed, 58 fulfilled criteria for inclusion in this systematic review. Of the 58 studies, 33 were conducted in healthy subjects and 25 in patients complaining of fatigue. The exams of the “adrenal glands” that were most assessed were the Cortisol Awakening Response (CAR), that evaluates how much cortisol increases in the 30 to 60 minutes after awakening, and the salivary cortisol rhythm (SCR), that analyses whether and how precisely the cortisol is following the circadian rhythm. Interestingly, the gold-standard method of direct stimulation of the adrenal glands using synthetic ACTH at 250ug or low-dose (1ug) was found in very few publications.

All results were conflicting, although the majority showed that cortisol levels and variations were normal. However, remarkable flaws were detected in these studies: 1. Heterogeneity of the assessment methods between different studies, with a lack of standardization of the parameters; 2. The majority of the studies were merely descriptive and somewhat speculative, rather than providing actual new data; 3. The quality of the assessment of “fatigue” was poorly based, allowing multiple conceptions of “fatigue” and mixing up different populations; 4. Absence of the description of glucocorticoid therapies that may falsely reduce cortisol levels; 5. Lack on the discussion whether sleep quality could itself be the cause of impaired CAR and SCR, when actually it is extensively described that dysfunctional sleeping patterns may lead to abnormalities in cortisol secretion and in fatigue concurrently. In this case, cortisol abnormalities were not the cause of fatigue, but an additional consequence of dysfunctional sleep, as well as the consequence of having fatigue; 6. Just like sleeping, other potential confounding variables were not explored; and 7. The inability to distinguish association from causality, wrongly attributing to the impairment of cortisol release the complain of fatigue, or worse, attributing to the adrenal glands, when actually the impairment of cortisol release could be resulted from abnormalities in the secretion of CRH and ACTH from the hypothalamus and pituitary, respectively.

In summary, there is no substantiation at all to call “adrenal fatigue” the state of fatigue. Instead, other diseases including Chronic Fatigue Syndrome (CFS), myalgic encephalomyelitis (ME), burnout syndrome, overtraining syndrome, chronic lombalgia, post-chemotherapy after breast cancer, and more than 400 causes of chronic fatigue, including hormonal dysfunctions, inflammatory diseases, vitamins and minerals deficiencies, and….a fatigue that naturally occurs when we overexpose ourselves to multiple stressors for prolonged periods of time. The majority of the papers focused on symptomatic patients were focused on burnout syndrome, post-chemotherapy due to breast cancer, and overtraining syndrome, that can be grossly understood as the ‘burnout syndrome of the athlete’, although there are environmental differences between burnout syndrome of the athlete and overtraining syndrome.

This systematic review that ran worldwide and has been used as the basis to debunk the existence of “adrenal fatigue” since its publication. And the large number of papers describing fatigue in athletes, we decided to focus on the understanding of overtraining syndrome.


Cadegiani FA, Kater CE. Adrenal Fatigue does not exist: a Systematic Review. BMC Endoc Dis. 2016 Aug. DOI: 10.1186/s12902-016-0128-4. PMID: 27557747.

Study Abstract

The term “adrenal fatigue” (“AF”) has been used by some doctors, healthcare providers, and the general media to describe an alleged condition caused by chronic exposure to stressful situations. Despite this, “AF” has not been recognized by any Endocrinology society, who claim there is no hard evidence for the existence. The aim of this systematic review is to verify whether there is substantiation for “AF”.

A systematic search was performed at PUBMED, MEDLINE (Ebsco) and Cochrane databases, from the beginning of the data until April 22nd, 2016. Searched key words were: “adrenal” + “fatigue”, “adrenal” + “burnout”, “adrenal” + “exhaustion”, “hypoadrenia”, “burnout” + “cortisol”, “fatigue” + “cortisol”, “clinical” + “burnout”, “cortisol” + “vitalility”, “adrenal” + “vitality”, and “cortisol” + “exhaustion”. Eligibility criteria were: (1) articles written in English, (2) cortisol profile and fatigue or energy status as the primary outcome, (3) performed tests for evaluating the adrenal axis, (4) absence of influence of corticosteroid therapy, and (5) absence of confounding diseases. Type of questionnaire to distinct fatigued subjects, population studied, tests performed of selected studies were analyzed.

