Higher Risk and Earlier Onset Glaucoma in Cushing’s Syndrome

Posted on November 27, 2024 by MaryO

Abstract

Purpose

Glaucoma incidence in patients with endogenous Cushing’s syndrome (CS) has never been established. We aim to assess the risk for glaucoma among CS patients compared to controls and determine the age of disease onset.

Methods

A nationwide retrospective matched-cohort study of patients with endogenous CS diagnosed between 2000 and 2023. Patients with CS were matched in a 1:5 ratio, with a control group individually matched for age, sex, socioeconomic status and body mass index. Main outcomes were the incidence of glaucoma and disease onset.

Results

A total of 609 patients [396 women (65%); mean age 48.1 ± 17 years] were included in the CS group and 3018 controls. Follow-up duration was 14.6 years (IQR 9.8–20.2) for the study group. The aetiology of hypercortisolism was divided into pituitary (259, 42.6%), adrenal (206, 33.8%) and unconfirmed aetiology (144, 23.6%) patients. At baseline, 44 (7.2%) CS patients had a diagnosis of glaucoma, compared with 151 (5%) controls. The overall risk for glaucoma was 74% higher in patients with CS compared with matched controls (hazard ratio = 1.74, p = 0.002). Patients with CS who developed glaucoma were younger (mean age of 62 ± 14.7 years) than controls (mean ± SD age, 62 ± 14.7 years), (p = 0.02). The overall risk for glaucoma in CS was high for both patients in remission and patients with persistent hypercortisolism (p = 0.048). Patients with active hypercortisolism experienced an earlier glaucoma onset (82.1 ± 88.0 months).

Conclusions

Endogenous CS is associated with increased risk for glaucoma regardless of remission status and develops at a younger age compared with the general population.

1 INTRODUCTION

Glaucoma is a chronic, irreversible vision-threatening disease affecting more than 80 million people worldwide (Quigley & Broman, 2006). It is the leading cause of irreversible blindness and the second cause of overall global blindness after cataracts (Tham et al., 2014).

Steroid-induced glaucoma, categorized as secondary open-angle glaucoma, is commonly associated with exogenous topical steroid administration rather than endogenous glucocorticoid overproduction (Phulke et al., 2017). Approximately, 30% of the general population are classified as steroid responders, experiencing elevated intraocular pressure (IOP) following corticosteroid administration (Becker, 1965).

Cushing syndrome (CS) is an endocrine disorder which results from excess cortisol production. The most common cause of CS is exogenous steroid use, followed by endogenous cortisol overproduction (Gadelha et al., 2023). In most cases (60%–70%), the corticotropin excess is produced by an adrenocorticotropic-hormone (ACTH)-secreting pituitary adenoma, followed by adrenal aetiologies (20%–30%) and ectopic ACTH-producing neuroendocrine tumours (Gadelha et al., 2023; Reincke & Fleseriu, 2023).

The treatment of CS typically commences with surgical intervention to remove the source responsible for excessive cortisol production, followed by medical therapies (Fleseriu et al., 2021).

There is a known higher risk of glaucoma in patients treated with glucocorticoids; however, data concerning the risk for developing high IOP and glaucoma in patients with CS are limited to case reports and small studies (Blumenthal et al., 1999; Gupta et al., 2015; Haas & Nootens, 1974; Khaw et al., 2010; Tsushima et al., 2019; Virevialle et al., 2014).

In this retrospective matched-cohort study, we aim to assess the risk for glaucoma in patients with CS, as compared with age, sex, socioeconomic status and body mass index (BMI)-matched controls. Furthermore, we assess the glaucoma risk according to the CS aetiology, degree of UFC elevation and remission status.

2 MATERIALS AND METHODS

A retrospective matched-cohort study compared patients with CS to controls without hypercortisolism. Data were sourced from Clalit Health Services (CHS), serving over 4.8 million members. Institutional ethics committee approval was obtained from Rabin Medical Center, adhering to the Declaration of Helsinki and good clinical practice (RMC-0779-22, 11.12.2022). As data were anonymized, written consent was deemed unnecessary.

Using International Classification of Diseases (ICD-10) codes, clinical diagnoses with matching dates were identified. Data were extracted from the electronic health record database via the CHS research data-sharing platform, operated by MDClone. Collected information for potential cases included patient demographics and clinical features at CS diagnosis, along with diagnoses of various comorbidities, including glaucoma.

Diagnosis time was defined as the first occurrence of elevated UFC, CS diagnosis or pituitary/adrenal surgery. Glaucoma diagnoses for both the patients with CS and control groups were acquired through ICD-10 coding. Patients with a diagnosis of glaucoma were identified by the appropriate ICD-10 coding, given by the treating ophthalmologist and incorporated to the patient’s medical record. Each patient with CS was matched 1:5 with controls by age, sex, socioeconomic status and BMI; notably, these controls have never had testing for hypercortisolism.

The follow-up duration commenced from the diagnosis date for both patients with CS and their matched controls, extending until death, CHS membership cessation or the data collection cut-off of 30 September 2023. Early biochemical remission was established as of 24-h UFC levels normalization without requiring medical intervention for hypercortisolism or necessitating glucocorticoid replacement therapy following pituitary or adrenal surgery, occurring within 26 months from the initial diagnosis of CS. The main outcome was defined as the timing of glaucoma diagnosis following the diagnosis of CS in the study group.

In secondary analyses, the occurrence of glaucoma was compared between patients who achieved biochemical remission and those who did not as well as by aetiology of CS and degree of maximal UFC elevation.

2.1 Statistical analysis

Statistical analysis was generated using SAS Software, Version 9·4, SAS Institute Inc., Cary, NC, USA. Continuous variables were presented by mean ± standard deviation or median and interquartile range [IQR]. Categorical variables were presented by (N, %). The t-test, the Mann–Whitney U-test, and the Chi-squared test were used for comparison, between cases and controls, of normally distributed, non-normal and categorical variables, respectively. Cumulative incidence plots, for glaucoma after CS, where death without glaucoma was treated as a competing risk, were created. The Cox proportional hazard model, with death without glaucoma treated as a competing risk, was used to calculate hazard ratios (HR). The appropriateness of the proportional hazard assumption was assessed visually. Two-sided p-values less than 0.05 were considered statistically significant.

3 RESULTS

3.1 Study cohort and patient characteristics

Between 1 January 2000 and 30 September 2023, a cohort of 609 patients (65% women) with CS was included, with a mean age of 48.1 ± 17 years. Each patient was matched with up to five controls based on age, sex, socioeconomic status and BMI, resulting in a control group comprising 3018 patients. (Table 1).

