Abstract
Purpose
Acromegaly (AC) and Cushing’s disease (CD) increase morbidity and mortality due to cardio-metabolic alterations, and overall cause frailty in the affected patients, potentially making them more susceptible to infective diseases. However, up to now, very few studies evaluated the course of COVID-19 disease in this setting.
Methods
We investigated epidemiology, course, and outcomes of COVID-19 disease in patients with AC or CD, managed in the Endocrine Unit of a Sicilian University Hospital during 2 years of pandemic outbreak.
Results
We enrolled 136 patients with AC or CD (74 and 62 cases, respectively, 39 males) from Sicily and Calabria regions. Incidence of Sars-CoV-2 infection in these subjects was lower than in the general population, becoming quite similar after vaccines introduction (11%). No difference was observed concerning prevalence. Mean age of infected patients (IPs) was significantly lower than the unaffected ones (p < 0.02). No differences were found for sex, BMI, disease control, occurrence of diabetes mellitus, OSAS, cardiomyopathy, and hypopituitarism. The rate of IPs was similar in AC and CD patients’ groups. None of them died.
Conclusions
In conclusion, we did not find a significantly different incidence of Sars-CoV-2 infection in AC or CD patients compared to the general population. IPs were younger than the unaffected patients, but sex, BMI, or diabetes mellitus were not risk factors for infection/worse outcomes. Nevertheless, these results could have been biased by a safer behavior probably adopted by older and more complicated patients.
Keywords: Acromegaly, Cushing’s disease, COVID-19, Comorbidities
Introduction
Acromegaly (AC) and Cushing’s disease (CD) are rare endocrine diseases due to GH or ACTH-secreting pituitary tumors. Both diseases are associated with an increased risk for infectious disease that is also one of the most frequent causes of death in CD patients. Nevertheless, up to date, a few data concerning Sars-CoV-2 infection in these patients have been published [1, 2]. A higher prevalence of COVID-19 disease in CD patients than in the general population (3.2 vs. 0.6%) was recently reported by Serban et al., while 3 cases among 22 patients with active CD were described by Belaya et al. [3, 4]. After the first case of COVID-19 disease diagnosed on March 6th, 2020, in Messina city (Sicily, Italy), 977.088 people were infected by Sars-CoV-2 virus, and 11.766 out of them died, during the 1st 2 years of outbreak in Sicily and in Calabria region [5].
Sars-CoV-2 infection causes a broad clinical spectrum that includes asymptomatic forms, or a mild to severe symptomatic presentation. It is sometimes complicated by acute respiratory distress syndrome (ARDS) and/or septic shock leading to patient’s death due to severe pulmonary microvascular damage triggered by a “cytokine storm”. Overall, about 10–15% of cases evolve into a severe form of COVID-19 disease. This risk occurs especially in elderly patients, and in those with comorbidities such as type 2 diabetes mellitus (T2DM), arterial hypertension, obesity, and cardiovascular disease [6–8]. Typically, patients with AC and CD frequently show systemic comorbidities affecting cardio-respiratory function and glucose metabolism, which increase their mortality risk. Moreover, CD is associated with obesity, cardiovascular disease, and immune system impairment. A recent survey reported that one of the factors influencing the course of COVID-19 in AC patients was glucose metabolism alterations [9]. Even the coexistence of OSAS can significantly compromise respiratory function. On the converse, the course of viral infection in patients with Cushing’s syndrome seems to be predominantly influenced by age and severe hypercortisolism. As reported by Belaya et al., elderly CD patients with active disease, consequent lymphopenia and deteriorated renal function were more predisposed to a worse outcome of COVID-19, related to the development of multiorgan failure and massive pneumonia [4]. Furthermore, the second-generation somatostatin analog, pasireotide, used for treatment of both AC and CD, can lead to elevation of serum fasting glucose and HbA1c.
