Cushing's Syndrome in the Elderly

Abstract

Management of Cushing’s syndrome (CS) can be particularly challenging in older patients, compared with younger individuals, due to the lack of several clinical features associated with cortisol excess along with a greater burden of associated comorbidities. Moreover, the interpretation of diagnostic tests could be influenced by age-related physiological changes in cortisol secretion. While mortality is higher and quality of life is more impaired in the elderly with CS as compared with the younger, there is currently no agreement on the most effective therapeutic options in aged individuals, and safety data concerning medical treatment are scanty. In this review, we summarize the current knowledge about age-related differences in CS etiology, clinical presentation, treatment, and outcomes and describe the potential underlying mechanisms.

Keywords

Cushing’s syndrome - older patients - aging - hypercortisolism

Introduction

Cushingʼs syndrome (CS) due to an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma [Cushing’s disease, (CD)] is most commonly diagnosed in women (female to male ratio 2.3–4:1) in their fifth decade of life. Likewise, adrenal CS occurs at a similar age or in a slightly older population with an even stronger female preponderance (5.5:1) [1] [2].

Although several features are typically associated with hypercortisolemia, including central obesity, moon face, plethora, easy bruising, purple striae, muscle weakness, and signs of hyperandrogenism, there is no single lead symptom, and the clinical presentation can be extremely heterogeneous. In particular, CS may be misdiagnosed with metabolic syndrome, especially in the first phases of the disease, leading to a mean delay in diagnosis of about three years, also influenced by the rarity of the condition (estimated incidence 0.2–5/1000 000 per year) [3] [4].

Due to the increasing life expectancy and aging of the population in Western countries, the percentage of older people presenting with CS may be higher than previously reported, and this may represent a further diagnostic and therapeutic challenge for modern endocrinology. Indeed, while the clinical presentation of CS may vary according to age, some hypercortisolemia-related morbidities, such as hypertension, osteoporosis, and cognitive dysfunction, may be falsely attributed to aging, thus masking an underlying CS. The clinical risk scores that have been recently developed to assist clinicians in discriminating CS in the context of at-risk populations have not been validated in the elderly so far; however, they might lack sensitivity even in the target group. Preselecting patients with increased CS risk—which is crucial due to the rarity of the disease—remains challenging. Studies suggest that osteoporosis at a young age, muscular atrophy, skin changes, and dorsocervical fat pads are the most indicative symptoms suggesting the need for CS screening, while an extended screening approach in at-risk populations (patients with metabolic syndrome, diabetes or obesity) is not indicated [4]. In older patients, the most characteristic clinical symptoms of hypercortisolemia, such as skin changes or central obesity, are often minimally present or lacking. Thus, the diagnosis of CS in the elderly may be even more difficult than that in a younger population. Moreover, standard therapy regimens may not be adequate in older patients, and the response to the treatment may be suboptimal.

There is no clear age limit to define elderly CS patients; most authors use, as a cutoff, an age of or above 65 years, as suggested by the World Health Organization [5].

Age-related differences in the etiology of Cushing’s syndrome

Recently, age-related differences in the etiology of CS have been shown. In a group of 142 females with CS, Cushing’s disease (CD) was more often observed in those younger than 45 years (70.6%), whereas a cortisol-producing adrenal adenoma was more frequent in those older than 65 years (68.4%) [6]. This is in line with another study on adrenal tumors, showing their highest prevalence among patients over 65 years (1900 per 100 000 inhabitants) with a slight female preponderance; about 0.4% of them had overt CS [7]. Also, patients with mild autonomous cortisol secretion are older than those with non-functioning adrenal incidentalomas (mean age 65.5 vs. 60.1) [8].

Similarly, in the European Registry on Cushing’s Syndrome (ERCUSYN) cohort containing 1519 subjects, patients with adrenal-dependent CS were significantly older than those with pituitary-dependent CS [1]. When analyzing only pituitary-dependent CS, compared to the younger group, older patients more commonly had a pituitary macroadenoma [9]. On the contrary, in a study by Qiao et al., including 45 patients with CD (age more than 60 years) and 90 patients (age less than 60 years), no age-related differences in adenoma size were reported [10]. Aging also appears to attenuate the typical female preponderance in the prevalence of pituitary CS, wherein slightly more than a half the number of elderly patients were females in the ERCUSYN population, and women represented almost three-quarters of the younger patients [9]. Such reduction of the “gender gap” in the prevalence of pituitary-dependent CS in the elderly may be due to the lack of estrogen in postmenopausal women and resembles that reported in prepubertal individuals [11]. Indeed, estrogens enhance corticotrope proliferation in vitro, and the expression of the estrogen receptor beta has been detected in the majority of the ACTH-secreting adenomas, suggesting that estrogens may promote the development of CD in premenopausal women [12].