TABLE 1. Demographics and Clinical Characteristics of Study Patients.
CS patients/controls All
CS patients Controls
Patients, n 609 3018 3627
Age at diagnosis, Mean ± SD 48 ± 17.17 47.97 ± 17.19 47.99 ± 17.18
Gender
Male 213 (35%) 1043 (35%) 1256 (35%)
Female 396 (65%) 1975 (65%) 2371 (65%)
Glaucoma 44 (23%) 151 (77%) 195 (5%)
Socioeconomic statusa
Low 74 (13%) 371 (13%) 445 (13%)
Middle 349 (60%) 1719 (60%) 2068 (60%)
High 153 (27%) 760 (27%) 913 (27%)
Smoking statusa
Never 198 (60%) 910 (63%) 1108 (62%)
Current/Past smoker 133 (40%) 544 (37%) 677 (38%)
BMI at diagnosis, Mean ± SDb 30.9 ± 7.6 30 ± 6.9 30.2 ± 7.01
Diabetes mellitus at diagnosis 140 (23%) 396 (13%) 536 (15%)
HTN at diagnosis 343 (56%) 957 (32%) 1300 (36%)
Dyslipidaemia at diagnosis 258 (42%) 874 (29%) 1132 (31%)
CAD at diagnosis 70 (11%) 191 (6%) 261 (7%)
History of stroke 27 (4%) 82 (3%) 109 (3%)
  • Abbreviations: BMI, body mass index; CAD, coronary artery disease; CS, Cushing’s syndrome; HTN, hypertension; N, number; SD, standard deviation.
  • a Data were not available for all patients.
  • b Number of patients were: 363 (60%) cases, 1549 (51%) controls and 1912 (53%) total.

Follow-up duration was 14.6 years (IQR 9.8–20.2) for the study group and 14.8 (IQR 9.9–20.2) for the matched controls.

Diabetes mellitus, hypertension, coronary artery disease, dyslipidaemia and stroke exhibited higher prevalence among CS patients compared to their matched controls (p < 0.01) (See Table 1).

The aetiology of hypercortisolism was divided into pituitary CS (pCS) in 259 (42.6%) patients and adrenal CS (aCS) in 206 (33.8%) patients. Disease aetiology could not be ascertained from the available data in 144 (23.6%) patients.

3.2 Risk factors for glaucoma in Cushing’s syndrome

Overall, 78 (78/609, 12.8%) patients with CS and 250 (250/3018, 8.3%) patients without CS developed glaucoma up to the last follow-up. When stratified by age group at the time of glaucoma diagnosis, patients with CS had the following distribution: 1.5% (nine patients) were diagnosed before the age of 40; 6.2% (38 patients) between the ages of 40 and 65; and 5% (31 patients) at the age of 65 and older. In comparison, among controls, the proportions were 0.3% (eight patients), 3.7% (113 patients) and 4.3% (129 patients) for the respective age groups.

These groups were further divided into patients with a history of glaucoma before and after the study baseline (CS diagnosis).

Reported prior history of glaucoma before CS diagnosis was noted in 34 patients with CS (5.58%), whereas among the controls, 99 patients (3.28%) had a history of glaucoma before the study baseline (p < 0.0089).

Following the diagnosis of CS, 44 (7.2%) patients with CS developed glaucoma, compared with 151 (5%) controls. (Table 1) The difference between groups was statistically significant (HR 1.74, 95% CI 1.17–2.60, p = 0.002).

The risk assessment for glaucoma, with death considered as a competing risk, revealed that by the end of the follow-up period, CS patients had a 74% higher overall risk for glaucoma compared to their matched controls (p = 0.002), (Figure 1).

Details are in the caption following the image

Overall risk for glaucoma with death as a competing event. CS = Cushing’s syndrome.

Patients with CS experienced glaucoma onset at a notably younger age than controls. The mean age of glaucoma onset among those with a history of glaucoma before CS diagnosis was 56.6 ± 12.9 years, in contrast to controls with a mean age of 61.6 ± 10.1 years (p = 0.005). After CS diagnosis, the age of glaucoma onset remained significantly younger in CS patients compared to their matched controls (mean age of 62 ± 14.7 years vs. 66 ± 11.3 years, respectively; p = 0.02).

We performed a subgroup analysis of patients with CS and glaucoma by the source of the excessive production of cortisol, including pituitary, adrenal and unknown-origin CS. No difference was observed in the risk for glaucoma in patients with either pituitary, adrenal or unknown-origin CS, compared to their matched controls. In the CD group, 15 patients (7%) were diagnosed with glaucoma, whereas in the control group, 47 patients (4%) developed glaucoma. Similarly, among patients with adrenal CS, 12 patients (7%) were diagnosed with glaucoma, compared with 45 (5%) individually-matched controls.

A univariate analysis to examine the effect of specific variables, including diabetes mellitus, BMI, smoking history, ischemic heart disease, hypertension, dyslipidaemia, history of stroke, socio-economic status and gender in CS patients with and without glaucoma was performed.

Severity of CS disease was evaluated by the maximal UFC levels that were ≥5 times higher in 8.1% (14/172) of patients with glaucoma, and ≤5 times higher in 8.8% (15/170). There was no correlation between maximal UFC levels and the risk for glaucoma (p = 0.19).

Of the 44 patients with CS diagnosed with glaucoma following a CS diagnosis, 13 cases (29%) had comorbid diabetes mellitus, compared to 85 of 441 (19.3%) patients without glaucoma. This suggests a trend towards an 82% higher risk of glaucoma in patients with diabetes mellitus compared to those without it (p = 0.06).

Additionally, a history of stroke was found to be more prevalent among patients with CS with glaucoma (three cases, 6.8%) compared to those without glaucoma (17 cases, 3.8%); however, the difference did not reach statistical significance. Gender did not emerge as a risk factor for glaucoma as the female-to-male ratio was consistent among patients with and without glaucoma.

3.3 Risk for glaucoma following remission of Cushing’s syndrome

Data on early biochemical remission status following a CS diagnosis were available for 471 patients; 312 (66%) achieved early biochemical remission, while 159 (34%) had persistent hypercortisolaemia. Overall, 62 (13%) patients CS, either with or without remission, had glaucoma in this study group. To assess the risk for glaucoma following a CS diagnosis, we excluded 28 patients who developed glaucoma before the CS diagnosis. Among the remaining 34 glaucoma patients diagnosed after a CS diagnosis, 22 (7.5%) achieved early biochemical remission, while 12 (7.9%) did not. The overall risk of glaucoma in Cushing’s syndrome was elevated for both individuals experiencing remission and those with persistent hypercortisolism (p = 0.048) (Figure 2). However, the difference between those who achieved remission and those who did not was not statistically significant (Table 2). Compared to their matched controls, patients with CS without early biochemical remission did not exhibit a statistically significant higher risk for glaucoma (p = 0.18). However, while the time span between CS diagnosis and glaucoma diagnosis was comparable between CS patients in remission and controls (88.6 ± 73.06 and 88.9 ± 88.4 months, respectively), CS patients not in remission experienced an earlier onset of glaucoma (82.1 ± 88.0 months).

Details are in the caption following the image

Risk for glaucoma in patients with and without early biochemical remission with death as a competing event.
TABLE 2. Patients with glaucoma and Cushing’s syndrome, with and without disease remission.
CS Glaucoma Glaucoma prior to CS
Total N. 471 34 28
Remission (n, %)a 312 (66%) 22 (65%) 20 (71%)
No remission (n, %) 159 (34%) 12 (35%) 8 (29%)
  • Abbreviations: CS, Cushing’s syndrome; N, number.
  • a Remission is defined as a normal 24-h UFC level without treatment for hypercortisolism, or hypocortisolism necessitating glucocorticoid replacement after pituitary or adrenal surgery, within 24 months following diagnosis of CS.

