Post-COVID-19 Condition and Endocrine Dysfunction

2.1 Adrenocortical function

The HPA axis is a central regulator of systemic homeostasis, stress responsiveness, energy metabolism, and neuropsychiatric function, primarily mediating adaptive responses to physiological and psychological stressors. Postmortem studies of individuals who died from SARS-CoV-2 infection have demonstrated a marked reduction in ACTH and GH-positive cells, accompanied by diminished immunoreactivity within the anterior pituitary gland [13]. In rodent models of PCC, hippocampal COR like hormone levels were decreased by approximately 31%–37% [14].

Clinically, patients with PCC frequently exhibit HPA axis dysfunction characterized by anterior pituitary hypofunction, resulting in secondary adrenal insufficiency (SAI) with impaired secretion of ACTH and COR [15, 16]. This dysfunction is often accompanied by deficiencies in other anterior pituitary hormones, including GH, thyroid-stimulating hormone (TSH), and gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]) [17]. Correspondingly, common PCC manifestations, such as fatigue, asthenia, gastrointestinal disturbances, affective symptoms, hypoglycemia, and hypotension, may be partially attributable to impaired HPA axis activity.

At present, the clinical diagnosis of SAI remains challenging and controversial. Some studies suggest that basal COR levels under resting conditions may serve as a reference for identifying SAI [18, 19]. However, in patients with PCC, adrenocortical dysfunction most commonly arises from pituitary injury rather than primary adrenal pathology, resulting in SAI. The defining feature of this condition is an inadequate secretion of ACTH and COR in response to physiological or pathological stress. In contrast, under resting conditions, basal ACTH and COR l levels may remain within the normal range or show only mild reductions. Therefore, reliance solely on basal ACTH and COR measurements is associated with low sensitivity and specificity for the diagnosis of SAI, particularly in patients with atypical clinical presentations, leading to substantial underdiagnosis [20].

ITT is widely regarded as the gold standard for evaluating both HPA and GH axis integrity by assessing the endocrine response to hypoglycemic stress [21, 22]. HPA axis dysfunction is diagnosed when peak serum COR following ITT fails to reach 500 nmol/L [23–25]. In PCC patients, ITT frequently reveals insufficient ACTH and COR secretion [16, 26, 27], typically manifested as a failure of hormone levels to increase or double at 30 and/or 60 minutes after hypoglycemia induction [28]. For patients in whom hypoglycemia is contraindicated, such as those with coronary artery disease or severe systemic illness, the arginine stimulation test may serve as an alternative. Abnormal responses are defined by inadequate ACTH and COR elevation or failure to double at 60 and/or 90 minutes post-stimulation [29].

Pituitary contrast-enhanced magnetic resonance imaging (MRI) in PCC patients has identified structural abnormalities, including pituitary microadenomas, glandular enlargement, and empty sella, in up to 44.4% of cases. Given that SARS-CoV-2 may also directly affect the adrenal glands, rapid ACTH stimulation testing is essential when concomitant primary adrenal insufficiency (PAI) is suspected. Using this approach, insufficient COR responses have been reported in 6.5%–16.2% of PCC patients [30]. Additionally, adrenal contrast-enhanced computed tomography (CT) has revealed adrenal thickening or microadenomas in approximately 25% of cases, suggesting possible autoimmune adrenalitis and coexisting primary adrenal dysfunction in a subset of PCC patients. Furthermore, chronic ACTH deficiency associated with PCC-related SAI may further contribute to progressive adrenal atrophy [31]. Several studies reporting normal adrenal function in long COVID relied solely on basal ACTH and COR measurements [32] or standard ACTH stimulation tests [33], approaches that may underestimate dynamic HPA axis impairment. Collectively, adrenocortical dysfunction in PCC is multifactorial, underscoring the importance of selecting appropriate dynamic diagnostic modalities for accurate endocrine assessment.