Patients with ectopic ACTH secretion (EAS) are a very heterogeneous population, typically diagnosed in adulthood [13]. Among 918 patients with thoracic and gastroenteropancreatic neuroendocrine tumors (NET), patients with EAS were younger than those without hypercortisolemia (median age 48.1 vs 58.7 years) [14]. However, other studies suggested that patients with ectopic CS are older than those with CD [15] [16]. In the cohort gathered at the National Institutes of Health over 20 years, the age of the patients with EAS ranged from 8 to 72 years (mean 37.6), showing that EAS may present throughout the lifespan with a variety of clinical symptoms [17].

In older women, a diagnosis of CS is often established within the evaluation of an adrenal incidentaloma (36.8%) or workup of hypertension and/or diabetes (31.6%). On the contrary, younger females more often looked for medical help due to weight gain, virilization, and oligomenorrhoea [6]. This is also in line with the observation that menstrual irregularities and reduced libido were more often seen in women with CD as compared with adrenal-dependent CS, due to a concomitant ACTH-dependent rise in adrenal androgen production [1].

Age-related differences in the clinical presentation of Cushing’s syndrome

A clear age-dependent difference in the clinical presentation of CS has been recently demonstrated in the ERCUSYN cohort. Patients older than 65 lacked the typical features of hypercortisolism, including skin thinning, easy bruising, striae rubrae, hirsutism, and central obesity, while showing lower BMI and waist circumference as compared with the younger [9]. In another study including 45 CD patients, those older than 60 less frequently had obesity as compared with the younger and their BMI was also lower [10]. On the other hand, older age correlated with the percentage of visceral fat and visceral to subcutaneous fat ratio in patients with active CS [18]. Several mechanisms in hypercortisolism-related obesity could be altered in older patients (e. g., diabetes-related catabolic effects or impaired AMPK signaling in adipose tissue, hyporexia); however, evidence in humans is lacking [19]. Older females with CS rarely reported hyperandrogenism-related signs, such as hirsutism, oligomenorrhoea, hair loss, and reduced libido, which, as mentioned above, often lead younger female patients to seek medical advice [6] [9] [10]. While the adrenal production of androgens may be less pronounced in older patients due to aging, age-related differences in etiology may also play a role. Indeed, older patients more often have adrenal CS, characterized by ACTH suppression and consequent inhibition of adrenal androgen synthesis. Of note, concentrations of 11-oxygenated C19 steroids were elevated in treatment-naïve females with CD and correlated with salivary cortisol, suggesting that this hormone excess is the main cause of hyperandrogenemia in CS [20]. However, it has been shown that 11-oxygenated C19 steroids were not lower in women aged>60 years in comparison to females aged 20–40 years, in contrast to classic androgens concentration (testosterone, androstenedione, and dehydroepiandrosterone-sulfate), which were reduced after menopause [21].

The mechanisms whereby hypercortisolemia-related skin symptoms are lacking in the elderly are not clear, although aging is associated with skin structural derangements and decreased basal cell proliferation, which could make skin less susceptible to the catabolic effects of cortisol [22].

Older patients more frequently present with muscle wasting and weakness, as compared with their younger counterparts [9] [10]. Such elevated prevalence of muscle dysfunction in older CS patients is likely associated with age-related sarcopenia, sedentary behavior, vitamin D deficiency, and concomitant disabilities, although a specific effect of cortisol excess on aged muscle cannot be excluded [23]. Indeed, the administration of dexamethasone to older mice reduced protein synthesis and promoted muscle atrophy and hyperglycemia, partly by antagonizing the leucine stimulatory effect on muscle [24] [25]. Interestingly, in a longitudinal study by Vogel et al., CS patients presented with sustained reduction of muscle strength after successful treatment, which was associated with older age [26].

Moreover, type 2 diabetes was also more common in older CS patients as compared with the younger, and this may contribute to the increased prevalence of muscle weakness in the former [9]. An inverse association between reduced handgrip strength and diabetes risk has been shown in older healthy people [27]. In CS patients, Vogel et al. also showed that metabolic derangements, such as greater waist-to-hip ratio and higher HbA1C, predicted low muscle functionality in older subjects [26].

Growth hormone deficiency and hypogonadotropic hypogonadism, two common pituitary hormone dysfunctions in both active CS and aging, maybe other important contributors to the elevated prevalence of muscle weakness in aged patients with cortisol excess [28] [29]. Also, 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), which converts inactive cortisone into active cortisol, was up-regulated in healthy older women and associated with reduced grip strength, insulin resistance, and adverse body composition profile [30].

