Hypothalamic-pituitary-adrenal Axis in Patients Presenting to Psychosomatic Medicine with Fatigue, 2025, Matsubayashi et al

[forestglip]

Hypothalamic-pituitary-adrenal Axis in Patients Presenting to Psychosomatic Medicine with Fatigue

Sunao Matsubayashi, Makoto Yamashita, Takeshi Hara, Makito Tanabe, Shuichi Matsumoto

Abstract
Many patients with fatigue are referred to psychosomatic medicine, but few studies have examined the hypothalamic- pituitary-adrenal (HPA) axis in these patients. We conducted a corticotropin-releasing hormone (CRH) test on 86 patients with fatigue, no history of oral steroid use, and no pre-existing hypothalamic or pituitary disease. We confirmed non-oral steroid use and performed pituitary magnetic resonance imaging (MRI) in patients with peak cortisol levels <18 μg/dL.

The baseline cortisol level was 7.6±3.4 μg/dL, and the peak cortisol level in the CRH test was 15.4±3.6 μg/dL. Nineteen had a history of non-oral steroid use, and their peak cortisol levels were significantly lower at 13.7±4.3 μg/dL (vs. 15.9±3.4 μg/dL in non-users; F=5.825, p=0.0179). Sixty-seven patients had peak cortisol levels <18 μg/dL, and 43 patients had levels <15.67 μg/dL.

Fourteen patients were newly diagnosed with pituitary MRI abnormalities, and their peak cortisol level was significantly lower than that of those without pituitary abnormalities (12.4±4.1 μg/dL vs. 14.7±2.7 μg/dL; F=6.5130, p=0.0129).

In conclusion, some patients with fatigue in psychosomatic medicine have a decreased HPA axis associated with non-oral steroid use or undetected pituitary abnormalities. However, a significant number also exhibit a decreased HPA axis, despite having no history of non-oral steroid use or pituitary abnormalities.

Link | PDF (Journal of Hospital General Medicine) [Open Access]

 

[Hutan]

Sunao Matsubayashi1), MakotoYamashita1), Takeshi Hara1), Makito Tanabe1) and Shuichi Matsumoto2)
1) Department of Psychosomatic Medicine, Endocrinology, and Diabetes Mellitus, Fukuoka Tokushukai Hospital, Kasuga, Japan
2) Department of Internal Medicine, Uwajima Tokushukai Hospital, Uwajima, Japan

If that first department is accurately named, it's a really weird department. But, maybe it's good. Because, the tools they applied aren't just psychotherapy and gaslighting - they actually do hormone testing. And so they seem to be approaching patients referred to their department a little more holistically, a bit more open minded. The possibilities still are probably constrained by the clinicians' mindset, but the possibilities are wider.

Many patients referred to psychosomatic medicine have already undergone a differential diagnosis for physical illnesses by their primary care physicians or general internal medicine departments at general hospitals. These patients are often suspected of having stress-related disorders, such as depression, adjustment disorders, anxiety disorders, somatic symptom disorders, panic disorders, functional somatic disorder, or medically unexplained physical symptoms, but a differential diagnosis of adrenal insufficiency is necessary. However, in clinical practice, few patients have been evaluated for the hypothalamic-pituitary-adrenal (HPA) axis.

From October 2016 to September 2023, 86 patients who visited the Psychosomatic Medicine Department of Fukuoka Tokushukai Hospital with complaints of fatigue lasting more than 2 weeks and with performance status 3 or higher [4]underwent a CRH test. Many of these patients had non-specific symptoms, often gastrointestinal symptoms in addition to fatigue, such as nausea and appetite loss, pain, and dizziness.

"A normal baseline cortisol level in the morning (around 8 a.m.) is generally considered to be between 5 to 25 micrograms per deciliter (mcg/dL). Cortisol levels naturally fluctuate throughout the day, peaking in the morning and decreasing as the day progresses. In the evening, levels are typically lower, ranging from 3 to 13 μg/dL"

The baseline cortisol level taken at 9 am was 7.6±3.4 μg/dL. So, the mean baseline cortisol levels of the 86 patients was in the normal range. But some of these patients clearly have abnormal cortisol levels and responses.

All 86 patients underwent an ACTH test and 67 patients had an ACTH response that was less than the 18 μg/dL that is considered a normal response.

The 67 patients with an abnormal ACTH response underwent an MRI, and 14 were diagnosed with pituitary abnormalities visible on an MRI. That seems pretty significant. Of the 86 people, all of whom the authors described as 'no pre-existing pituitary disease' and who were given a psychosomatic explanation for their fatigue, 14 did in fact have pituitary abnormalities. That's at least 16% of the people being told that they are psychosomatic when they in fact have a fairly easily identified structural cause for their symptoms.

 

[Utsikt]

That's at least 16% of the people being told that they are psychosomatic when they in fact have a fairly easily identified structural cause for their symptoms.

Yet the FND crowd think it’s fine to use positive rule in signs..