2.2 GH deficiency in PCC

SARS-CoV-2 may damage the pituitary gland through direct viral invasion and autoimmune-mediated mechanisms [16]. Among anterior pituitary cell populations, GH-secreting acidophilic cells appear to be particularly vulnerable, which may explain why GH deficiency often manifests earlier than deficiencies of other pituitary hormones [34]. In adults, GH deficiency typically results from structural or functional impairment of the hypothalamic-pituitary axis, including pituitary adenomas, traumatic brain injury, and autoimmune disorders [35]. Increasing evidence indicates that GH deficiency is also highly prevalent in patients with PCC, and the severity of GH impairment has been associated with worse clinical outcomes [36]. In PCC, symptoms such as fatigue, generalized weakness, dyslipidemia, hypoglycemia, and reduced bone mineral density may be partially attributable to disruption of the GH-insulin-like growth factor (IGF) axis.

ITT remains the gold standard for assessing GH axis function. Data from an unpublished cohort indicate that up to 53.4% of PCC patients exhibit peak GH levels below 5 ng/mL following insulin-induced hypoglycemia, meeting the diagnostic criteria for GH deficiency [37]. When patients are stratified according to peak GH levels at 60 minutes after hypoglycemic stress, those with peak values below 5 ng/mL also demonstrate significantly reduced COR responses at 30, 60, 90, and 120 minutes, frequently failing to reach the threshold of 500 nmol/L required for an adequate COR response. In classical GH deficiency, reduced GH secretion is typically accompanied by decreased circulating insulin-like growth factor 1 (IGF-1). However, in PCC patients, markedly reduced IGF-1 concentrations are observed only in a minority of individuals with severe GH deficiency, suggesting partial preservation of peripheral GH signaling in some cases.

For patients with contraindications to hypoglycemia, such as coronary heart disease or severe systemic infection, the arginine stimulation test may be used as an alternative for evaluating GH reserve. Arginine stimulates GH secretion from pituitary somatotrophs. In cases of partial somatotroph dysfunction, peak GH levels at 30 and 60 minutes after arginine stimulation may remain within the normal range. However, persistently suppressed GH levels at 30, 60, and 90 minutes indicate severe GH axis impairment in PCC and are frequently associated with concomitant dysfunction of the HPA axis [29].

2.3 Dysregulation of the RAAS

COR plays a crucial role in maintaining water and electrolyte homeostasis. COR deficiency leads to increased renal sodium excretion, contraction of extracellular fluid volume, and reduced circulating blood volume, often manifesting clinically as hypotension. In more severe cases, impaired free water excretion may result in water retention, hyponatremia, and edema. Renin is secreted by juxtaglomerular cells in response to reduced sodium delivery to the macula densa and decreased renal perfusion pressure. Activation of renin release subsequently stimulates the RAAS cascade, resulting in secondary hyperaldosteronism.

Experimental evidence supports this mechanism. In Pomc-deficient mouse models, uninhibited plasma renin activity and secondary hyperaldosteronism are observed under basal conditions. Administration of dexamethasone suppresses renin activity and reduces aldosterone levels, highlighting the regulatory role of glucocorticoids in renin secretion [38]. In clinical practice, the supine-to-upright test is commonly used to evaluate renin and aldosterone responses in PCC patients with suspected concomitant SAI. Following furosemide stimulation, these patients frequently demonstrate concurrent increases in both renin and aldosterone, often exceeding supine values by more than 50%. In addition, serum sodium levels have been shown to correlate negatively with upright renin activity.

COR deficiency impairs renal potassium retention, sodium excretion, and hydrogen ion secretion, which may lead to hyperkalemia and mild metabolic acidosis. In contrast, aldosterone enhances renal potassium excretion and sodium retention, potentially resulting in metabolic alkalosis. When COR deficiency and secondary hyperaldosteronism coexist in the same individual, overt electrolyte disturbances may be masked, complicating clinical recognition.

Beyond central regulatory mechanisms, SARS-CoV-2 may directly invade adrenal cortical cells and the juxtaglomerular apparatus via ACE2 receptors, thereby disrupting negative feedback regulation within the RAAS [39, 40]. This dysregulation may further exacerbate multi-organ injury involving the heart, lungs, kidneys, and other systems [41]. Clinically, when PCC patients present with unexplained hyponatremia or hypokalemia, clinicians should maintain a high index of suspicion for the coexistence of SAI and overactivation of the RAAS system. Particular attention should be paid to symptoms such as palpitations, chest tightness, or activity-related arrhythmias. Further endocrine evaluation using the ITT and the supine-to-upright test may be warranted to clarify the underlying pathophysiology.