In this paper, we report on the incidence rate and characteristics of COVID-19 infection among our cohort of patients with AC and CD, during the pandemic outbreak until March 2022. Thus, the difficulties in disease management should be kept into account, during a period of recurring lockdowns when patients have been mostly managed via telemedicine, being this last modality characterized by both advantages and weak points. In fact, some studies have also demonstrated an overall lower treatment adherence during pandemic closures, although the application of remote selection criteria for face-to-face visits (i.e., triage by phone) has been proven to be useful in scheduling a more precise follow-up [10, 11]. In addition, we aimed to verify if and how much the infection course was influenced by the typical complications of AC and CD (i.e., hypertension and metabolic issues).
Methods
We investigated epidemiology, course, and outcomes of COVID-19 disease in a group of 136 patients (71.3% female) with AC or CD, followed-up at the Endocrine Unit of University Hospital of Messina during 2 years of COVID-19 pandemic (March 2020–March 2022). All patients came from Sicily and Calabria regions. Authorization from the Ethics Committee of the province of Messina was obtained for the study, and a written informed consent was signed by each patient included in the study for personal information use. All procedures performed in studies involving human participants were in accordance with the ethical standards of the local research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Diagnosis of AC was based on increased serum IGF-1 levels according to gender and age, lack of GH suppression during oral glucose tolerance test (OGTT), and detection of a pituitary tumor by MRI [12]. Serum IGF-1 levels were normalized as upper limit of normality for gender and age (xULN). According to the most recent consensus statement on acromegaly, adequate disease control resulted from IGF-1 levels ≤ 1.0 xULN and random GH < 1.0 ng/ml, while only normal IGF-1 values were considered in patients treated with pegvisomant [11]. All AC patients were periodically screened for systemic complications, as per guidelines [13, 14]. Diagnosis of CD was based on the measurement of late-night salivary cortisol, 24-h urinary free cortisol (UFC), and low-dose dexamethasone suppression test (1 mg overnight). Cortisol and ACTH responses to CRH and DDAVP stimulation, paired with MRI imaging revealing a pituitary adenoma and/or—when appropriate-petrosal sinus sampling conclusive for pituitary origin of ACTH excess, were consistent with CD. CD status was considered adequately controlled when 24-h UFC was within the normal range. In addition, CD patients were periodically screened for systemic complications, as per guidelines [15].
Of each patient, demographical and clinical parameters were collected, namely age, body mass index (BMI), presence of comorbidities (OSAS, arterial hypertension, cardiomyopathy, T2DM/IGT) and/or pituitary function alterations (central hypothyroidism, secondary adrenal insufficiency, hypogonadotropic hypogonadism, hyperthyroidism from coexisting TSH hypersecretion, growth hormone deficit—GHD). Patients were called by phone and administered a brief questionnaire, investigating the presence of Sars-CoV-2 infection. For patients tested positive, dedicated items first concerned information about virus detection, i.e., if the nose-pharyngeal swab was performed in presence of symptoms or only for screening purposes (for example, before acceding to hospital). Then, COVID-19 infection characteristics were analyzed, like presence of symptoms (anosmia/ageusia, fever > 40 °C, sore throat, dry cough, rhinorrhea, weakness, muscle pain, headache, dyspnea, abdominal pain with or without nausea/vomiting, cutaneous manifestations, i.e., erythema) and their duration. Finally, disease course and management were investigated: specific COVID-19 disease treatments (antibiotics, NSAIDs, corticosteroids, heparin, etc.), need for hospitalization, interval before testing negative, and need for endocrine therapy dose modification/withdrawal. COVID-19 was managed and treated—for the most part by patients’ general practitioners—according to the indications provided by the Italian Drug Agency (AIFA) and the Italian Ministry of Health, while the Italian Society of Endocrinology (SIE) expert opinion on glucocorticoid therapy was followed in patients with adrenal insufficiency [8].
Statistical analysis
Numerical data are expressed as mean ± standard error (SE) and categorical variables as numbers and percentages. Since examined variables were not normally distributed, the non-parametric approach was used (Kolmogorov–Smirnov test). We analyzed the prevalence of COVID-19 infection among our enrolled patients, comparing the prevalence of complications (T2DM, OSAS, hypertension, obesity, cardiopathy and hypopituitarism) between the infected patients (IPs) and the other ones.
