GHRP-2

Abstract

Long COVID (LC) may involve endocrine dysfunction; however, the underlying mechanism remains unclear. To examine hypothalamic-pituitary responses in patients with LC, we conducted a single-center retrospective study of patients with refractory LC referred to our University Hospital who underwent anterior pituitary stimulation tests. Between February 2021 and November 2025, 1251 patients with long COVID were evaluated, of whom 207 (19%) had relatively low random ACTH or cortisol levels. Ultimately, 16 underwent anterior pituitary stimulation tests and were included. All tests were performed in an inpatient setting without exogenous steroids. Fifteen patients (six women, mean age 35.6 years) underwent corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone (GnRH) tests. All patients had mild acute COVID-19, eight had ≥2 vaccinations, and the mean interval from infection was 343 days. Frequent symptoms included fatigue (100%), insomnia (66.7%), headache (60.0%), anorexia/nausea (40.0%), and brain fog (40.0%). Mean early-morning cortisol and 24 h urinary free cortisol were 7.5 μg/dL and 41.0 μg/day, respectively. MRI showed an empty sella in one case. Peak hormonal responses were preserved (ΔACTH 247%, ΔTSH 918%, ΔPRL 820%, ΔFSH 187%, ΔLH 1150%); however, peaks were delayed beyond 60 min in ACTH (13%), LH (33%), and FSH (87%). Notably, significantly delayed elevations remained at 120 min in the responses of TSH (4.1-fold), PRL (1.8-fold), LH (9.3-fold), and FSH (2.8-fold), suggesting possible hypothalamic involvement, particularly in the gonadotropin responses. Additionally, serum IGF-I was lowered (-0.70 SD), while GH response (mean peak 35.5 ng/mL) was preserved by growth hormone-releasing peptide (GHRP)-2 stimulation. Low-dose hydrocortisone and testosterone were initiated for three patients. Although direct viral effects and secondary suppression have been proposed, our findings may suggest that, at least in part, the observed response characteristics are consistent with functional secondary hypothalamic dysfunction rather than irreversible primary injury. These findings highlight the need for objective endocrine evaluation before initiating hormone replacements.

Abstract

Our patient is a 28-year-old male who was being treated by a local doctor for Hashimoto's thyroiditis. Four days prior to admission, nausea and diarrhea appeared, and it gradually became difficult for him to eat. The night before admission, his level of consciousness decreased (Japan Coma Scale (JCS) II-20), and he was rushed to the hospital. His other vital signs were stable. After completing a detailed examination, the cause was diagnosed as hypoglycemia with a blood glucose level of 21 mg/dl. After the administration of glucose, he regained consciousness and became alert, allowing him to return home, with the expectation that he would return to the hospital for a follow-up visit at a later date. However, an altered consciousness (JCS I-3) appeared again the next morning. Similar to the previous day, the cause of the altered consciousness was determined to be hypoglycemia. After making a detailed inpatient examination, his early morning fasting serum cortisol level was found to be less than 0.1 μg/dL, and his blood adrenocorticotropic hormone (ACTH) was 3.1 pg/mL, thus indicating decreases in both. After performing rapid ACTH testing, almost no increase in the serum cortisol levels was observed after 30 minutes and 60 minutes following ACTH administration, thus suggesting the presence of adrenal insufficiency. According to a contrast-enhanced CT of the abdomen, atrophy of both adrenal glands was observed; however, there was no macroadenoma or the like according to the contrast-enhanced MRI of the brain. Based on the results of the ACTH continuous load test, triple anterior pituitary stimulation test with corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone (GnRH), growth hormone-releasing peptide-2 (GHRP-2) load test, and insulin hypoglycemic load test, no abnormalities were found in his pituitary functions other than ACTH-cortisol, and no history of trauma or adenoma lesions, leading to a diagnosis of a sudden isolated ACTH deficiency. The patient has remained stable with no hypoglycemic episodes since treatment with hydrocortisone was initiated. Based on the fact that isolated ACTH deficiency is often associated with a complication of autoimmune endocrine disease, an autoimmune mechanism has been speculated. Although the disease is rare, it is an important disease that affects the quality of life (QOL) of patients, and it should therefore be considered when making a differential diagnosis.