2.4 Thyroid function associated with immune dysregulation in PCC

Thyroid dysfunction has been reported in patients with PCC and most commonly presents as autoimmune thyroiditis, subclinical or overt hypothyroidism, subclinical or overt hyperthyroidism, or exacerbation of pre-existing thyroid disorders [42, 43]. Even in patients with reduced free thyroxine (FT4) levels secondary to low TSH levels or with positive anti-thyroid peroxidase antibodies, thyroid dysfunction is generally mild and may improve in parallel with overall recovery from PCC following appropriate treatment [33].

COR plays a context-dependent role in immune regulation, exerting both pro-inflammatory and anti-inflammatory effects depending on its concentration and temporal dynamics. Under conditions of systemic stress, an appropriate endogenous COR surge, reaching approximately three times the normal daily peak, suppresses excessive early innate pro-inflammatory responses while facilitating controlled immune cell recruitment to sites of inflammation [44, 45]. This mechanism is essential for limiting immune-mediated tissue injury.

Clinically, PCC patients with recurrent or progressive thyroid injury often exhibit persistently elevated IgG titers against latent viruses, including cytomegalovirus (CMV), rubella virus, and herpes simplex virus (HSV). Therefore, thyroid injury in PCC is less likely driven by primary thyroid pathology and is more closely related to impaired HPA axis responsiveness. Inadequate COR secretion in response to stress may permit sustained immune activation, resulting in cumulative immune-mediated thyroid damage and the establishment of a self-perpetuating cycle of thyroid dysfunction.

2.5 Glucose metabolism disorders associated with HPA and GH dysfunction

Disorders of glucose metabolism represent one of the most frequently observed endocrine and metabolic abnormalities in patients with PCC [46, 47]. Although it remains unclear whether SARS-CoV-2 infection directly induces new-onset diabetes or primarily exacerbates pre-existing metabolic dysfunction, increasing evidence suggests that HPA axis impairment plays a contributory role. Inadequate COR responses to stress may fail to restrain immune activation, thereby amplifying immune-mediated tissue injury and metabolic dysregulation [44, 45].

During the acute phase of SARS-CoV-2 infection, pancreatic injury may occur through direct viral interaction with ACE2 receptors expressed in pancreatic endocrine tissues [48]. In addition, virus-induced cytokine release can further increase the risk of glucose metabolism disorders [47, 49]. Some studies suggest that corticosteroid exposure and stress-related physiological activation may precipitate diabetes onset. However, available evidence also indicates that incident diabetes is strongly influenced by underlying metabolic susceptibility, particularly a prior history of prediabetes. Moreover, patients with diabetes may have an increased risk of developing PCC symptoms [50, 51].

A substantial proportion of PCC patients exhibit anterior pituitary dysfunction, with deficiencies of COR and GH being particularly prevalent. Both hormones function as critical counter-regulatory mediators of glucose homeostasis. Deficiency of either hormone may predispose individuals to hypoglycemia, affecting both non-diabetic and diabetic populations. In patients with diabetes, concurrent COR and GH deficiency can impair normal glucose counter-regulation, resulting in pronounced fluctuations between hypoglycemia and hyperglycemia. Notably, dipeptidyl peptidase 4 (DPP4) has been identified as a potential binding target for the SARS-CoV-2 spike protein [52], supporting a mechanistic link between viral infection and glucose dysregulation. In patients with PCC and diabetes, early recognition of endocrine deficiencies and timely intervention using physiological replacement doses of COR and GH, together with appropriate use of DPP4 inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists, may improve glycemic control and potentially facilitate recovery from new-onset diabetes.

2.6 Gonadal dysfunction and reproductive endocrine disturbances in PCC

The impact of PCC on gonadal function appears to be more extensively documented in female patients, whereas data regarding male reproductive involvement remain limited. In women, reproductive dysfunction primarily manifests as menstrual irregularities, ovarian dysfunction, impaired fertility, and disturbances related to the menopausal transition. Menstrual abnormalities commonly include exacerbation of premenstrual symptoms, worsening dysmenorrhea, alterations in cycle length and duration, changes in menstrual flow volume [53, 54], and intermenstrual bleeding [55].