Older CS patients more often experience bone fractures than their younger counterparts, partly due to age-related frailty and muscle weakness, which increase the risk of falls [9]. Older age and prior hypercortisolism predicted low trabecular volumetric bone mineral density and impaired measures of bone quality at the proximal femur in patients with CS in remission, suggesting that fracture risk may be especially significant in the elderly who had been exposed to elevated cortisol levels in the past [31].

As stated above, an age-related decline in sex steroids and growth hormones may also contribute to bone loss [32] [33]. An age-related increase in the expression of 11βHSD1 has been described in animal models at the vertebral bone, although there was no clear association with bone loss. Therefore, further studies are needed to clarify the association between age-related changes in tissue expression of 11ΒHSD1 and musculoskeletal impairment in CS [34].

Older age was also described as an important risk factor for venous thromboembolism (VTE). In a study comprising 176 patients with active CS, the age over 69 years, reduced mobility, infections, previous cardiovascular events, increased cortisol level, and shortened APTT were independent VTE risk factors, with age and mobility being the strongest among them [35]. However, other data showed that VTE risk was the highest at 3–6 postoperative months, and a number of operations, male sex, and urine-free cortisol level (UFC) were associated with VTE on multivariate analysis in patients with treated CS [36].

Cognitive impairment is another important issue in CS patients, which improves only partially after successful treatment [37]. Studies in animals suggest that hypercortisolemia contributes to age-related cognitive dysfunction [38]. It has been shown that aging, together with a lower level of education and a longer duration of hypercortisolism, were related to both visual and vertebral memory impairment and smaller hippocampal volume [39]. However, studies using functional magnetic resonance imaging (MRI), especially longitudinal, are needed to evaluate the deleterious effect of hypercortisolemia on cognitive function in different age groups, as well as its reversibility after treatment [40].

Finally, whereas older CS patients typically presented with a significantly higher burden of comorbidities, including hypertension, diabetes, cardiovascular disease, and VTE, as compared with younger individuals, the prevalence of depression was lower in the former [9]. This surprising finding may be due to underdiagnosing. Indeed, late-life depression is often characterized by less mood and motivation symptoms and more somatic features in comparison to that diagnosed in younger patients, which may make the diagnosis of affective disorders particularly challenging in aged people [41].

Although the available data do not show any age-related differences in terms of delay in diagnosis, recognition of hypercortisolism in older patients may be difficult due to lack of the typical stigmata of CS in them and attribution of comorbidities to aging rather than hypercortisolemia [3] [9].

Clinical presentation of ECS is frequently different from that in pituitary and adrenal CS, in that symptoms are more severe, and their onset is more rapid. Therefore, catabolic symptoms and comorbidities, such as hypertension and diabetes, may predominate in the clinical picture, similar to what is reported in the elderly. However, the profound hypokalemia and rapid progression are clues that often evoke the diagnosis of EAS [13]. In a study using machine learning, the most important features to distinguish EAS from CD were serum potassium, ACTH, and MRI, while other clinical variables, including age, were less important [42].

Potential mechanisms underlying the age-related differences in clinical presentation of CS are summarized in [Table 1].

Table 1 Clinical presentation in the older patients with CS compared with younger counterparts and potential mechanisms associated.

	Older patients	Potential mechanisms
Etiology	Mostly ACTH-independent	Increase in the prevalence of adrenal adenomas Decrease in the prevalence of corticotropinomas in postmenopausal women
Gender distribution	Weaker female preponderance	Potential influence of estrogens on the growth of corticotropinomas
Proteocatabolic symptoms
Skin changes (plethora, easy bruising, purple striae, thin skin)	Less frequent	Age-related skin structural derangements; underestimation of skin thinning
Hyperandrogenism-related symptoms
Hirsutism/hair loss	Less frequent	Lower androgen levels in ACTH-independent CS
Obesity	Lower BMI and waist circumference	Age-related sarcopenia, hyporexia
Cardiometabolic comorbidities	Higher rate of hypertension, diabetes, cardiovascular disease, and venous thromboembolism	Physiological age-related increase in cardiometabolic risk factors (endothelial dysfunction, atrial fibrillation, dyslipidemia, insulin resistance) and alteration of coagulation and fibrinolytic factors
Depressive symptoms	Less frequent	Underreporting in older age; atypical symptoms of late-life depression (lower mood and motivation symptoms, more somatic symptoms)
Low libido	Less frequent	Underreporting and physiological decrease in sex-hormone levels

CS, Cushing’s syndrome; ACTH, adrenocorticotropic hormone; IGF-I, Insulin-like growth factor 1.