4 DISCUSSION

While data on glucocorticoid treatment and glaucoma are more established, the incidence of glaucoma in patients with CS is not known. In this nationwide retrospective matched-cohort study, the first of its kind to assess the risk for glaucoma in patients with CS, we demonstrated that individuals with endogenous CS exhibit a heightened risk of early-onset glaucoma. Additionally, patients with CS tended to develop glaucoma at a significantly younger age compared to matched controls from the general population. Importantly, this difference persisted even after excluding both cases and controls with a prior diagnosis of glaucoma.

The mechanism of steroid-induced glaucoma is not well understood; decreased trabecular meshwork outflow due to increased resistance is suspected to be the main cause of IOP elevation (Kersey & Broadway, 2005).

The overall prevalence of glaucoma in the general population increases with age and ranges from 1.5% to 1.9% in ages 40 to 65 years, increasing to 2% to 7% in patients 65 and older (Friedman, 2004). In our cohort, we observed that while the incidence of glaucoma in the control group increased with age, among patients with CS, the highest incidence of glaucoma was observed among those aged between 40 and 65 years. Additionally, the incidence of glaucoma before the age of 40 was five times higher among patients with CS compared to controls, highlighting a significantly elevated risk of early-onset glaucoma among individuals with hypercortisolism. Glaucoma prevalence in Israel is similar to worldwide reported rates (Levkovitch-Verbin et al., 2014). The higher incidence of glaucoma observed in both the study and control groups in our study as compared to the literature may be attributed to the study’s definition of glaucoma, which is based on ICD-10 codes in patients’ medical records. Furthermore, patients receiving medications potentially increasing IOP were not excluded. Thus, despite the overall higher glaucoma rates observed here, since both the study and control groups rely on the same diagnostic criteria, the increased incidence of glaucoma in patients with CS as compared to matched controls in our study is significant and warrants attention.

In addition, patients with CS experienced the onset of glaucoma at a notably younger age compared to controls, with CS patients exhibiting glaucoma onset 4 years earlier than controls. When examining the ages of patients before their CS diagnosis, those diagnosed with glaucoma were statistically significantly younger than controls, with mean ages of 56 and 61 years, respectively. This observation, coupled with the well-documented diagnostic delay of CS (Rubinstein et al., 2020), suggests that the hypercortisolism before the formal diagnosis of CS did put them at a heightened risk of developing glaucoma at a younger age.

Notably, we did not find any correlation between maximum elevation of UFC and the risk of developing glaucoma. We postulate that extended hypercortisolism exposure could exert a more significant influence than the maximum UFC levels measured in the urine, which has known significant variability also.

The association between diabetes mellitus and glaucoma remains inconclusive due to conflicting findings in cohort and epidemiological studies (de Voogd et al., 2006; Hennis et al., 2003). However, a comprehensive meta-analysis published in 2014 suggested that individuals with diabetes mellitus face an elevated risk of developing glaucoma (Zhou et al., 2014). In our study, we observed that patients with CS and diabetes mellitus were more likely to develop glaucoma compared to those without diabetes mellitus. Another significant risk factor for developing high IOP and consequently glaucoma is chronic corticosteroids use, specifically topical steroids. When the IOP remains high for a prolonged duration, damage to the optic nerve (steroid-induced secondary glaucoma) may occur (Kersey & Broadway, 2005).

Though it seems intuitive that endogenous CS could match the exogenous CS numbers, there are no large population studies examining the association between CS and glaucoma. Several studies suggested a role for endogenous cortisol in the development of ocular hypertension and glaucoma, noting increased plasma and aqueous humour cortisol levels in glaucoma patients (Patel et al., 2023). However, only a few small cohort clinical studies have been performed on endogenous hypercortisolism in patients with CS causing increased IOP and glaucoma (Jonas et al., 1990; Ma et al., 2022), while another study showed no correlation between endogenous hypercortisolism and increased IOP (Mishra et al., 2017). There are several published case reports on endogenous hypercortisolism as a cause for secondary glaucoma; Virevialle et al. reported a case of a young female with painless loss of vision who had severe open-angle glaucoma with uncontrolled high IOP, requiring glaucoma surgery, which later was found to be secondary to CS related to an adrenal adenoma (Virevialle et al., 2014). Another case report published by Blumenthal et al. described a 33-year-old man with increased IOP represented as a manifestation of hypercortisolism caused by ectopic CS. Importantly, after surgical removal of the tumour, the high IOP resolved (Blumenthal et al., 1999). CD has also led to ocular hypertension and glaucoma in two cases, with IOP returning to normal levels in all four eyes after transsphenoidal tumour resection (Gupta et al., 2015). Noteworthy, in some of the reports, ocular hypertension and glaucoma were the presenting manifestations for CS diagnosis (Jonas et al., 1990; Ma et al., 2022; Mishra et al., 2017).

The overall risk for glaucoma was high for both patients with early biochemical remission and patients with no remission, which can be due to the limited number of patients in each group. However, patients with persistent hypercortisolaemia were diagnosed with glaucoma approximately 6 months earlier compared to both patients with CS in remission and controls. This observation could be attributed to the prolonged hypercortisolaemia in patients with CS without remission, leading to elevated IOP and subsequent development of glaucoma.

This study has several strengths, including a sufficiently large sample size for the primary analysis, long-term follow-up, and strict criteria for diagnosing CS, along with consideration of disease aetiology and remission status. The control group was carefully matched to minimize the influence of factors like age, sex, socioeconomic status and BMI on cancer risk. Additionally, the database encompasses the entire population, eliminating the risk of selection bias. Given the increased mortality associated with CS, we accounted for death as a competing risk in all analyses. Lastly, we performed necessary sensitivity analyses to ensure the robustness of our results.

The limitations of this study include the potential for missing data, which, due to its retrospective design, may have affected our ability to identify patients with CS and glaucoma, as well as to determine disease aetiology or remission status in some cases. Additionally, ascertainment bias cannot be excluded, as patients with CS may have been diagnosed with glaucoma more frequently due to more regular ophthalmologic examinations. Surveillance bias, where patients with more frequent healthcare visits or monitoring are more likely to be diagnosed with additional conditions due to being examined more often than others, could also result in an overestimation of the association between CS and glaucoma.

In this large nationwide retrospective matched-cohort study, we have shown for the first time that endogenous CS, whether caused by a pituitary or adrenal adenoma, is associated with an increased risk for glaucoma and a clinical manifestation at an earlier age versus general population, regardless of remission status or degree of UFC elevation. A delay in diagnosing both CS and glaucoma can result in significant ocular and systemic morbidities. Guidelines should also incorporate recommendations for periodic monitoring for intraocular pressure and/or glaucoma development to be routinely performed for patients with CS, especially if they also have concomitant comorbidities. Further research using larger multinational databases is warranted to validate our findings and uncover additional insights.

FUNDING INFORMATION

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

CONFLICT OF INTEREST STATEMENT

Y.S., A.Z., Y.R., S.K., I.S. and T.S. do not have any financial or personal relationships with other people or organizations to disclose. A.A. has received occasional scientific fee for scientific consulting and advisory boards from Medison, C.T.S. pharma and Neopharm. M.F. has received research support from Oregon Health & Science University as a principal investigator from Recordati, Sparrow and Xeris and has performed occasional scientific consultancy for Recordati, Sparrow and Xeris.

