First Documented Long COVID Case Study Involving Impaired Secretion of Adrenocorticotropic Hormone Due To SARS-CoV-2 Infection

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SARS-CoV-2 infections can also cause a variety of disruptions or dysregulation of the endocrine system causing the impairment of various hormones critical for life sustenance. Some of the Long COVID symptom manifestations are actually due to impairment of certain hormone secretions.

The study case study was published in the peer reviewed Endocrine Journal.
https://www.jstage.jst.go.jp/article/endocrj/advpub/0/advpub_EJ22-0108/_article
 

PITUITARY INSUFFICIENCY is associated with various conditions, including neoplasms, autoimmune disease, infectious disease, head injury, brain surgery, or irradiation [1]. Although cases of pituitary insufficiency triggered by virus infection are rare, viruses associated with this endocrinopathy include hantavirus [2-8], coxsackievirus [9], herpes simplex virus [10, 11], and human immunodeficiency virus [1, 12].

In addition, transient secondary adrenal insufficiency also developed in patients infected with SARS coronavirus 1 (SARS- CoV-1) during the recent pandemic of a severe acute respiratory syndrome (SARS) [13].

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has been associated with various nonres‐ piratory manifestations [14], including those affecting cardiovascular, gastrointestinal, neural, coagulation, and locomotor systems, although endocrine disorders such as diabetes mellitus [15], thyroiditis [16-18], male infertility [19, 20], adrenal hemorrhage [21, 22], and adrenal in‐ sufficiency [23] have been described as complications of COVID-19, except for a few cases of pituitary apoplexy in patients with underlying pituitary tumors [24-26].

Although there have been several reports suggesting COVID-19-associated secondary adrenocortical insufficiency, they have been tentatively diagnosed with secondary cause based on low basal ACTH and cortisol levels in addition to a low cortisol response during cosyntropin tests instead of performing insulin tolerance test (ITT) or corticotropin-releasing hormone test [27-29].

Discussion

The present patient suddenly developed catecholamine- resistant, hydrocortisone-responsive hypotension during treatment for COVID-19, without any other apparent cause for this drop in blood pressure. ACTH and GH insufficiencies responses were revealed using an  ITT, and the condition persisted for more than a year before recovery. These observations suggest that the hypopitui‐ tarism of the present case was induced by COVID-19. Impaired function of the HPA axis has been detected in

Table 4 Circulating hormone levels at 3, 6, 12, and 15 months after discharge

HormoneValueReference range
3 months  
 IGF-I (ng/mL)6972.0–221.0*
 FT3 (pg/mL)2.72.3–4.0
 FT4 (ng/dL)1.00.90–1.70
 Free testosterone (pg/mL)3.15.3–11.5
6 months  
 IGF-I (ng/mL)7772.0–221.0*
 TSH (mIU/mL)3.310.610–4.230
 FT4 (ng/dL)1.10.90–1.70
 Prolactin7.33.58–12.78
 FSH (mIU/L)41.12.0–8.3
 LH (mIU/L)34.30.79–5.72
 Free testosterone (pg/mL)3.05.3–11.5
12 months  
 IGF-I (ng/mL)6172.0–221.0*
 FT4 (ng/dL)1.00.90–1.70
 FSH (mIU/L)3.42.0–8.3
 LH (mIU/L)1.40.79–5.72
 Free testosterone (pg/mL)9.45.3–11.5
15 months  
 ACTH (pg/mL)15.8 
 Cortisol (μg/dL)19.5 
 IGF-I (ng/mL)8670.0–219.0*
 TSH (mIU/mL)5.050.610–4.230
 FT4 (ng/dL)1.170.90–1.70
 Prolactin6.03.58–12.78
 FSH (mIU/L)34.42.0–8.3
 LH (mIU/L)31.10.79–5.72
 Free testosterone (pg/mL)6.25.3–11.5

* The reference range for IGF-I matched to age and sex for the Japanese population was determined by a previous study [32].

individuals with SARS, a disease caused by SARS- CoV-1. A prospective study in Singapore revealed that 24 (39%) of 61 patients who survived SARS had appa‐ rent secondary adrenal insufficiency [13]. A recent study in Saudi Arabia showed that, among 28 patients with COVID-19 who underwent random measurement of cir‐ culating levels of ACTH and cortisol, 9 individuals (32%) were suspected of having adrenal insufficiency based on a serum cortisol concentration <300 nmol/L [23]. More recently, Turkish investigators reported that cortisol and GH responses in pituitary function tests were impaired in individuals who had recovered from acute COVID-19 [27]. Another Turkish group also reported that adrenal insufficiency was observed in 8.2% of patients with COVID-19 whose adrenal function has recovered in 6 months [33]. Additionally, several reported cases exhibited rather higher basal ACTH for the lower level of cortisol, suggesting that the study group might include patients with primary adrenal insuf‐ ficiency [23, 27]. Indeed, the adrenal gland is known as the target of SARS-CoV2, which causes adrenalitis and primary adrenal insufficiency [34].

Individuals with serious illness sometimes manifest high levels of serum cortisol as a result of suppression of cortisol metabolism and a consequent decrease in the cir‐ culating ACTH concentration [35]. Moreover, long-term use of dexamethasone, sometimes adopted for virus- induced acute respiratory failure, may give rise to adrenocortical insufficiency as a result of steroid with‐ drawal syndrome. However, the present patient had received only 200 μg of ciclesonide through inhalation for 2 days, and treatment with this drug for 4 weeks has not been found to result in substantial cortisol suppres‐ sion [36].