Results
Clinical characteristics of our 136 patients are summarized in Table 1. Their mean age was 55.7 ± 1.4 years and 53 of them (38.9%) had a body mass index (BMI) ≥ 30 kg/m2 (mean BMI 29.87 ± 0.6 kg/m2). Overall, 76 patients were affected by AC and 60 by CD. In 108 cases (79.4%), primary disease was controlled (59 AC, 49 CD). Pituitary function was impaired in 61.02% of patients (47.05% hypothyroidism, 11.02% hypoadrenalism, and 16.2% hypogonadism). AC and CD were complicated by T2DM or impaired glucose tolerance (IGT) in 30.1%, arterial hypertension in 61.02%, and cardiomyopathy in 60.3%, overall. In addition, AC was complicated by OSAS in 41.6% of cases.
Table 1.
General characteristics of enrolled patients
| Total n | 136 |
|---|---|
| M/F | 39/97 |
| Age (mean ± SD) | 55.7 ± 1.4 |
| BMI kg/m2 | 29.87 ± 0.6 |
| AC/CD | 76/60 |
| Controlled | 108 (79.4%; 59 AC/49 CD) |
| Impaired pituitary function | 83 (61.02%) |
| Hypothyroidism | 64 (47.05%) |
| Hypoadrenalism | 15 (11.02%) |
| Hypogonadism | 22 (16.2%) |
| OSAS | 37 out of 89 with data (41.6%) |
| Obesity | 53 (38.9%) |
| Type 2 diabetes mellitus/IGT | 41 (30.1%) |
| Hypertension | 83 (61.02%) |
| Cardiomyopathy | 82 (60.3%) |
AC acromegaly, CD Cushing’s disease, OSAS obstructive sleep apnea syndrome, IGT impaired glucose tolerance
The overall prevalence of Sars-CoV-2 infection among our patients was 11.02%, with 15/136 subjects (5 M, 10 F) tested COVID-positive and 121/136 (34 M, 87 F) negative. Mean age of infected patients (IPs) was significantly lower than that of the other ones (46.8 ± 3.7 vs. 56.5 ± 1.4, p 0.01) (Table 2). No significant differences were observed regarding sex, BMI (30.11 ± 2.2 among COVID-positive vs. 29.9 ± 0.7 kg/m2), and disease control (73.3% in COVID-positive and 80.2% in COVID-negative, respectively). The rate of patients with DM/IGT was significantly lower in IPs than in the other ones (6.7 vs. 33.05%, p 0.03, χ2 4.41), while the occurrence of arterial hypertension, OSAS, cardiomyopathy, and hypopituitarism did not differ among the two groups (Table 2). The rates of IPs between AC and CD groups were similar (10.5 vs. 11.7%, NS). Among IPs, 3 (2 M, 1 F, 20%; 1 AC, 2 CD, respectively) were asymptomatic, while none of them needed hospitalization or died. Regarding disease duration, the affected patients tested negative after 12.2 ± 6.5 days: specifically, AC patients after 11.5 ± 6.4 days, while CD patients after 18 ± 8.8 days (p < 0.01).
Table 2.
Comparison of patients’ clinical characteristics relating to the occurrence of Sars-CoV-2 positivity
| COVID+ve n. 15 | COVID−ve n. 121 | p value | |
|---|---|---|---|
| M/F | 5/10 | 34/87 | NS |
| Age | 46.8 ± 3.7 | 56.5 ± 1.4 | 0.01 |
| BMI kg/m2 | 30.1 ± 2.2 | 29.9 ± 0.7 | NS |
| AC/CD | 8/7 | 68/53 | NS |
| Controlled disease | 11 (73.3%) | 97 (80.2%) | NS |
| Hypothyroidism | 6 (40%) | 58 (47.9%) | NS |
| Hypoadrenalism | 3 (20%) | 12 (9.9%) | NS |
| Hypogonadism | 3 (20%) | 19 (15.7%) | NS |
| OSAS | 4/12* (33.3%) | 33/77* (42.8%) | NS |
| Diabetes mellitus or IGT | 1 (6.7%) | 40 (33.05%) | 0.03 |
| Hypertension | 10 (66.7%) | 73 (60.3%) | NS |
| Cardiomyopathy | 8 (53.3%) | 74 (61.1%) | NS |
| Obesity | 5 (33.3%) | 48 (39.7%) | NS |
Bold stands for statisitically significant
AC acromegaly, CD Cushing disease, OSAS obstructive sleep apnea syndrome
*N. of patients with available information about sleeping disturbances
During the same period of the study, Sars-CoV-2 infection was detected in 14.7% of the general population from Sicily and Calabria region (6.626.775 people).