From https://onlinelibrary.wiley.com/doi/10.1111/aos.16787

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Bone Material Strength index is low in Patients with Cushing’s Syndrome even after long-term remission

Posted on November 25, 2024 by MaryO

Abstract

Objective: Hypercortisolism in endogenous Cushing’s syndrome (CS) results in decreased bone mineral density (BMD) and increased fracture risk. Although after remission BMD improves, fracture rate remains elevated, suggesting that BMD may not adequately reflect fracture risk in this group. The aim was to evaluate bone material properties, another component of bone quality, using Impact Microindentation (IMI) in patients with CS in remission.

Methods: Cross-sectional study in 60 patients and 60 age-, sex-, and BMD-matched controls at a tertiary referral center between 2019 and 2021. Bone material strength index (BMSi) was measured by IMI using the OsteoProbe® device at the tibia. In addition, laboratory investigation, BMD, and vertebral fracture assessment were performed.

Results: By design, patients and controls were comparable for age (median age 56.5 years), sex (48 women), BMD at the lumbar spine and femoral neck. They were also comparable regarding the number of fragility fractures (21 vs. 27, p=0.22). Median time of remission in patients was 6 years (range 1 to 41). Despite comparable BMD, BMSi was significantly lower in patients compared to controls (76.2±6.7 vs 80.5±4.9, p<0.001). In patients, BMSi was negatively correlated with BMI (r= -0.354, p=0.01), but not related to the presence of fracture, physiological hydrocortisone replacement use, other pituitary insufficiencies, or time since remission.

Conclusion: Bone material properties remain altered in patients with endogenous CS, even after long-term remission. These abnormalities, known to be associated with fractures in other populations, may play a role in the persistent bone fragility of steroid excess.

Keywords: Bone Material properties; Bone fragility; Bone quality; Fractures; Impact Microindentation (IMI); Secondary osteoporosis.

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From https://pubmed.ncbi.nlm.nih.gov/39562003/

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Iatrogenic Cushing Syndrome and Adrenal Suppression Presenting as Perimenopause

Posted on November 12, 2024 by MaryO

JCEM Case Reports, Volume 2, Issue 11, November 2024, luae183, https://doi.org/10.1210/jcemcr/luae183

Abstract

Secondary adrenal insufficiency is a life-threatening condition that may arise in the setting of iatrogenic Cushing syndrome. Intra-articular corticosteroid injections (IACs) are a standard treatment for osteoarthritis, and they carry a high risk of secondary central adrenal suppression (SAI). We present the case of a 43-year-old woman who was referred to reproductive endocrinology for evaluation of abnormal uterine bleeding with a provisional diagnosis of perimenopause. She reported new-onset type 2 diabetes mellitus, abdominal striae, hot flashes, and irregular menses. Laboratory evaluation revealed iatrogenic Cushing syndrome and SAI attributable to prolonged use of therapeutic IACs for osteoarthritis. Treatment included hydrocortisone replacement and discontinuation of IACs followed by hydrocortisone taper over the following 16 months that resulted in the return of endogenous ovarian and adrenal function. This case demonstrates the many hazards of prolonged IAC use, including suppression of ovarian and adrenal function and iatrogenic SAI.

Introduction

Intra-articular corticosteroid injections (IACs) are commonly used for the treatment of symptomatic osteoarthritis [1]. Synovial injections carry the highest risk of secondary central adrenal suppression (SAI) [2-5]. Further, exogenous glucocorticoid administration may also result in secondary Cushing syndrome. Symptoms associated with exogenous glucocorticoid administration vary significantly, and misdiagnosis is common [6, 7]. Here, we present a case of exogenous IAC use resulting in SAI and Cushing syndrome in a 43-year-old woman who was referred for evaluation and treatment of abnormal uterine bleeding with a provisional diagnosis of perimenopause.

Case Presentation

A 43-year-old woman with a past medical history of fibromyalgia, osteoarthritis, bursitis, asthma, gastroesophageal reflux, and diabetes was referred to reproductive endocrinology with a chief complaint of hot flashes for over 2 years and a presumptive diagnosis of perimenopause. Approximately 2 years before the onset of her symptoms, she reported irregular menses, followed by 11 months of amenorrhea, then 3 menstrual intervals with prolonged bleeding lasting 45, 34, and 65 days, respectively. She reported menarche at 11 years old, regular menstrual cycles until the last 2 years, and 4 pregnancies that were spontaneously conceived. She delivered 3 liveborn term children and had one spontaneous miscarriage. Her only complication of pregnancy was gestational hypertension during her last pregnancy that occurred 9 years prior when she was 34 years old.

In addition to menstrual irregularity, she also reported hot flashes, increasing truncal weight gain over the last 5 years, new-onset diabetes mellitus, and hypertension. Eighteen months prior to referral, she had an endometrial biopsy, which demonstrated secretory endometrium without hyperplasia, and cervical cancer screening was negative.

She initially reported the following medications: inhaled fluticasone/propionate + salmeterol 232 mcg + 14 mcg as needed and albuterol 108 mcg as needed. Her daily medications were glimepiride 1 mg, furosemide 20 mg, omeprazole 20 mg, montelukast 10 mg, azelastine hydrochloride 137 mcg, ertugliflozin 5 mg, and tiotropium bromide 2.5 mg. Importantly, she did not report IAC treatments.

Diagnostic Assessment

Initial physical examination showed height of 160 cm, weight of 103.4 kg, body mass index (BMI) of 46 kg/m2, and blood pressure (BP) of 128/80. Physical exam was significant for round facies with plethora, bilateral dorsocervical neck fat pads, and violaceous striae on her abdomen and upper arms (Fig. 1). The patient ambulated with a cane and reported severe bilateral proximal leg atrophy and weakness.

 

Abdominal and upper extremity striae prior to treatment with truncal obesity immediately before (A) and 1 year after initial diagnosis (B).

Figure 1.

Abdominal and upper extremity striae prior to treatment with truncal obesity immediately before (A) and 1 year after initial diagnosis (B).

A laboratory evaluation was recommended but was not initially completed. She was scheduled for a transvaginal ultrasound that required prior authorization; the pelvic ultrasound showed a heterogeneous and thickened anterior uterine wall, suggestive of adenomyosis, with a posterior intramural fibroid measuring 15 × 15 mm and an anterior intramural fibroid measuring 15 × 8 mm. Endometrial lining was thin at 5 mm. Both ovaries were small, without masses or antral follicles. Three-dimensional reconstruction showed a normal uterine cavity with some heterogeneity of the endometrial lining but no discrete masses suggestive of polyps or intracavitary fibroids as the cause of irregular bleeding. Upon additional questioning, she acknowledged receiving bilateral shoulder, hip, and knee injections of triamcinolone 80 mg every 2 to 3 months to each joint for about 5 years. Table 1 shows the initial laboratory evaluation and includes age-appropriate low ovarian reserve as evidenced by anti-Müllerian hormone (AMH), secondary hypothalamic hypogonadism, diabetes mellitus, and central adrenal suppression. Of note, the diabetes mellitus developed after 3 years of IAC use. Additional diagnostic assessment for adrenal insufficiency by synacthen testing was scheduled, however, the patient declined further investigation.