From 3,470 articles found, 58 studies fulfilled the criteria: 33 were carried in healthy individuals, and 25 in symptomatic patients. The most assessed exams were “Direct Awakening Cortisol” (n = 29), “Cortisol Awakening Response” (n = 27) and “Salivary Cortisol Rhythm” (n = 26). Discussion We found an almost systematic finding of conflicting results derived from most of the studies methods utilized, regardless of the validation and the quality of performed tests. Some limitations of the review include: (1) heterogeneity of the study design; (2) the descriptive nature of most studies; (3) the poor quality assessment of fatigue; (4) the use of an unsubstantiated methodology in terms of cortisol assessment (not endorsed by endocrinologists); (5) false premises leading to an incorrect sequence of research direction; and, (6) inappropriate/invalid conclusions regarding causality and association between different information.

This systematic review proves that there is no substantiation that “adrenal fatigue” is an actual medical condition. Therefore, adrenal fatigue is still a myth.





Pharmacological use of Vitamin D: A Step to Success in Autoimmune Diseases?

July 02, 2021

Myasthenia gravis and vitamin D


Vitamin D is amongst the most controversial vitamins in terms of benefits and causality relationship with reduction of risk of multiple diseases. While studies of association have remarkably associated higher vitamin D levels with reduction of multiple diseases from different systems, prospective studies of intervention not always confirmed the benefits.

Plausibility to justify its benefits vary from very likely in the bone metabolism until questionable in the gastrointestinal system, for example.

Vitamin D is known to present immunomodulatory effects, specially under its bioactive isoform, 1,25(OH)D, converted from the 25(OH)D by the 1alpha-hydroxylasis enzyme mostly located in the kidneys. The correlation between low vitamin D and autoimmune diseases has been reported by multiple studies in several different diseases. The controversy behind the ‘lack of response’ in autoimmune diseases when normalizing vitamin D is claimed to occur due to the non-achievement of optimal levels. Some authors claim that for autoimmune diseases, vitamin D should be way above the usually requested.

Due to its known immunomodulatory effects, some protocols started giving massive doses of vitamin D not for replacement purposes, but as a pharmacological treatment, just like therapies with glucocorticoids. Concerns regarding the risk of hypercalcemia and hypercalciuria, for example, make sense, and should be focused in these patients. This therapy has been extensively offered despite the lack of evidence for multiple sclerosis, with many reports of unexplained recovery that not the vitamin D, not attributable to other causes. However, confirmatory studies and long-term safety profile lack.

This is a case report of a patient that presented severe myasthenia gravis refractory to traditional, standardized, evidence-based therapies, that attempted to try an alternative therapy by herself using 100,000iu daily of vitamin D. She improved almost completely, which corresponded to the reduction of anti-cholinergic antibodies. However, she changed the place where she gets the vitamin D, and the new place, which was a compounding pharmacy, did not insert the right amount of vitamin D, or the quality was not the same. Without realizing the difference, she suddenly started to develop symptoms and get so much worse that she had to be hospitalized and required ICU and mechanical ventilation. After a few days in the ICU, I was contacted to discuss the case with the hospital staff, since she was not responding to the therapy. I ordered new vitamin D and anti-cholinergic antibodies, which decreased dramatically and increased substantially, respectively. High-dose vitamin D was restarted, and she improved almost immediately, being extubated and the discharged a few days later. This was an unhappy situation to demonstrate the exposure-response, followed by interruption-relapse, and new exposure-response, the last one without placebo effect, since she was sedated.

Whether vitamin D could become a sort of new glucocorticoid therapy is unknown. But this case report certainly calls attention for the possibility of vitamin D as a therapy to start to be considered for further clinical trials.


Cadegiani FA. Remission of Severe Myasthenia Gravis After Massive-Dose Vitamin D Treatment. Am J Case Rep. 2016; Jan. 17:51-51.

Study Abstract

Background: Vitamin D has been shown to be related to autoimmune diseases, such as multiple sclerosis and psoriasis. Correlations have been reported between vitamin D levels and prevalence and severity of other autoimmune disorders, and also between vitamin D therapy and disease improvement and remission.

Case report: This is a case report of a patient with severe and refractory myasthenia gravis (MG) who followed a "high-dose vitamin D treatment", a massive-dose treatment (80,000 to 120,000 IU/day) promoted by a medical center in Brazil (but still not proven), and she had her first complete remission after this type of treatment with increased vitamin D serum levels (400 to 700 ng/mL).

Conclusions: This case report may reinforce the reported correlation between vitamin D level and disease severity and introduces a possible new use for vitamin D as a potential target for treating autoimmune diseases. We recommend large, double-blind, placebo-controlled, randomized studies using high-dose vitamin D treatment for refractory autoimmune diseases to reliably assess this pharmacotherapy target for these diseases.

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Sex Hormone Balancing is Hhat Matters

July 02, 2021

Hormones in males


Recently, higher estradiol levels have been associated with increased libido, muscle mass, bone mass, among other benefits, in males. However, whether this was correlated with concurrent increase of testosterone levels was not clear in the majority of the study.