 

[Hutan]

The authors give this example:
Case 3. 36-year-old, female

A 30-year-old woman with a history of anorexia nervosa, onset at age 20, was referred to our clinic. She complained of a strong fear of eating and gaining weight. Her body mass index (BMI) at presentation was 14.7 kg/m2. She was treated with supportive psychotherapy and escitalopram, but her weight did not improve. Although she was employed, she was often forced to recuperate at home due to persistent fatigue. The patient’s background included domestic violence by her father during childhood and divorce of her parents during adolescence.

Prolonged fatigue led to suspicion of adrenal insufficiency, and a CRH test was performed at age 36. Her baseline cortisol level was 5.7 μg/dL, then 9.4 μg/dL at 30 minutes, 14.8 μg/dL at 60 minutes, and 14.1 μg/dL at 90 minutes. Her baseline ACTH level was 5.3 pg/mL, then 28.6 pg/mL at 30 minutes, 36.3 pg/mL at 60 minutes, and 25.7 pg/mL at 90 minutes. Pituitary MRI revealed a Rathke’s cleft cyst. Central adrenal insufficiency was diagnosed and hydrocortisone replacement therapy was started at 10-15 mg/day. Subsequently, fatigue symptoms improved markedly, food intake increased, BMI increased to 17.7 kg/m2, and menstrual cycle resumed. Long-term recuperation at home became unnecessary, yet the continuation of overtime work for several days sometimes required a short period of rest.

"If a RCC grows large enough, it can press on nearby structures like the pituitary gland or optic nerves, potentially causing:

• Vision changes (like blurry vision or visual field defects)
• Headaches
• Hormone imbalances
• Fatigue or drowsiness
• Nausea "

"Yes, a Rathke's cleft cyst can cause a lack of appetite according to multiple sources. This is because the cyst can affect the pituitary gland, which produces hormones that regulate appetite and other bodily functions. If the cyst is large enough, it can compress the pituitary gland, leading to a deficiency in these hormones, which can result in symptoms like loss of appetite, weight loss, fatigue, and other hormonal imbalances."

So, very possibly, this woman has spent 16 years going through the trauma and harm to her body of not eating enough and being dreadfully fatigued, and the trauma of being told that she isn't thinking right and going over her childhood issues. From what I can see of the literature, hydrocortisone therapy can be enough to correct things and re-establish appetite. I'm not sure though why the cyst would not have been removed to allow the pituitary to function - it seems like a fairly safe operation.

Table 1 reports that 8 of the patients had diagnoses of eating disorders.

 

[Hutan]

Among the patients, 29 (33.7%) had baseline cortisol levels below the reference value (6.24 μg/dL), and only 1 patient (1.1%) exceeded the upper reference limit (18 μg/dL).

The peak cortisol levels during the CRH test in patients using non-oral steroids were significantly lower at 13.7±4.3 μg/dL than the 15.9±3.4 μg/dL in non-users (F=5.825, p=0.0179). Among the patients, 67 (77.9%) had peak cortisol levels below 18 μg/dL and 43 (50%) had levels below the Yoshikawa et al. [2] cutoff of 15.67 μg/dL.
Conversely, 15 patients (17.4%) had baseline ACTH levels below the reference value (7.2 pg/mL), whereas the remaining patients had ACTH levels within the reference range (7.2-63.3 pg/mL).

Another issue worthy of comment is the impact of steroids on cortisol levels. The researchers had excluded anyone who had been using oral steroids. But, they found that the people who had been using other sorts of steroids had lower peak cortisol levels. These steroids were

• inhaled steroids for bronchial asthma
• nasal steroids for allergic rhinitis
• steroid ointments for allergic dermatitis

Peak cortisol levels during the CRH test were lower in non-oral steroid users than in non-users, suggesting that the use of non-oral steroids might lead to iatrogenic central adrenal insufficiency, resulting in fatigue

 

[Hutan]

The Discussion and Conclusion sections are interesting. It's a weird combination of practical thinking (e.g.people with chronic fatigue should be properly assessed for pituitary problems, and treated appropriately), just possibly plausible BPS speculation and just straight out wrong psychosomatic twaddle.

Here's a paragraph on ME/CFS (oddly included, because the study did not appear to be on people with ME/CFS):

Although hydrocortisone treatment has been shown to be effective in patients with myalgic encephalomyelitis/chronic fatigue syndrome, it is not recommended because of potential side effects, with cognitive behavioral therapy (CBT) being the preferred approach [18].

However, if the HPA axis of individual patients complaining of chronic fatigue is accurately assessed and found to be significantly impaired scheduled or intermittent administration of hydrocortisone may be permissible. In addition, to avoid placing excessive strain on the already compromised HPA axis, adjusting the workload and employing stress management techniques focused on healing and relaxation, such as mindfulness-based therapy, may be more beneficial than CBT [19]. Therefore, further investigation is warranted.

18. Castro-Marrero J, Sáez-Francàs N, Santillo D, et al. Treatment and management of chronic fatigue syndrome/myalgic encephalomyelitis: all roads lead to Rome. Br J Pharmacol. 2017;174(5):345-369.