Initial laboratory values at presentation

Result Reference range
Basic metabolic panel
 Sodium 141 mEq/L; 141 mmol/L 135 to 145 mEq/L; 135 to 145 mmol/L
 Potassium 3.7 mEq/L; 3.7 mmol/L 3.7 to 5.2 mEq/L; 3.7 to 5.20 mmol/L
 Chloride 104 mEq/L; 104 mmol/L 96 to 106 mEq/L; 96 to 106 mmol/L
 Carbon dioxide 25 mEq/L; 25 mmol/L 23 to 29 mEq/L; 23 to 29 mmol/L
 Creatinine 0.42 mg/dL; 37.14 µmol/L 0.6 to 1.3 mg/dL; 53 to 114.9 µmol/L
 Urea nitrogen 14 mg/dL; 5 mmol/L 6 to 20 mg/dL; 2.14 to 7.14 mmol/L
Adrenal function
 Cortisol 0.8 µg/dL; 22.07 nmol/L 4-22 µg/dL; 138-635 nmol/L
 ACTH <5 pg/mL; <1 pmol/L 6-50 pg/mL; 5.5-22 pmol/L
 DHEAS 8 mcg/dL; 0.02 µmol/L 15-205 mcg/dL; 1.36-6.78 µmol/L
Endocrine function
 HbA1c 8.5% <5.7%
 Random glucose 124 mg/dL; 6.9 mmol/L 80-100 mg/dL; 4.4-5.5 mmol/L
 TSH 1.74 mIU/L 0.5-5 mIU/L
 tT4 10.5 µg/dL; 135.2 nmol/L 5.0-12.0 µg/dL; 57-148 nmol/L
 Free T4 index 2.6 ng/dL; 33.4 pmol/L 0.7-1.9 ng/dL; 12-30 pmol/L
 tT3 165 ng/dL; 2.5 nmol/L 60-180 ng/dL; 0.9-2.8 nmol/L
 TPO antibody Negative n/a
Ovarian function
 FSH 5.6 IU/L 4.5-21.5 IU/L
 LH 2.9 IU/L 5-25 IU/L
 Progesterone <0.5 ng/mL; 1.6 nmol/L Varies
 Estradiol 21 pg/mL; 77.1 pmol/L Varies
 AMH 1.1 ng/mL; 7.9 pmol/L 1.0-3.0 ng/mL; 2.15-48.91 pmol/L

Abbreviations: ACTH, adrenocorticotropic hormone; AMH, anti-Müllerian hormone; DHEAS, dehydroepiandrosterone sulfate; eGFR, estimated glomerular filtration rate; FSH, follicle-stimulating hormone; HbA1c, hemoglobin A1C; LH, luteinizing hormone; TPO antibody, thyroid peroxidase antibody; TSH, thyroid stimulating hormone; tT4, total thyroxine.

Treatment

The patient was immediately started on hydrocortisone 10 mg twice daily for glucocorticoid replacement, which was gradually reduced to 5 mg daily each morning at 16 months. Endocrine function testing was trended over the following months as replacement cortisone therapy was tapered.

Outcome and Follow-Up

Within 6 months of replacement and cessation of IACs, hot flashes ceased, and she reported regular menses. She lost 6.8 kg, her truncal obesity and striae significantly improved (Fig. 1), and she could now ambulate without assistance. Her glycated hemoglobin (HbA1c) level decreased from 8.5% to 6.8%. Fourteen months after her initial diagnosis and cessation of IAC, laboratory studies demonstrated partial recovery of adrenal and ovarian function and improved metabolism, as evidenced by increases in morning cortisol, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEAS), and decreased HbA1c. At 16 months, she had a return of ovulatory ovarian function.

Discussion

Cortisol is the main glucocorticoid secreted by human adrenal glands. The secretion pattern is precisely regulated by an integrated limbic-hypothalamic-pituitary (LHP) drive with the physiologic goal of homeostasis [1]. Conditions that result in deviations in glucocorticoid concentrations carry a variety of consequences. Our patient was referred because of a provisional diagnosis of abnormal uterine bleeding and perimenopause, which distracted from recognition of iatrogenic Cushing syndrome and secondary central adrenal suppression. This patient vignette underscores the importance of explicitly asking patients about nonoral medications, as patients may not report their use.

Exogenous administration of long-acting synthetic glucocorticoids may suppress adrenal function via negative feedback at the limbic and hypothalamic levels, which was reflected in this patient by undetectable ACTH and low cortisol levels (Table 1). In addition, excess glucocorticoid levels result in other neuroendocrine concomitants, including suppression of gonadotropin-releasing hormone (GnRH) drive that results in hypothalamic hypogonadism [8, 9], decreased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and anovulation despite AMH levels indicating residual ovarian reserve [10]. The clinical phenotype is variable and reflects individual glucocorticoid receptor sensitivities [9].

Regardless of cause, Cushing syndrome often presents with hallmark features of central obesity, violaceous striae, easy bruising, round facies, and nuchal adiposity with lower limb muscle atrophy and loss of strength [11]. Additionally, glucocorticoid excess causes insulin resistance and metabolic syndrome [8]. Truncal obesity is a common presenting symptom of excess cortisol. Cortisol inhibits metabolic response to insulin centrally and peripherally and increases gluconeogenesis, which together predispose to and cause diabetes [10].

Exogenous use of injectable glucocorticoids carries the highest risk of adrenal suppression when compared to other routes of exogenous steroids [5]. Patients typically report fatigue, malaise, and gastrointestinal complaints. Oligomenorrhea is a common presenting complaint in women, as was the case in our patient. Hyponatremia, water retention, and hypotension may occur in SAI because of endogenous glucocorticoid deficiency. A thorough laboratory evaluation in this patient revealed low LH, FSH, estradiol, and progesterone levels, indicating hypothalamic hypogonadism and not perimenopause/menopause [12] and low levels of cortisol, ACTH, and DHEAS confirmed SIA [10].

Adrenal insufficiency can be a life-threatening condition that requires supplementation with glucocorticoids [10, 13, 14]. A review of patients diagnosed with SAI suggested tapering of hydrocortisone before discontinuing all replacement therapy and revealed most patients recover without the need for exogenous steroids after 2 years from diagnosis [14]. ACTH stimulation testing may indicate the return of adrenal function [14, 15]. Our patient showed increased ACTH, cortisol, and DHEAS at 14 months. Ovulatory ovarian function, indicated by progesterone < 5 ng/mL (< 1.59 nmol/L) (Table 2), returned at 16 months after cessation of IACs. The improvement in adrenal and ovarian function following cessation of IACs and tapering of hydrocortisone replacement therapy was accompanied by decreased HbA1c, weight loss, truncal obesity, and stria, and increased muscle strength scalp hair.

 
Table 2.