Ovarian and fertility-related manifestations encompass a variety of disorders, including premature ovarian insufficiency, endometriosis, dyspareunia, vulvitis, ovarian cysts, polycystic ovary syndrome, uterine fibroids, abnormal uterine bleeding, pelvic congestion syndrome, and chronic non-menstrual pelvic pain. Women with PCC who become pregnant often experience exacerbation of long COVID symptoms [56] and face increased risks of adverse pregnancy outcomes, including preterm birth, miscarriage, stillbirth, and maternal mortality. In perimenopausal women, PCC has been associated with earlier onset of menopause, aggravation of menopausal symptoms, and postmenopausal bleeding. Ovarian impairment in PCC is often characterized by reduced oocyte quality [57, 58] and elevated circulating gonadotropin levels [59, 60]. In contrast, a subset of patients with concomitant pituitary involvement may present with hyperprolactinemia and inappropriately low gonadotropin levels, reflecting central hypogonadism rather than primary gonadal failure.

4.1 Clinical diagnosis of multi-endocrine axis impairment

Patients with PCC often present with fatigue, anxiety, and/or depressive symptoms. Clinicians frequently face difficulty distinguishing whether these manifestations stem from psychological distress or underlying physiological impairments [78]. Notably, such symptoms may signal impairment of multiple endocrine axes in these patients. Neurologically, PCC patients are commonly diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) [79]. Furthermore, when these patients seek repeated clinical intervention from specialties including pulmonology, cardiology, and gastroenterology, clinicians often find themselves unsure of the optimal clinical management approach. Impairment of multiple endocrine axes represents the core pathological issue in PCC patients. This is supported by the observation that most PCC patients, after a confirmed diagnosis of multiple endocrine axes impairment, experience spontaneous relief from fatigue, anxiety, and/or depressive symptoms with comprehensive endocrine hormone therapy – even in the absence of psychological interventions. Additionally, neuropathic pain involving the head, neck, and upper extremities often resolves spontaneously without targeted clinical interventions. PCC patients demonstrate varying degrees of dysregulation in the HPA axis, RAAS, and growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, which results in concomitant multisystem impairment. Such endocrine axis dysregulation causes overlapping clinical manifestations: one hormone may damage multiple organ systems, while distinct hormones can impair the same system. Hence, patients with PCC show consistent endocrine hormone abnormalities but heterogeneous clinical symptoms. Studies have shown that more than three years following initial SARS-CoV-2 infection, impairment of endocrine axes and immune function becomes progressively more severe. As a result, PCC patients who present to non-endocrine outpatient departments face considerable barriers to timely diagnosis and clinical management.

In patients with a high clinical suspicion of multiple endocrine axis impairment, key associated manifestations include:

1. ACTH deficiency may present with reduced skin pigmentation, lighter body hair, or patchy depigmentation.

2. COR deficiency may lead to hyponatremia and increased free water retention, resulting in sensations of formication (ants crawling on the skin), skin rashes, edema, generalized weakness, fatigue, hypotension, hypoglycemia, and neuromuscular pain.

3. GH deficiency is associated with decreased muscle mass, reduced exercise tolerance, and neuropsychiatric symptoms such as depressed mood and social withdrawal.

4. Secondary hyperaldosteronism may result in hypokalemia and metabolic alkalosis, manifesting as muscle weakness, polyuria, hypertension, cardiac arrhythmias, heart failure, neuromuscular pain, and tetany.

For patients highly suspected of PCC, screening for basal levels of ACTH, COR, GH, aldosterone, and renin should be performed. Venous blood should be collected at 9:00 AM after the patient has rested quietly for 30 minutes. When a definitive diagnosis and formulation of a treatment plan are required, dynamic endocrine function tests should be performed, including the ITT, recumbent-upright test, and rapid ACTH stimulation test, among others.