Since we discovered that the testosterone:estradiol (T:E) ratio was a better predictor of multiple body composition and metabolism benefits, rather than testosterone or estradiol alone, at least in athletes, and that higher estradiol may be a marker of metabolic or inflammatory diseases in males, we hypothesized that more important than the estradiol is the reason why estradiol is higher: whether secondary to testosterone increase, as an inherent action of the aromatase activity, or due to pathologically enhanced aromatase, that consequently leads to reduction of testosterone. To differentiate the physiological from the pathological increase in estradiol levels, intuitively the most accurate marker would be the T:E ratio. This, in combination with the T:E ratio as a predictor of outcomes in athletes, allowed us conduct a systematic search for evidence of whether T:E ratio is a good marker or not. Of the more than 1,000 articles initially screened, 38 articles were selected, including 27 that evaluated healthy males and 11 with metabolic or inflammatory diseases. Benefits that occurred with increase of estradiol irrespective of testosterone were in bone mass and reduction of anger. When estradiol and testosterone were proportionally increased, improvement of libido, overall mood states, cognitive functions, muscle mass, basal metabolic rate, fat oxidation, and reduction of fat mass cardiovascular markers. These benefits were found when T:E ratio was above 13.7. Under pathological increase of estradiol, when the T:E ratio is below 9.5, reduction of quality of life and increase risk of disease-specific complications were detected. We found sufficient data to conclude that the proportion between testosterone and estradiol, translated into the T:E ratio, is a better predictor of overall outcomes than each hormone alone.

Links: LB8/5833662?searchresult=1

Cadegiani F, da Silva PLH, Abrao TPC, Kater CE. The Testosterone-To-Estradiol Ratio, Rather Than Testosterone or Estradiol Alone, Is a More Precise Marker of Metabolic-Related Outcomes in Males: Insights From a Systematic Review. J Endocr Soc. 2020;4(Suppl 1):SAT-LB8. Published 2020 May 8. doi:10.1210/jendso/bvaa046.2293.

Study Abstract

Background: Estradiol (E2) has been shown to exert beneficial effects on males, particularly for metabolic outcomes. However, these benefits tend to be more evident when accompanied by concurrent increase in testosterone (T) levels, when the increase of E2 is secondary to the increase of T. Oppositely to its benefits in healthy males, when under metabolic and inflammatory diseases, E2 has been reported to be a marker of worse prognosis, once E2 is unproportionally high compared to testosterone in pathological conditions, which results in hypogonadism. The collective analysis of T and E2 shows that the balance between these two hormones determines whether increase in E2 levels is physiological or pathological, demonstrated by balanced T and E2, i.e., intact T:E2 ratio compared to healthy males, and disrupted balance between T and E2, with impaired T:E2 ratio, respectivey. Hence, it seems that the dual relationship between E2 and health markers in males is based on the balance, or ratio, between T and E2. The objective of the present study is to propose a ratio between T and E2(testosterone-to-estradiol ratio, or T:E ratio) as a better predictor of health outcomes than testosterone or estradiol alone, and to differentiate health from pathological states within this single marker, from a review of the literature. 

Methods: We systematically searched for articles using the following criteria: 1. Any of the combinations of the expressions “testosterone” (AND) ”estradiol” (AND) “male(s)” (OR) ”men” (OR) “masculine”, or “testosterone-to-estradiol” (OR) “testosterone:estradiol” (OR) “estradiol-to-testosterone ratio” (OR) “estradiol:testosterone” (AND) “male(s)” (OR) ”men” (OR) “masculine”, to be present in the title and/or abstract; 2. Fully written in English; 3. Performed in humans; 4. Throughout the literature until Jan 30th 202020; and 5. Original researches.

Results: We selected 39 articles, from which 27 were performed in healthy males, and 11 under metabolic or inflammatory conditions. Benefits of E2 in healthy males occurred irrespective of T for bone mass and quality, and anger levels. Benefits that were better identified when E2 and T were evaluated together include better libido, improved cognitive functions, improved well-being and other mood states, increased muscle mass, enhanced loss of fat mass, quality, increased basal metabolic rate, increased fat oxidation, and reduced cardiovascular markers, including reduced maximal intimal-media carotids thickness, when T:E ratio was > 13.7. In pathological states, increased estradiol was associated to increased risk of disease-specific complications, and worse quality of life, particularly when T:E was < 9.5. T:E ratio was also able to accurately identify healthy athletes from those affected by any sport-related metabolic conditions. Conclusion: Testosterone-to-estradiol (T:E) ratio is likely a more precise predictor of metabolic-related health outcomes in both healthy and pathological states, compared to testosterone or estradiol alone.


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