Biochemical tests in elderly patients with Cushing’s syndrome

Biochemical diagnosis may also be more challenging for older patients

Daily cortisol secretion, assessed as the summation of the major glucocorticoid metabolites of 24-hour urine samples (C21) when corrected for body surface area, decreases slightly from 3–4 years to 7–8 years and, subsequently, starts to rise again. After the age of 11–12 years, it becomes divergent between the sexes, with significantly higher levels in males [43]. In the cohort of elderly included in the Baltimore Longitudinal Study of Aging, the UFC/creatinine ratio presented a U-shaped pattern across the lifespan, with the lowest results in the 20 s and 30 s, relative stability until the 50 s, and increase thereafter [44]. Another study showed that 24-hour plasma-free cortisol concentrations and cortisol production rate increased with age, independent of body size [45]. Moreover, a meta-analysis evaluating if healthy elderly had an abnormal cortisol response to challenge showed a higher responsivity to stimulation and less inhibition after a suppression test compared to that in younger people [46]. However, other authors reported that, in acute stress conditions, older adults showed overall lower cortisol and a lower stress-induced cortisol increase than younger adults [47]. In the ERCUSYN cohort, UFC concentrations less frequently supported the diagnosis of hypercortisolism in the older patients with pituitary CS in comparison to the younger, whereas other hormonal tests did not differ according to age [9].

In the study by Qiao et al., no differences in any hormone measurements, including late-night salivary cortisol (LNSC) and UFC, were documented (10). In 137 CD patients treated with long-acting pasireotide, Newell-Price et al. showed greater LNSC levels in patients older than 60 years as compared with their younger counterparts [48]. A linear relationship between increasing age and LNSC levels has also been described in healthy individuals [49].

Future studies are needed to evaluate the hypothalamus-pituitary-adrenal axis in the elderly and assess the potential interference of several factors, including suboptimal renal function, malnutrition, chronic illness, and concomitant medications, on the reliability of the tests commonly used to diagnose hypercortisolism in them.

Treatment and outcome according to age

Transsphenoidal surgery (TSS) remains the first-choice treatment for CD, but older patients should be carefully selected, preferably based on complication avoidance protocols in dedicated excellence centers. Transsphenoidal surgery was proven to be a safe and effective procedure in 123 elderly patients with a pituitary adenoma operated on in a tertiary neurosurgery center, with delayed hyponatremia being the main reason for readmissions, which highlights the need for particular attention to postoperative fluid restriction and sodium control protocols in this vulnerable population [50]. Qiao et al. reported that, despite a higher number of comorbidities and worse scores in preoperative risk evaluation, older patients had similar complication and surgical remission rates as those in the younger patients [10]. They also found that recurrent disease after pituitary surgery was more frequent in the younger patients than the older, which was confirmed in another study on 273 patients with CD followed up during 3.4 years [51]. Younger age was also one of three predictors of relapse, together with postoperative cortisol and ACTH concentrations, in a study aimed at developing machine-learning-based predictive models of disease recurrence [52]. These findings suggest that the biological behavior of corticotropinomas in younger patients may have a more aggressive pattern compared with that in the older population [52]. In line with this, estrogen-sufficient CD women in the ERCUSYN showed a greater recurrence rate when compared with postmenopausal female patients [9].

On the other hand, older European CD patients of both sexes more commonly had a macroadenoma and less frequently experienced remission after TSS when compared with the younger population [9].

Conservative approaches, such as radiotherapy and or medical therapy, were the preferred therapeutic options in the older patients included in the ERCUSYN, whereas surgery was the first-choice treatment in the younger [9].

The response to medical treatment might potentially differ according to age; nonetheless, the data are scarce. Osilodrostat, a recently introduced 11βhydroxylase inhibitor, was effective in normalizing hypercortisolemia also with a favorable safety profile; however, the trials included only patients below 70 years of age [53] [54]. Ketoconazole was also used in patients over 75 years of age with no increase in the percentage of adverse effects, compared with younger patients, while age was not a significant predictor of the drug efficacy [55] [56]. Metyrapone was also administered to patients older than 70, but detailed information about effectiveness and side effects in this group is lacking [57]. In case of severe hypercortisolemia, etomidate infusion may be used in older patients, but they may require lower than standard doses [58]. In a study concerning mitotane use in CS (patients aged 14–71 years), age was not a predictor of drug efficacy [59]. In a longitudinal study on twice-daily use of pasireotide, only one of five patients older than 65 reached 60 months of therapy, therefore no relevant conclusions could be drawn in this group of patients [60].