19. Vink M, Vink-Niese A. Cognitive behavioural therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective. Reanalysis of a Cochrane review. Health Psychol Open. 2019;6(1):2055102919840614.

I don't recall that Vink paper promoting mindfulness therapy...

 

[forestglip]

The authors give this example:
Case 3. 36-year-old, female

That's interesting. Hydrocortisone cured her fear of gaining weight? I feel like anorexia is one of the best examples of a condition your doctor would send you to a therapist to fix, yet a cheap medication did the job.

 

[Hutan]

I feel like anorexia is one of the best examples of a condition your doctor would send you to a therapist to fix, yet a cheap medication did the job.

And six years of care in this psychosomatic clinic, prior to the discovery and treatment of her pituitary issue, did not.

Of course, it's a case study, and it is reported by researchers wanting to make the case for their recommended approach, with all the biases that go along with that. Rathe's cleft cysts can also be asymptomatic. I guess BPS proponents might say that the MRI finding was irrelevant, and the treatment gave the woman a face-saving way to think differently, and begin to eat better, which fixed her fatigue.

 

[Sean]

Some years back the wife of a friend of mine was having all sorts of health troubles, and was bundled off to the psychs.

Long story short, eventually somebody did some appropriate (and standard, widely available) testing and it came back positive for a specific and well known gland problem (can't remember the details).

Was put on appropriate medication and all the symptoms resolved within a day or two.

There's a pattern here.

 

[Peter T]

There desperately needs to be good data on the percentage of people given a psychogenic diagnosis of some sort that resulted the missing of or delay in diagnosing a treatable biomedical condition.

I have given here before the example of a friend referred to counselling services because of unexplained persistent chest pain following heart surgery. It took over eighteen months for her to find a doctor willing to refer her for the simple chest X-ray that revealed the eleven inch stainless steel surgical instrument left in her chest cavity. Fortunately she had ignored previous repeated medical advice to push through the pain.

Unless a patient is made aware of the risks of missed treatable conditions, including conditions potentially fatal if untreated, surely they can not be considered as able to give informed consent for psycho behavioural interventions for presumed psychogenic conditions.

Also the assumption that psycho behavioural interventions don’t have associated risks needs addressing, as I would have thought there are potential risks of such interventions inappropriately given in presumed ‘eating disorders’, just as we have seen their risks in ME/CFS.

 

[bobbler]

Some years back the wife of a friend of mine was having all sorts of health troubles, and was bundled off to the psychs.

Long story short, eventually somebody did some appropriate (and standard, widely available) testing and it came back positive for a specific and well known gland problem (can't remember the details).

Was put on appropriate medication and all the symptoms resolved within a day or two.

There's a pattern here.

I think that is sadly very unusual that anyone looks further (and then of course there are many hoops more to someone actually signing off treatment even if it seems logical because it hits the bar and the treatment would work) - depending on the person and their support system/status/connections, what they are deemed to have and how strong the attitude is in those they come across in the journey there. I think that once at mental health it is a sausage machine with no access to or interest in alternatives and a particular assumption that where things don't fit it is due to the patient lacking insight/not having learned that if they want to get out of the situation ever they will be required to 'play along' (like getting parole requires pleading guilty, protesting you never had or thought x is either ignored or held as some sort of additional mental problem) and things become really closed down as people's testimony gets more likely to be even more ignored/questioned.

I have known someone who thought they had CFS for many years, a male and not thin, who turned out to have a pituitary tumour which had to be treated as it was near to affecting vision if it were to be left.

Just going by the small numbers of people I know who I'd know that level of info about then I assume this theme is actually common. A step beyond patterns, although there are many patterns behind them that are obvious to most it is just hard to work out what benefit there must be in it being left like that level obvious.

I get a horrible feeling that there are some quarters where it is almost being pushed to treat illnesses that were/are known to have biomedical causes and straightforward treatments (and pernicious anemia/B12 and similar things in those who have had bowel operations or significant bowel conditions is another one, thyroid perhaps another one if you count getting the treatment right etc) as if those can be treated as if they are psychosomatic or just not treated or are seen as just 'wellness' level of things or bundled in with 'other generic buckets for x symptoms'.

Sadly I don't think that a condition meeting the bar of being objectively testable and measured and have a relatively cost-effective treatment, particularly those where for example there should be some sort of 'care' in the sense of a clinic+GP system wanting to get that level correct, is actually an even automatic slam-dunk with regards the medical system these days. And I'd be intrigued to see whether literature and beliefs, or the decision chart type system (plus bucketing on symptoms but then 'only one assumption/place to refer' once bucketed) plays any part in that.

And does the vicious cycle of labelling those with certain symptoms from not getting the correct treatment these days lead to some automatic lowered status given to their testimony when perceiving what is 'good enough' for them to manage on etc. ?

 

[Sean]

Unless a patient is made aware of the risks of missed treatable conditions, including conditions potentially fatal if untreated, surely they can not be considered as able to give informed consent for psycho behavioural interventions for presumed psychogenic conditions.

Absolutely this.