Endocrine lab results 7 years prior, at presentation (T0), and over the next 16 months

Analyte Reference range 7 years prior T0 1 month 7 months 13 months 14 months 16 months
DHEAS 15-205 µg/dL; 1.36-6.78 nmol/L — 8 µg/dL; 0.22 nmol/L 5 µg/dL;
0.14 nmol/L		 6 µg/dL;
0.16 nmol/L		 22 µg/dL; 0.59 nmol/L 28 µg/dL; 0.76 nmol/L 24 µg/dL; 0.65 nmol/L
Cortisol 4-22 µg/dL; 138-635 nmol/L — 0.9 µg/dL;
24.83 nmol/L		 5.8 µg/dL;
160.01 nmol/L		 3.0 µg/dL;
82.76 nmol/L		 3.9 µg/dL;
107.59 nmol/L		 11.2 µg/dL;
308.99 nmol/L		 12.6 µg/dL;
347.61 nmol/L
ACTH 6-50 pg/mL; 5.5-22 pmol/L — <5 pg/mL;<1.10 pmol/L <5 pg/mL;<1.10 pmol/L <5 pg/mL;<1.10 pmol/L <5 pg/mL;<1.10 pmol/L 11 pg/mL;
2.42 pmol/L		 10 pg/mL;
2.20 pmol/L
HbA1c <5.7% 5.0% 8.5% 8.5% 7.8% 5.8% 5.7% 5.7%
LH 5-25 IU/L — 5.8 IU/L 2.9 IU/L — 3.3 IU/L 5.2 IU/L 5.7 IU/L
FSH 4.5-21.5 IU/L — 6.2 IU/L 5.6 IU/L — 2.0 IU/L 3.5 IU/L 1.3 IU/L
Estradiol Varies — 21 pg/mL;
77.09 pmol/L		 74 pg/mL;
271.65 pmol/L		 — 101 pg/mL;
370.77 pmol/L		 — 121 pg/mL;
444.19 pmol/L
Progesterone Varies — <0.5 ng/mL;<1.59 nmol/L <0.5 ng/mL;<1.59 nmol/L — <0.5 ng/mL;<1.59 nmol/L — 6.6 ng/mL;
20.99 nmol/L

Abbreviations: ACTH, adrenocorticotropic hormone, DHEAS, dehydroepiandrosterone sulfate, FSH, follicle-stimulating hormone, LH, luteinizing hormone, T0, time at presentation.

In conclusion, exogenous glucocorticoids, specifically intra-articular injections, carry the highest potential for iatrogenic Cushing syndrome and secondary adrenal insufficiency. Glucocorticoid excess has a variable presentation that often obscures diagnosis. As this scenario demonstrates, careful physical and laboratory assessment and tapering of hydrocortisone replacement eventually can lead to restoration of adrenal, ovarian, and metabolic function and improved associated symptoms.

Learning Points

  • Exogenous intra-articular glucocorticoid use may suppress adrenal and ovarian function via central suppression of ACTH and GnRH.
  • Cushing syndrome presents with a broad spectrum of signs and symptoms that may be mistaken for individual conditions, such as perimenopause and isolated diabetes mellitus.
  • Exogenous steroid use may lead to Cushing syndrome and subsequent adrenal insufficiency, which is life-threatening.
  • Treatment of adrenal insufficiency with a long-term exogenous glucocorticoid taper allows for subsequent return of adrenal and ovarian function.

Contributors

All authors contributed to authorship. S.L.B. was involved in the diagnosis and management of the patient, and manuscript editing. S.A. was involved in patient follow-up and manuscript development. J.M.G. was responsible for manuscript development and editing. All authors reviewed and approved the final draft.

Funding

None declared.

Disclosures

S.L.B. reports ClearBlue Medical Advisory Board, 2019—present

Emblem Medical Advisory Board, Amazon Services, 2022—present

Medscape, 2023

Myovant, May 2023

Omnicuris, 2023

Sage Therapeutics and Biogen Global Medical, Zuranolone OB/GYN Providers Advisory Board, Dec 2022, March 2023

Member, Board of Trustees, Salem Academy and College, Salem, NC: 2018-present (Gratis)

Informed Patient Consent for Publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Originally data generated and analyzed in this case are reported and included in this article.

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Abbreviations

 

  • ACTH

    adrenocorticotropic hormone

  • AMH

    anti-Müllerian hormone

  • DHEAS

    dehydroepiandrosterone sulfate

  • FSH

    follicle-stimulating hormone

  • HbA1c

    glycated hemoglobin

  • IAC

    intra-articular corticosteroid

  • LH

    luteinizing hormone

  • SAI

    secondary central adrenal suppression

Published by Oxford University Press on behalf of the Endocrine Society 2024.
This work is written by (a) US Government employee(s) and is in the public domain in the US. See the journal About page for additional terms.

Filed under: adrenal, adrenal crisis, Cushing's, Rare Diseases, symptoms | Tagged: , , , , , | Leave a comment »

Atypical Presentation of Cushing’s Disease With Weight Loss and Hypokalemia

Posted on October 29, 2024 by MaryO

Abstract

Summary

ACTH-secreting pituitary adenomas causing Cushing’s disease (CD) typically present with weight gain, whereas weight loss and hypokalemia in endogenous Cushing’s patients are suggestive of ectopic ACTH production. We report a case of CD presenting with atypical features of marked weight loss and hypokalemia. A 75-year-old female was admitted to the hospital with a history of profound weight loss, associated with uncontrolled hypertension, hyperglycemia, severe proximal muscle weakness, and hypokalemia. Subsequent investigations, including 24-h urinary free cortisol, 48-h low-dose dexamethasone suppression test, MRI of the sella, and bilateral inferior petrosal sinus sampling, confirmed CD without any evidence of ectopic ACTH production. She became eucortisolemic with medical therapy of ketoconazole and cabergoline, subsequently regained her weight, and became normokalemic. This case illustrates that patients with CD may present with symptoms and biochemical findings that would otherwise suggest ectopic ACTH production.

Learning points

  • Patients with CD do not always present with classical clinical features and may present with symptoms and biochemical findings that would otherwise suggest ectopic ACTH production.
  • While most patients with CD typically lose weight after biochemical remission, some patients gain weight after the normalization of cortisol levels.
  • This case highlights the need to entertain a broad differential in patients presenting with hypokalemia and weight loss and the need to exclude hypercortisolemia.

Background

Pituitary corticotropin (ACTH)-induced Cushing’s disease (CD) accounts for approximately 70% of patients presenting with Cushing’s syndrome (1). ACTH-producing pituitary adenomas are typically microadenomas and, in over a third of CD patients, there is no demonstrable lesion on MRI (2). Clinical and biochemical diagnosis of CD may be challenging, as patients can present with varied symptoms that overlap with other comorbidities. Progressive weight gain associated with central adiposity is a common manifestation of CD occurring during the early stage of the disease. While nonspecific features such as hypertension, diabetes, cardiac hypertrophy, arterial and venous thrombosis, electrolyte abnormalities, and psychiatric disturbances also occur frequently, the more discriminatory signs of hypercortisolemia include proximal myopathy, facial plethora, easy bruising, and wide striae (2). Weight loss with associated hypokalemia typically suggests an underlying ectopic ACTH production. Here we report an unusual case of pituitary ACTH-induced CD who presented with significant hypokalemia and marked weight loss which resolved with medical control of CD.

Case presentation

A 75-year-old female with a history of type 2 diabetes, hypertension, osteoporosis, and coronary artery disease presented to the emergency department (ED) with profound proximal muscle weakness associated with a serum potassium of 2.4 mmol/L (normal = 3.6–5.2 mmol/L). She also reported a weight loss of 90 lbs over the previous 2 years. In addition, she had uncontrolled hypertension despite taking three anti-hypertensive agents and worsening glycemic control requiring increasing anti-hyperglycemic therapy; her hemoglobin A1c at presentation was 9.3%.