4.2 Exploration of treatment strategies for multi-endocrine axis impairment

In PCC, multi-endocrine axis impairment predominantly reflects hypothalamic-pituitary dysfunction, leading to SAI, GH deficiency, and secondary hyperaldosteronism. Importantly, patients with SAI often retain partial residual COR secretory capacity [59], which has implications for therapeutic decision-making. Current treatment strategies focus on restoring physiological endocrine balance, mitigating immune-mediated injury, and stabilizing metabolic and electrolyte disturbances. Based on available evidence and clinical experience, the following approaches may be considered:

1. Intermittent ACTH supplementation: Moderate, intermittent administration of ACTH may be considered, such as tetracosactide 25 IU per dose, administered intramuscularly every 1–2 weeks. ACTH supplementation can stimulate endogenous COR production and may exert additional immunomodulatory effects by acting directly on immune cells [80]. Restoration of ACTH signaling may also reduce negative feedback on hypothalamic corticotropin-releasing hormone and potentially facilitate recovery from immune-mediated hypothalamic or pituitary injury.

2. Physiological glucocorticoid replacement: Low-dose glucocorticoid therapy may be initiated, preferably with methylprednisolone at physiological doses (e.g., 5–15 mg/day), to modulate immune activity and reduce tissue edema. In patients with persistent hyponatremia despite treatment, switching to hydrocortisone (e.g., 20–60 mg/day) may be considered to achieve more balanced mineralocorticoid and glucocorticoid effects.

3. Low-dose GH therapy: Recombinant human GH may be administered at low physiological doses (e.g., 1.0–2.0 IU/day via subcutaneous injection). In some patients with combined SAI and GH deficiency, glucocorticoid replacement alone may partially restore GH secretion [81]. However, in cases where unexplained persistent hypoalbuminemia coexists with GH deficiency, combined glucocorticoid and GH replacement therapy may be appropriate.

4. Aldosterone Antagonist: Treatment with an oral nonsteroidal mineralocorticoid receptor antagonist, such as finerenone (e.g., 5–10 mg per dose, twice daily), may be considered with careful titration to the maximum tolerated dose. For patients with concurrent SAI and secondary hyperaldosteronism, a combined regimen, including glucocorticoids, an aldosterone antagonist, and sodium supplementation, may be required to manage fluid and electrolyte disturbances.

5. Immune modulation: Intravenous immunoglobulin may be considered when clinically indicated. In addition, certain traditional herbal agents with reported adrenal-modulating properties, such as ginseng, licorice, and Cordyceps sinensis, may be used as adjunctive therapy at appropriate doses.

6. Symptomatic and supportive care: Supportive measures aimed at improving cerebral circulation, providing neurotrophic support, and correcting micronutrient deficiencies should be implemented to address associated symptoms and promote functional recovery.

7. Antiviral treatment: Infection with SARS-CoV-2 impairs the body’s neuroendocrine system. When immune function remains persistently compromised, CMV, rubella virus, and HSV may opportunistically reactivate, plunging the body’s neuroendocrine glands into a vicious cycle of recurrent injury; thus, active antiviral treatment should be administered.

For PCC patients, all symptoms are significantly alleviated approximately one month after initiating multi-endocrine axis therapy. However, many patients discontinue medication after one month, resulting in disease recurrence. Notably, the recovery of damaged endocrine glands often lags behind the improvement of clinical symptoms. A treatment course of at least 3–18 months is recommended, and the medication dosage may be reduced after three months based on the degree of disease remission.

4.3 Regular follow-up

PCC patients require regular follow-up assessments. At one month post-treatment, clinical markers, including serum sodium, potassium, and plasma albumin, should be measured, with treatment regimens adjusted as appropriate based on the degree of clinical symptom resolution. Basal levels of ACTH, COR, growth hormone (GH), aldosterone, and renin should be quantified every three months. If clinically indicated, repeat pituitary MRI and adrenal CT are recommended, and the duration of hormonal therapy is tailored to these findings. Repeat testing for CMV, rubella virus, and HSV IgG antibodies may also be performed as needed to prevent recurrent invasion of multiple systemic neuroendocrine glands by these viruses in the setting of immune compromise. Currently, hormonal therapy may be discontinued in patients with mild PCC following three months of treatment. The first patient in this study, with a confirmed diagnosis of multiple endocrine axes impairment secondary to PCC, discontinued hormonal medications after 18 months of treatment and has maintained a favorable prognosis for 1 year post-discontinuation. Notably, all instances of disease flare or recurrence in PCC patients are attributable to recurrent infections with CMV, rubella virus, and HSV.