Radiotherapy is an important treatment option in elderly CD patients with contraindications to surgery due to an estimated general efficiency in two-thirds of patients [61]. Indeed, older CD patients included in the ERCUSYN more commonly underwent radiotherapy as a first-line treatment as compared with the younger, in whom surgery was the preferred approach [9]. Among risks potentially associated with this treatment, cerebrovascular complications, cognitive deterioration, and hypopituitarism seem especially important in the elderly population [61]. Age, however, was not associated with initial and durable control of hypercortisolism after stereotactic radiosurgery in a study comprising 278 patients with CD [62]. Longitudinal head-to-head data comparing the efficacy and safety of each treatment option according to age are needed.

Mortality

In longitudinal studies with longer periods of observation, older age was associated with an increased mortality, mainly due vascular events, regardless of remission status [63] [64]. Moreover, older age, depression, diabetes, and male sex predicted the occurrence of cardiovascular events in a group of 346 patients with CD [65]. In the ERCUSYN cohort, mortality was 3% during a median follow-up of 2.7 years and was independently associated with older age. Moreover, age was the only factor that remained significant in a subanalysis of mortality within 90 days from the start of treatment [66].

In ectopic CS, the most important predictors of overall survival are tumor histology and non-lymph node metastases, while age-related differences in survival have not been described [67].

Quality of life (QoL)

Older age negatively impacts the QoL in CS patients [68]. Younger CD patients more frequently experienced an improvement in QoL compared to their older counterparts after successful treatment. Elderly patients more often present with other factors that may contribute to persistent QoL impairment, such as comorbidities, residual morbidity, and multiple treatments [69]. In a questionnaire addressing many factors related to QoL in CS patients, some age-related differences were observed. Younger patients more often reported concerns about hair loss, loneliness, pain, and the impact of the disease on their marriage or children than their older counterparts. The commonest complaints were related to anxiety/depression, loss of physical strength, memory loss, and fatigue, without any differences based on age [70].

Telomere theory

Telomeres are repetitive DNA sequences located at the end of linear chromosomes, which prevent the loss of genetic material during cell division. Their critical shortening induces apoptosis. Aging is characterized by a progressive shortening of telomeres, which compromises their structure and function [71]. Telomerases are enzymatic complexes maintaining telomere length, and their function might be regulated by genetic, epigenetic, environmental, and hormonal factors [72]. Some studies have shown that cortisol levels are correlated negatively with telomerase activity or telomere length [73] [74] [75]. Therefore, hypercortisolemia might predispose to the acceleration of telomeres shortening in CS, similar to what occurs in aging. After successful treatment of CD, telomeres length increased compared to that observed during the active phase of the disease and correlated with the time of remission. However, during the baseline case-control study, no difference in telomere length was observed between patients and controls. Of note, age was one of the factors related to telomeres shortening in patients with CS [76]. However, because there is no evidence that older CS patients have shorter telomeres than their younger counterparts, future studies are needed to confirm the speculation that there is a potential association between CS and telomere length over the course of the disease.

Conclusions

Management of CS in the elderly may be more challenging than in younger individuals due to many potential pitfalls in terms of symptom recognition and reliability of hormone testing, greater burden of comorbidities, and lack of information about the safety and efficacy of treatment options ([Table 2]). Thus, future studies are needed to establish the most effective approach aimed at shortening the exposure time to excessive cortisol and optimizing the diagnostic and therapeutic strategies specifically addressed to older patients, with the ultimate goal to normalize survival and promote a satisfactory, age-adjusted QoL.

Table 2 Potential pitfalls in CS management in the elderly population.

DIAGNOSIS	Lack of some typical CS symptoms (skin changes, weight gain – see Table 1)
	Overlap between some symptoms/comorbidities that might be related to CS and aging (hypertension, diabetes, muscle weakness, cognitive impairment)
	Many factors influencing laboratory results in diagnostics of hypercortisolism (age-related changes in hypothalamus-pituitary-adrenal axis, suboptimal renal function, malnutrition, comorbidities, drugs)
TREATMENT	High preoperative risk
	Lack of data concerning safety and efficacy of new drugs in older population
OUTCOME	High mortality rate
	Persistent QoL impairment after successful treatment

CS, Cushing’s syndrome; QoL, quality of life.

Conflict of interest

Authors have no conflict of interest to disclose.

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Publication History

Received: 05 February 2024
Received: 11 April 2024

Accepted: 30 April 2024

Accepted Manuscript online:
02 May 2024

Article published online:
25 June 2024