Investigation

During hospitalization, she underwent further investigation for hypokalaemia and resistant hypertension, which showed an elevated 24-h urine free cortisol (24-h UFC) of 1904.4 nmol/d (upper limit of normal: 485.4 nmol/d) and consequently was referred to Endocrinology for further assessment. Repeat outpatient-based investigations after discharge from the hospital confirmed an elevated 24-h UFC of 1578.4 nmol/d, elevated AM serum cortisol of 1749.2 nmol/L (normal: 80–477.3 nmol/L), non-suppressed serum cortisol of 1238.8 nmol/L (normal response: < 50 nmol/L) after a 48-h low dose dexamethasone suppression test, and an elevated serum ACTH at 8.2 pmol/L (normal: 0.5–2.2 pmol/L). MRI of the sella as well as gallium DOTATATE PET-CT did not show any demonstrable lesion (Figs 1A, B and 2A, B). Subsequently, she underwent bilateral inferior petrosal sinus sampling (BIPSS) using 100 µg ovine CRH, which showed a post-CRH central to peripheral ACTH ratio of 3, lateralizing to the right with a ratio of 2.1. Based on these findings, a diagnosis of MRI-negative CD was made.

Figure 1View Full Size
Figure 1
(A and B) MRI Sella post-GAD coronal and sagittal sections showing no pituitary lesion.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 3; 10.1530/EDM-24-0011

Figure 2View Full Size
Figure 2
(A and B) Ga68 DOTATATE scan. PET-CT showing non-specific uptake through the distal esophagus and proximal stomach, but otherwise within normal physiological limits.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 3; 10.1530/EDM-24-0011

Treatment

While awaiting surgical opinion, the patient was started on Ketoconazole 200 mg po TID. She was unable to tolerate a larger dose; therefore, cabergoline 1 mg twice a week was added. The options of trans-sphenoidal pituitary surgery and bilateral adrenalectomy were discussed with the patient, which she declined, and decided to continue with medical therapy.

Outcome and follow-up

Medical therapy was adjusted over the next several weeks until 24-h UFC normalized and remained normal during 24 months of follow-up with the most recent being 85 nmol/d. With biochemical remission of CD, her blood pressure normalized, and she required a reduction in the dose of anti-hypertensive and anti-hyperglycaemic therapy. Her serum potassium levels also normalized. She initially regained 15 lbs but called the clinic when, despite taking medical therapy, she once again began losing weight and her serum potassium dropped to 2.7 mmol/L. Repeat serum AM cortisol was significantly elevated at 935.3 nmol/L, as was 24h UFC at 1457.3 nmol/d. Further inquiry revealed that she had been prescribed omeprazole therapy by her family physician for symptoms of reflux. Omeprazole was discontinued due to its potential effect on decreasing the efficacy of ketoconazole therapy, and her cortisol and potassium levels rapidly normalized. Since then, she has regained 50 lbs, being almost back to her baseline weight, and her mobility and strength have improved from being initially bed-bound to now mobilizing independently using a walker. Pre and post therapy values are summarized in Table 1.

Table 1Key investigations at presentation and recent follow-up visit.

Test Reference range At presentation Recent follow-up
24-h urine cortisol (nmol/TV) ULN=486 1908  85
AM cortisol (nmol/L) 133-537 2371 796
Cortisol post-48h low DMS dose (nmol/L) <1.8 44.9 NA
ACTH (pmol/L) 2.3-10.1 37.5 14
Potassium (mmol/L) 3.6-5.2  2.4 4.5

DMS= dexamethasone suppression; NA = Not Applicable; ULN = upper limit of normal.

Discussion

Here we report an unusual case of CD presenting with features that were initially highly suggestive of ectopic ACTH production with weight loss rather than the usual weight gain. All of the initial symptoms resolved following biochemical control of hypercortisolemia. In our review of the literature, CD associated with weight loss has previously only been reported in association with severe depression, psychosis, eating disorders, or malignancy (3, 4). For instance, a case of familial CD was reported in a child who also had an intercurrent eating disorder (anorexia), which led to weight loss despite CD (3). Weight loss due to ectopic ACTH-induced CD has also been previously reported, where weight loss was thought to be due to the underlying malignancy (4). However, our patient had well-documented pituitary ACTH-induced CD.

Chronic hypercortisolemia is associated with increased abdominal adiposity that is thought to be caused by the downregulation of adenosine monophosphate-activated protein kinase (AMPK), which is responsible for regulating lipid metabolism (5). Furthermore, glucocorticoids also induce a direct orexigenic effect, which leads to weight gain (6). Weight loss in association with hypercortisolemia, on the contrary, can be a presenting feature of ectopic ACTH-producing tumors such as small cell lung cancer. While the underlying mechanism of weight loss is not fully understood, it is thought to be partly due to cAMP/Protein kinase A (PKA) pathway activation, with an increase in PKA activity resulting in altered downstream regulation of cAMP-related lipogenic and lipolytic proteins (6). In addition, high ACTH secretion and the malignant characteristics of the neoplastic process are also thought to play roles in weight loss (7). Our patient had no evidence of ectopic ACTH production.

A previous study (8) comparing the clinical features of CD in older vs younger patients reported that weight gain was more common in younger individuals, whereas older patients typically presented with catabolic changes, likely due to age-related variability in tissue sensitivity to glucocorticoid receptors and intracellular cortisol signaling. The overall rates of central adiposity were 71.1% in older patients compared with 80.0% in younger patients (8).

Another unusual feature was hypokalemia, which is generally associated with ectopic ACTH production. However, up to 10% of CD patients present with low potassium. Hypokalemia is caused by the mineralocorticoid effect of excess cortisol. Supraphysiologic production of cortisol tends to saturate 11β-hydroxysteroid dehydrogenase type II (11β-HSD2) activity in the renal tubule, which is primarily responsible for converting active cortisol into inactive cortisone. This could lead to excess binding of cortisol to mineralocorticoid receptors, resulting in an increase in potassium excretion and thus hypokalemia. While some studies have suggested that ACTH can also lead to lowering 11β-HSD2 activity causing hypokalemia, others have not found any such correlation (9, 10). In our patient, serum potassium normalized after she achieved eucortisolemia with medical therapy.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient/parent/guardian/relative of the patient.

Author contribution statement

All authors reviewed the results and approved the final version of the manuscript.

Acknowledgements

We thank Dr Brian Moses (Yarmouth Regional Hospital, NS, Canada) and Dr Scott Lee (Valley Regional Hospital, NS, Canada) for their contributions in managing the patient.

References

Filed under: Cushing's, symptoms | Tagged: , , | Leave a comment »

‘Cortisol Face’ Is Real, But It’s Not As Common As You Might Think

Posted on September 6, 2024 by MaryO

Across social media platforms, the hashtag “#cortisolface” has gained traction, with many users claiming that facial swelling and puffiness are due to elevated cortisol levels. Influencers often start their videos with statements like, “You’re not ugly, you just have cortisol face,” and promote various remedies and lifestyle changes as solutions. However, experts warn that although high cortisol can contribute to these symptoms, it is not the sole cause of facial puffiness.

Before blindly believing social media trends, it’s crucial to explore the underlying causes, which might include medications, health conditions or lifestyle factors. Addressing high cortisol levels requires a different approach than what many of these social media influencers suggest.

Dr. Maria Olenick, associate professor at Texas A&M University School of Nursing, offers valuable insights into the concept of “cortisol face,” its effects on the body, and methods for lowering cortisol levels.

What Is ‘Cortisol Face’?

Although high cortisol levels are a factor in some cases of facial swelling and puffiness, the symptom is not as common as social media is making it out to be. In some cases, it’s not cortisol but the foods you eat. For example, eating a meal or snack that’s high in sodium can make you feel bloated because the salt can cause you to retain fluid and look a little puffier than normal.