In addition, antiviral drugs such as ritonavir and lopinavir can increase steroid metabolism by inhibit‐ ing the enzyme cytochrome P450 3A4 (CYP3A4) [37], which might have exacerbated the adrenal insufficiency of the present patient. Whereas cases of adrenal insuffi‐ ciency have been reported for individuals with SARS or COVID-19 [13, 23, 27], hormone tests that discriminate between primary and secondary adrenal insufficiency were not performed for these cases. Thus, the present case is the first of secondary adrenal insufficiency con‐ firmed using an ITT after recovery from COVID-19.

A conserved GH response during the GHRP-2 test in our case suggested that the somatotroph function seemed to be at least conserved. However, since GHRP-2 stimulates somatotrophs and the hypothalamus, our case cannot be diagnosed whether pituitary or hypothalamus origin [38]. Furthermore, Giustina et al. reported that glucocorticoid supplementation recovers GH secretion in cases with GH deficiency combined with adrenal insuffi‐ ciency, while the period for recovery of GH secretion varies from 8 months to 3 years [39]. Therefore, transi‐ ent GHD in our case might be explicable by this mecha‐ nism.

Although the underlying mechanism by which COVID-19 might trigger pituitary insufficiency also remains unknown, it has been reported that viral infec‐ tions such as influenza-A, herpes simplex, and puumala virus-induced meningoencephalitis are associated with transient hypopituitarism [40-43]. Therefore, the central nervous system is likely a target for SARS-CoV-2 infec‐ tion and angiotensin-converting enzyme 2 (ACE2), an enzyme that plays an essential role in the regulation of the renin-angiotensin-aldosterone system. Moreover, transmembrane protease serine 2 (TMPRSS2) is an enzyme that belongs to the serine protease family. Both enzymes are required for cellular entry of the virus and are expressed in the hypothalamic-pituitary axis [44]. Intriguingly, the hypothalamus exhibited higher TMPRSS2 expression than that of the pituitary, while there was no difference in the expression level of ACE2 between the pituitary and hypothalamus, which indicates that SARS-CoV2 may target the hypothalamic as well as the pituitary [44].

Pituitary insufficiency in the present case might have been caused by direct infection of the axis by SARS- CoV-2. Laboratory data suggestive of a blood coagula‐ tion disorder were obtained at the time of onset of adrenal insufficiency. Given that thrombotic and hyper‐ coagulability complications of COVID-19 have been described [45], hemodynamic changes such as ischemia- induced by such abnormalities in the hypothalamus- pituitary region might have contributed to the hormonal disorders of the proband.

In the present case, the symptoms of hypogonadism developed after the recovery from COVID-19 and have persisted to date. In addition, the testis expresses both  ACE2 and TMPRSS2 and serves as a target of SARS- CoV-2 [44]. Furthermore, germ cell destruction associ‐ ated with the infiltration of macrophages and lymphocytes was detected by pathological examination of the testis of patients with SARS [46]. Cases of acute orchitis have also been associated  with  COVID-19  [47]. Moreover, a quarter of sexually active men were found to manifest disorders of semen, such as azoosper‐ mia and oligospermia, after recovery from COVID-19 [48, 49].

The immunological response to the virus infection may also have contributed to the pathogenesis of the multiple endocrine disorders in the present case. Various autoantibodies against phospholipids and SSA/Ro auto‐ antigen, which were originally identified in patients with Sjögren’s syndrome, have been identified during the clin‐ ical course of COVID-19 [50]. Autoimmune conditions, including systemic autoimmune rheumatic diseases, Guillain-Barré syndrome, immune thrombocytopenic purpura, and autoimmune hemolytic anemia, have also been newly diagnosed during the treatment  of COVID-19 [50]. In addition, endocrinopathies such as autoimmune polyglandular syndrome, hypophysitis, autoimmune thyroid disease, type 1 diabetes mellitus, and Addison disease [51, 52] are triggered by autoim‐ munity. Turkish group reported that anti-hypothalamus and anti-pituitary antibodies were detected in the sera obtained from patients with COVID-19 with adrenal insufficiency [33]. Thus, an exaggerated immune response triggered by SARS-CoV-2 may have resulted in the dysfunction of multiple endocrine organs in the present patient.

Certain COVID-19-associated conditions develop  after the onset of or the recovery from respiratory disor‐ ders, as was apparent in the present case. Prolonged symptoms of COVID-19 include fatigue, weakness, hair loss, diarrhea, arthralgia, and depression, with such symptoms also being associated with pituitary insuffi‐ ciency, most frequently with secondary adrenocortical insufficiency [53, 54]. Dexamethasone administration for the treatment of COVID-19 might mask adrenocortical insufficiency if the endocrine condition occurs during the acute phase of the disease. The possibility of pituitary insufficiency should be considered in patients with pro‐ longed symptoms of COVID-19, given that appropriate hormone supplementation in individuals with pituitary insufficiency markedly ameliorates their symptoms and improves their quality of life.

In conclusion, we present a case of multiple endocrine deficiencies affecting the HPA axis, GH–IGF-I axis, and testis that was likely triggered by COVID-19. However, the mechanisms linking hormonal disorders and infec‐ tious diseases remain to be elucidated. An important finding in the present case is the eventual recovery from hypopituitarism over time, but not from hypogonadism. Further study is required to determine whether other COVID-19-associated hormonal disorders share such a transient nature. Given that certain prolonged symptoms of COVID-19 may be accounted for by hormone defi‐ ciency, it might be worthwhile to screen for endocrine dysfunction in patients with such persistent symptoms after their recovery from the acute disease.

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