Discussion
Sars-CoV-2 infection shows a broad clinical spectrum that ranges from asymptomatic to mild to severe forms. Severe presentation is sometimes complicated by acute respiratory distress syndrome (ARDS) and/or septic shock, and approximately 10–15% of patients with mild presentation can evolve into a severe form of COVID-19 disease. This risk occurs especially in elderly patients, and in those with comorbidities such as arterial hypertension, obesity, decompensated T2DM, malignant neoplasms, chronic obstructive pulmonary disease (COPD), nephropathy, and heart disease [16].
We reported on the epidemiology, course, and outcome of COVID-19 disease among 136 patients with GH- and ACTH-secreting pituitary adenomas, being most of them female subjects (71.3%). Considering the whole cohort of enrolled patients, more than 11% experienced Sars-CoV-2 infection, the same prevalence of general population. This finding does not confirm the results of a study conducted on 61 patients with CD, which showed a daily positivity rate from Sars-CoV-2 higher than that recorded in the general population (3.2 vs. 0.6%) [3, 17]. Regarding incidence, it was lower in the first year of pandemic, becoming a similar to that recorded in the general population after the introduction of vaccines. In our study, the rate of Sars-CoV-2 positive patients was similar in both AC and CD groups (10.5% among AC and 11.7% among CD patients, respectively). Furthermore, our epidemiological analysis showed that mean age of the 15 Sars-CoV-2 positive patients was significantly lower (around 47 years) than the general population (p < 0.02). This is in contrast with the data reported by literature during the first outbreak, where the average age of Sars-CoV-2 positive patients was higher in the general population.
Both AC and CD are associated with multiple chronic comorbidities, which could predispose to worse clinical outcomes of Sars-CoV-2 infection. Indeed, data from literature suggest that T2DM, arterial hypertension and obesity increase the risk of complications related to COVID-19 [6]. T2DM is the most clinically relevant comorbidity reported in patients hospitalized for COVID-19 and is also one of the main complications associated with AC and CD. Development of T2DM may increase cardiovascular risk in patients affected by AC and CD, already afflicted by other specific comorbidities and systemic complications. In addition, in both cases, medical therapies include the use of the second-generation somatostatin analog, pasireotide, whose main adverse event is the development of fasting hyperglycemia. Therefore, the presence of impaired glucose metabolism has significant prognostic and therapeutic implications that can often be difficult to control. Shekar et al. reviewed data from 16 studies carried out among IPs, with prevalence of DM between 2 and 56.6% [6]. In our experience, the prevalence of T2DM was 6.7% in IPs, significantly lower than in the other ones, although this represents a frequent complication of AC and one of the main comorbidities related to CD. Nevertheless, in our experience, the prevalence of hypertension was not higher in patients infected with Sars-CoV-2. The prevalence of obesity in COVID-19 patients reported in the literature is 48.3%, while in our study it was similar (around 40%) between IPs and the other patients, also with a comparable body mass index (BMI).
As far as it concerns the data gathered among our IPs, they demonstrated an overall satisfactory glycemic compensation. Besides, all patients were well educated on the home management of medical treatment for their diseases, which mainly consisted of first-generation somatostatin analogs and/or GH receptor antagonist, pegvisomant. Only a 36-year-old patient practiced therapy with the second-generation somatostatin analog, pasireotide, but she never recorded alterations in the glycemic profile. Therefore, most patients (75%) presented at the time of infection with adequate disease control or even in remission. It should also be highlighted that the presence of OSAS could significantly impair respiratory function, especially in acromegaly patients. In our experience, only one of IPs had OSAS on home therapy with cPAP and showed good apnea control.