“Some of the more severe things like moon face and other symptoms are what you might consider a serious issue when a person should really go and see their health care provider, because that would require some medical diagnosis,” Olenick said.

Moon face—or moon facies, in medical terminology—describes an increase of facial swelling due to high cortisol levels. This is a more serious condition that doesn’t just appear or disappear from one day to the next.

How Does Cortisol Affect The Body?

Cortisol is referred to as the body’s “built-in alarm system” because it plays a crucial role in the body’s response to stress, metabolism, immune activity and maintaining homeostasis. The amount of cortisol produced will differ from day to day due to different mental and physical stressors.

“Among healthy individuals, cortisol follows a diurnal pattern in which levels are higher upon waking, increase significantly over about 30 minutes, and steadily decrease from the peak throughout the rest of the day, reaching the nadir in the middle of the night,” said Olenick, whose research focuses on effective stress management techniques and therapies for veterans dealing with post-traumatic stress disorder (PTSD).

Hormones act as chemical messengers working through your bloodstream to regulate various bodily functions. Cortisol, often called the stress hormone, utilizes receptors that receive and use the hormone in different ways by communicating with your brain to control your mood, motivation and fear.

Different ways cortisol reacts and adapts to cope in a stress state include:

  • Regulating blood pressure
  • Regulating metabolism
  • Regulating blood sugar
  • Managing how your body uses carbohydrates, fats and proteins
  • Suppressing inflammation
  • Helping control your sleep/wake cycle
  • Aiding in forming memories

Cortisol secretion is regulated by a hormonal axis through a feedback loop that involves your hypothalamus, pituitary gland, adrenal glands and certain hormones known as the hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus and pituitary gland in your brain monitor your blood’s cortisol levels before signaling the adrenal glands, which sit on top of each kidney. When a change in cortisol levels is detected, your adrenal glands react to these signals by adjusting the amount of cortisol needed to be released.

The feedback system starts when the hypothalamus detects stress and releases corticotrophin-releasing hormone (CRH) accordingly. This hormone travels into the pituitary gland, signaling it to secrete adrenocorticotropic hormone (ACTH). ACTH will then make its way to the adrenal glands, stimulating them to produce cortisol. Once produced, cortisol is released into the bloodstream, where it helps regulate various functions including stress response, metabolism and immune activity. The HPA axis feedback loop is completed when cortisol levels rise and signal the hypothalamus to reduce CRH production, which maintains an effective secretion loop.

What Causes High Cortisol Levels?

Cortisol is increased at times of stress for your body, but our bodies aren’t designed to handle long-term stress. When there’s too much cortisol or an excess amount of cortisol produced, it can cause major changes in your body’s everyday functions.

Chronic emotional or physical distress can lead to sustained high levels of cortisol as part of the body’s stress response system. Stress activates signals that prompt the adrenal glands to release hormones like adrenaline and cortisol, leading to an increased heart rate and heightened energy for the fight-or-flight response.

Cortisol temporarily suppresses non-essential functions such as digestion, reproduction and inflammation in the short term to prepare for danger. However, if stress is constant, this response can remain active, which can negatively impact many bodily functions such as sleep, weight management, memory, focus and mental health. Chronic stress can also increase the risk of anxiety, depression, digestive issues, headaches, muscle tension, pain and high blood pressure.

However, stress is not the only culprit for excess cortisol levels. It could indicate serious underlying health issues.

“You need to make sure that if you are having issues with cortisol levels that you don’t really have a tumor or something more serious. If you feel like you are having symptoms and they’re not resolved by implementing lifestyle changes, make sure you see a health care provider, because that could be something very different and it might need significant medical care,” Olenick said.

Cushing Syndrome

Cushing syndrome, also known as hypercortisolism, is characterized by excessive levels of cortisol in the body. Prolonged use of corticosteroid medications can result in exogenous Cushing syndrome, where the excess cortisol originates from external sources rather than the body’s own production. One common cause of high cortisol levels is the use of glucocorticoid medications, such as prednisone, which are prescribed for inflammatory conditions like asthma, rheumatoid arthritis and lupus.

“Sometimes people are on steroids such as prednisone for a different condition. When you’re taking steroids, if you start to show signs of serious cortisol issues, talk to your provider,” Olenick said.

Another significant cause of Cushing syndrome is pituitary tumors that secrete excessive amounts of ACTH, which overstimulates the adrenal glands to produce more cortisol. This form of Cushing syndrome, known as Cushing disease, is attributed to benign pituitary adenomas and accounts for a large proportion of cases in both adults and children. Effective management of Cushing syndrome involves addressing the underlying cause, which may include surgical removal of tumors or adjusting medication regimens to reduce cortisol levels and mitigate associated health challenges.

Adrenal gland tumors can also contribute to high cortisol levels. These tumors may be benign or malignant, leading to similar symptoms as those caused by pituitary tumors. Tumors affecting either the pituitary gland or adrenal glands can lead to elevated cortisol levels, but most of these tumors are noncancerous and may be manageable with proper medical care.

Understanding the underlying causes of high cortisol levels is crucial for appropriate diagnosis and treatment, as the medical implications of these conditions extend beyond the portrayals seen in popular media.

What Are Common Symptoms Of High Cortisol Levels?

Having the right cortisol balance is essential for your health, and producing too much or too little can cause health problems, including:

  • Puffiness or weight gain in the face
  • Weight gain in the midsection or abdomen
  • Excess fat behind the neck, above the back
  • Memory and concentration problems, or brain fog
  • Trouble sleeping, or insomnia
  • Severe fatigue
  • High blood pressure
  • Psychiatric disturbances

Symptoms may vary, so the only real way to validate if your cortisol levels are higher than normal is to get them checked, either with blood, urine or saliva tests. When Olenick evaluates cortisol levels in veterans for PTSD research, her preferred method is to collect samples of saliva. A saliva test can be conducted at home, but it’s most effective when collected at different times throughout the day.

How Can Someone Lower Their Cortisol Levels?

Maintaining a healthy diet, sticking to a regular sleep schedule and incorporating regular, moderate exercise can all help lower cortisol. It’s also important to manage stress effectively; this can involve finding healthy ways to cope with stress, such as talking to someone you trust or allowing yourself time to relax and unwind. Self-care is crucial—taking breaks and engaging in activities that rejuvenate you is not a waste of time but a necessary part of maintaining balance.

Avoid extreme measures like severe caloric restriction or high-intensity workouts, which can increase cortisol levels due to the stress they place on the body. Instead, go for low-intensity exercises like walking. Additionally, Olenick says natural remedies and supplements, such as apple cider vinegar and vitamins, may support cortisol management, but it’s wise to monitor their effects and consult with a health care provider if needed. Ultimately, finding a balance between self-care, stress management and maintaining a healthy lifestyle is key to controlling cortisol levels effectively.

“There are a lot of things you can do to regulate your cortisol, like eating well, sleeping well and lowering our stress. Basically, things to take care of ourselves,” Olenick said.

Olenick says social media platforms are great attention grabbers, but it’s important to take health trends with a grain of salt and pay attention to your body’s needs. If you relate to any of the symptoms and feel concerned about your cortisol levels, notify your health care provider and seek medical attention.

This article by Teresa Saenz originally appeared on Vital Record.

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