The course of viral infection in patients with CD in general seems to be predominantly influenced by age and cortisol levels during COVID-19 disease. As reported by Belaya et al. elderly CD patients with active disease, consequent lymphopenia and deteriorated renal function were more prone to a worse outcome of COVID-19, due to the development of multiorgan failure and massive pneumonia [4]. In our experience, IPs had a mean age of 42 years, significantly lower than the unaffected ones.
Furthermore, the most part (75%) of our Sars-CoV-2-positive patients were in good disease control, which could explain a substantially favorable course despite some of them complained of symptoms. Indeed, none of patients involved in our study was hospitalized or died. Only one individual among the positive cases was affected by central hypoadrenalism, but he was under adequate corticosteroid replacement therapy. Moreover, the significant difference observed in disease duration, lower in AC patients compared to CD ones, could be related to the possible role of GC-mediated immune suppression.
In conclusion, in our experience, the prevalence of Sars-CoV-2 infection was not higher in patients with AC or CD than in the general population. Sars-CoV-2-positive patients had a lower average age than unaffected patients, but sex, BMI, or diabetes mellitus did not seem to influence disease susceptibility or worsen the outcome in our cohort. On the other hand, it has to be highlighted that these data have been collected in a single center in a limited time interval during pandemic lockdowns/restrictions, so that it could have had an impact on the number of patients involved and the precise reporting. Also, our results could be influenced by the fact that older patients—especially acromegaly patients with frailty related to obesity and/or movement limitations—generally behaved more prudently regarding infection exposure and were also more careful in the home management of their chronic therapies. Moreover, the high rate of controlled patients among the affected subjects could in part explain the absence of differences in COVID-19 prevalence compared to the general population, as suggested by some evidence in the literature that CD treatment can improve the immune detrimental effects of hypercortisolism through circadian rhythm restoration [18].
Funding
Italian Government, PRIN 2017, PRIN 2017S55RXB, Salvatore Cannavo.
Declarations
Conflict of interest
Regarding conflict-of-interest disclosure, FF is a member of the Journal Editorial Board. The paper has been supported by the following grant (Progetto Rilevante di Interesse Nazionale, PRIN 2017): identification of new biomarkers and clinical determinants for management improvement of patients with pituitary tumor related syndromes (code: PRIN 2017S55RXB) of the Italian Government.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics committee of the Province of Messina and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
M. Ragonese and G. Giuffrida are to be considered as the first authors.
F. Ferraù and S. Cannavò equally contributed to the coordination of the study and to the manuscript’s revision.
References
- 1.Crisafulli S, Luxi N, Sultana J, Fontana A, Spagnolo F, Giuffrida G, Ferrau F, Gianfrilli D, Cozzolino A, De Martino MC, Gatto F, Barone-Adesi F, Cannavò S, Trifirò G. Global epidemiology of acromegaly: a systematic review and meta-analysis. Eur J Endocrinol. 2021;185(2):251–263. doi: 10.1530/EJE-21-0216. [DOI] [PubMed] [Google Scholar]
- 2.Giuffrida G, Crisafulli S, Ferraù F, Fontana A, Alessi Y, Calapai F, Ragonese M, Luxi N, Cannavò S, Trifirò G. Global Cushing’s disease epidemiology: a systematic review and meta-analysis of observational studies. J Endocrinol Invest. 2022;45(6):1235–1246. doi: 10.1007/s40618-022-01754-1. [DOI] [PubMed] [Google Scholar]
- 3.Serban AL, Ferrante E, Carosi G, Indirli R, Arosio M, Mantovani G. COVID-19 in Cushing disease: experience of a single tertiary centre in Lombardy. J Endocrinol Invest. 2021;44(6):1335–1336. doi: 10.1007/s40618-020-01419-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Belaya Z, Golounina O, Melnichenko G, Tarbaeva N, Pashkova E, Gorokhov M, Kalashnikov V, Dzeranova L, Fadeev V, Volchkov P, Dedov I. Clinical course and outcome of patients with ACTH-dependent Cushing’s syndrome infected with novel coronavirus disease-19 (COVID-19): case presentations. Endocrine. 2021;72(1):12–19. doi: 10.1007/s12020-021-02674-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.https://www.salute.gov.it/portale/nuovocoronavirus/dettaglioNotizieNuovoCoronavirus.jsp?lingua=italiano&menu=notizie&p=dalministero&id=5839. Accessed 20 June 2022
- 6.Shekhar S, Wurth R, Kamilaris CDC, Eisenhofer G, Barrera FJ, Hajdenberg M, et al. Endocrine conditions and COVID-19. Horm Metab Res. 2020;52:471–484. doi: 10.1055/a-1172-1352. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Isidori AM, Pofi R, Hasenmajer V, Lenzi A, Pivonello R. Use of glucocorticoids in patients with adrenal insufficiency and COVID-19 infection. Lancet Diabetes Endocrinol. 2020;8(6):472–473. doi: 10.1016/S2213-8587(20)30149-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Isidori AM, Arnaldi G, Boscaro M, Falorni A, Giordano C, Giordano PR, Pofi R, Hasenmajer V, Venneri MA, Sbardella E, Simeoli C, Scaroni C, Lenzi A. COVID-19 infection and glucocorticoids: update from the Italian society of endocrinology expert opinion on steroid replacement in adrenal insufficiency. J Endocrinol Invest. 2020;43(8):1141–1147. doi: 10.1007/s40618-020-01266-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Giustina A, Legg E, Cesana BM, et al. Results from ACROCOVID: an international survey on the care of acromegaly during the COVID-19 era. Endocrine. 2021;71:273–280. doi: 10.1007/s12020-020-02565-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.De Vincentis S, Domenici D, Ansaloni A, Boselli G, D’Angelo G, Russo A, Taliani E, Rochira V, Simoni M, Madeo B. COVID-19 lockdown negatively impacted on adherence to denosumab therapy: incidence of non-traumatic fractures and role of telemedicine. J Endocrinol Invest. 2022;45(10):1887–1897. doi: 10.1007/s40618-022-01820-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Ceccato F, Voltan G, Sabbadin C, Camozzi V, Merante Boschin I, Mian C, Zanotto V, Donato D, Bordignon G, Capizzi A, Carretta G, Scaroni C. Tele-medicine versus face-to-face consultation in endocrine outpatients clinic during COVID-19 outbreak: a single-center experience during the lockdown period. J Endocrinol Invest. 2021;44(8):1689–1698. doi: 10.1007/s40618-020-01476-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Katznelson L, Laws ER, Jr, Melmed S, et al. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:3933–3951. doi: 10.1210/jc.2014-2700. [DOI] [PubMed] [Google Scholar]
- 13.Giustina A, Barkhoudarian G, Beckers A, et al. Multidisciplinary management of acromegaly: a consensus. Rev Endocr Metab Disord. 2020;21:667–678. doi: 10.1007/s11154-020-09588-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Melmed S, Bronstein MD, Chanson P, et al. A consensus statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol. 2018;14:552–561. doi: 10.1038/s41574-018-0058-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, et al. Diagnosis and complications of Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2003;88:5593–5602. doi: 10.1210/jc.2003-030871. [DOI] [PubMed] [Google Scholar]
- 16.Lisco G, De Tullio A, Stragapede A, Solimando AG, Albanese F, Capobianco M, Giagulli VA, Guastamacchia E, De Pergola G, Vacca A, Racanelli V, Triggiani V. COVID-19 and the endocrine system: a comprehensive review on the theme. J Clin Med. 2021;10:2920. doi: 10.3390/jcm10132920. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Frara S, Allora A, Castellino L, et al. COVID-19 and the pituitary. Pituitary. 2021;24:465–481. doi: 10.1007/s11102-021-01148-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Minnetti M, Hasenmajer V, Pofi R, Venneri MA, Alexandraki KI, Isidori AM. Fixing the broken clock in adrenal disorders: focus on glucocorticoids and chronotherapy. J Endocrinol. 2020;246(2):R13–R31. doi: 10.1530/JOE-20-0066. [DOI] [PubMed] [Google Scholar]